Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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,


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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


Obstentrics_Williams

Obstentrics_Williams. 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


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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


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Obstentrics_Williams. 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


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Obstentrics_Williams. 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


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Obstentrics_Williams. 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


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Obstentrics_Williams. 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


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Obstentrics_Williams. 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


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Obstentrics_Williams. 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


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Obstentrics_Williams. 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


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Obstentrics_Williams. 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


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Obstentrics_Williams. 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


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Obstentrics_Williams. 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)


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Obstentrics_Williams. -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


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Obstentrics_Williams. 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


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Obstentrics_Williams. 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


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Obstentrics_Williams. 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.


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Obstentrics_Williams. 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.


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Obstentrics_Williams. • 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.


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Obstentrics_Williams. • 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.)


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Obstentrics_Williams. 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.


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Obstentrics_Williams. • 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).


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Obstentrics_Williams. • 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.


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Obstentrics_Williams. 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


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Obstentrics_Williams. 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.


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Obstentrics_Williams. 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.


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Obstentrics_Williams. 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.


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Obstentrics_Williams. 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.


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Obstentrics_Williams. 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.


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Obstentrics_Williams. 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.


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Obstentrics_Williams. 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


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Obstentrics_Williams. 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.


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Obstentrics_Williams. 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.


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Obstentrics_Williams. 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


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Obstentrics_Williams. medications in pregnancy. Five categories-A, B, C, D, and X-were intended to summarize available evidence from


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Obstentrics_Williams. 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).


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Obstentrics_Williams. 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


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Obstentrics_Williams. 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


Obstentrics_Williams

Obstentrics_Williams. 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


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Obstentrics_Williams. 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 .


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Obstentrics_Williams. • 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.


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Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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).


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Obstentrics_Williams. 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).


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Obstentrics_Williams. 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


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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.


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Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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.


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Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. 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).


Obstentrics_Williams

Obstentrics_Williams. 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.