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Obstentrics_Williams. Some of the immune functions necessary for pregnancy maintenance are discussed in Chapter 5 (p. 95). Given these important interactions, immunosuppressant drugs logically might afect pregnancy. hese medications include glucocorticoids and mineralocorticoids, which have antiinflammatory and immunosuppressive actions. They are frequently used to treat serious disorders such as asthma and autoimmune disease. Corticosteroids have been associated with clefts in animal studies. In one metaanalysis of case-control studies by the Motherisk Program, systemic corticosteroid exposure was associated with a threefold increase in the rate of clefts. his is an absolute risk of 3 cases per 1000 exposed fetuses (Park-Wyllie, 2000). A 10-year prospective cohort study by the same group, however, did not identiy higher risks for major malformations. Based on these findings, corticosteroids are not considered to represent a major teratogenic risk.


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Obstentrics_Williams. Unlike other corticosteroids, the active metabolite of prednisone, which is prednisolone, is inactivated by the placental enzyme 11�-hydroxysteroid dehydrogenase 2. Thus, it may not efectively reach the fetus. This inosine monophosphate dehydrogenase inhibitor, and a related agent, mycophenolic acid, are immunosuppressants. They are used to prevent rejection in organ-transplant recipients and to treat autoimmune disease (Chap. 59, p. 1142). Mycophenolate is a potent teratogen. From the National Transplantation Pregnancy Registry, of pregnancies in which mycophenolate was not discontinued until after the first trimester, birth defects complicated 30 percent, and another 30 percent spontaneously aborted (ing, 2017). One prospective review by the European Network of Teratology Information Services similarly identified a spontaneous loss rate of nearly 30 percent in exposed pregnancies. More than 20 percent of liveborn infants had major anomalies (Hoeltzenbein, 2012).


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Obstentrics_Williams. Many afected infants have a pattern of defects termed mycophenolate embyopathy. his includes microtia, auditory canal atresia, clefts, coloboma and other eye anomalies, short ingers with hypoplastic nails, and cardiac defects (Anderka, 2009; Merlob, 2009). A Risk Evaluation and Mitigation Strategy (REMS) has been developed for mycophenolate prescribers who treat women with reproductive potential. REMS are safety strategies mandated by the FDA to help manage known risks associated with a medicine yet still allow patients to have access to the benefits of a given drug.


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Obstentrics_Williams. Radioactive iodine-131 is used for treatment of thyroid cancer and thyrotoxicosis and for diagnostic thyroid scanning. It is also a component of iodine-131 tositumomab therapy, which is employed to treat a type of non-Hodgkin lymphoma. Radioiodine is contraindicated during pregnancy because it readily crosses the placenta and is then concentrated in the fetal thyroid gland by 12 weeks' gestation. It may cause severe or irreversible fetal and neonatal hypothyroidism, which can lead to decreased mental capacity and delayed skeletal maturation Qubilant DraxImage, 2016). Pregnancy testing should be performed before administration of radioiodine-131. Prenatal lead exposure is associated with fetal-growth abnormalities and with childhood developmental delay and behavioral abnormalities. According to the CDC (2010), no level of lead exposure is considered safe in pregnancy. Care and testing for at-risk pregnancies is discussed in Chapter 9 (p. 170).


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Obstentrics_Williams. Environmental spills of methyl mercury in Minamata Bay, Japan, and rural Iraq demonstrated that the developing nervous system is particularly susceptible to this heavy metal. Prenatal exposure causes disturbances in neuronal cell division and migration. This leads to a range of defects from developmental delay to microcephaly and severe brain damage (Choi, 1978). he principal concern for prenatal mercury exposure is the consumption of certain species of large fish (Chap. 9, p. 170). The FDA (2017a) advises that pregnant women and breastfeeding mothers avoid consumption of king mackerel, marlin, orange roughy, shark, swordfish, tilefish, and bigeye tuna. Treatment of psychiatric illness in pregnancy, including a discussion of the risks and benefits of various psychiatric medications, is described in Chapter 61 (p. 1173). Selected birth defects and adverse efects associated with specific medications are presented here.


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Obstentrics_Williams. This medication has been associated with Ebstein anomaly, a rare cardiac abnormality that otherwise complicates only 1 per 20,000 births. Ebstein anomaly is characterized by apical Teratology, Teratogens, and Fetotoxic Agents 245 displacement of the tricuspid valve, often resulting in severe tri confer signiicant morbidity. A report from the Lithium Baby Registry initially suggested that the risk for Ebstein anomaly was as high as 3 percent. However, subsequent series have iden right-sided cardiac anomalies of only 1 to 4 per 1000 exposed pregnancies (Patorno, 2017; Yacobi, 2008). In a review of fout case-control studies that included more than 200 infants with Ebstein anomaly, no cases were attributed to lithium exposure (Cohen, 1994).


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Obstentrics_Williams. Ebstein anomaly, no cases were attributed to lithium exposure (Cohen, 1994). ery. he manufacturer recommends that if possible, the dosage should be decreased or drug discontinued 2 to 3 days prior to delivery to reduce this risk (West-Ward, 2016). Findings typically persist for 1 to 2 weeks and may include neonatal hypothyroidism, diabetes insipidus, cardiomegaly, bradycar dia, electrocardiogram abnormalities, cyanosis, and hypotonia (American College of Obstetricians and Gynecologists, 2016).


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Obstentrics_Williams. As a class, these medications are not considered major teratogens (American College of Obstetricians and Gynecologists, 2016). The one exception is paroxetine, which has been associated with a higher risk for cardiac anomalies, particularly atrial and ventricular septal defects. Three large databases-a Swedish national registry, a United States insurance claims database, and the Motherisk Program-each identified a 1.5-to twofold greater risk for cardiac malformations following first-trimester paroxetine exposure (Bar-Oz, 2007; Sebela, 2017). For these reasons, the American College of Obstetricians and Gynecologists (2016) recommends that paroxetine be avoided in women planning pregnancy. Fetal echocardiography should be considered for those with first-trimester paroxetine exposure.


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Obstentrics_Williams. Neonatal efects have been associated with prenatal exposure to selective serotonin-reuptake inhibitors (SSRIs) and selective norepinephrine-reuptake inhibitors (SNRIs). Approximately 25 percent of neonates exposed to SSRIs in late pregnancy manifest one or more nonspecific findings considered to represent poor neonatal adaptation (Chambers, 2006; Costei, 2002; Jordan, 2008). Collectively termed the neonatal behavioral syndrome, findings can include jitteriness, irritability, hyper-or hypotonia, feeding abnormalities, vomiting, hypoglycemia, thermoregulatory instability, and respiratory abnormalities. Fortunately, these neonatal behaviors are typically mild and self-limited and last approximately 2 days. Jordan and coworkers (2008) reported that afected newborns were not more likely to require a higher level of care, to experience respiratory abnormalities, or to have prolonged hospitalization. Rarely, neonates exposed to SSRIs in late pregnancy demonstrated more severe adaptation


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Obstentrics_Williams. require a higher level of care, to experience respiratory abnormalities, or to have prolonged hospitalization. Rarely, neonates exposed to SSRIs in late pregnancy demonstrated more severe adaptation abnormalities (Ornoy, 2017).


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Obstentrics_Williams. Another concern with late-pregnancy exposure is the possible association of SSRI medications with persistent pulmonary hypertension of the newborn (PPH). he baseline incidence approximates 2 cases per 1000 term newborns. PPHN is characterized by elevated pulmonary vascular resistance with right-to-Ieft shunting and resultant hypoxemia. Two recent population-based cohort studies-together involving more than 5 million pregnancies-identiied an attributable risk of only 1 to 2 cases per 1000 births (Huybrechts, 2015; Kieler, 2012). Not only is the risk for this condition quite low, but cases associated with SSRI medication have not been severe (Ornoy,i2017).


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Obstentrics_Williams. No antipsychotic medications are considered teratogenic. Exposed neonates can manifest abnormal extrapyramidal muscle movements and withdrawal symptoms that include agitation, abnormally enhanced or diminished muscle tone, tremor, sleepiness, feeding diiculty, and respiratory abnormalities. These indings are nonspeciic and transient, similar to the neonatal behavioral syndrome that can follow SSRI exposure. An FDA (2011) alert cites all medications in this class. These include older drugs such as haloperidol and chlorpromazine, as well as newer medications such as aripiprazole, olanzapine, quetiapine, and risperidone.


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Obstentrics_Williams. hese vitamin A derivatives are among the most potent human teratogens. hree retinoids available in the United States are highly teratogenic when orally administered-isotretinoin, acitretin, and bexarotene. By inhibiting neural-crest cell migration during embryogenesis, they create a pattern of cranial neural-crest defects-termed retinoic acid embryopath-that involve the CNS, face, heart, and thymus (Fig. 12-5). Specific anomalies may include ventriculomegaly, maldevelopment of the facial bones or cranium, microtia or anotia, micrognathia, cleft palate, conotruncal heart defects, and thymic aplasia or hypoplasia.


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Obstentrics_Williams. 13-cis-Retinoic acid is a vitamin A isomer that stimulates epithelial cell diferentiation and is used for dermatological disorders, especially cystic nodular acne. First-trimester exposure is associated with a high rate of pregnancy loss, and up to a third of fetuses have malformations (Lammer, 1985). he iPLEDGE program is an FDA-mandated REMS for isotretinoin and is found at: ww.ipledgeprogram.com.ihis webbased, restricted-distribution program requires participation for all patients, physicians, and pharmacies to help eliminate embryonic-fetal exposure. Although other countries have instituted similar programs, inadvertent exposure remains a global concern (Crijns, 201l).


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Obstentrics_Williams. This retinoid is used to treat severe psoriasis and was introduced to replace etretinate. he latter is a lipophilic retinoid with such a long hal-life (120 days) that birth defects resulted more than 2 years after therapy was discontinued. Although acitretin has a short half-life, it is metabolized to etretinate, and thus remains in the body for prolonged periods (Stiefel Laboratories, 2015). To obviate exposure, the manufacturer of acitretin has developed a pregnancy risk management program. Called "Do Your P.A.R.T"-Eregnancy prevention Actively Required during FIGURE 12-5 Isotretinoin embryopathy. A. Bilateral microtia or anotia with stenosis of external (Kaplan, 2015). These results may be reassuring to pregnant women with inadvertent exposure. Notably, the manufacturer of tazarotene cautions that application over a suicient body surface area could be comparable to oral treatment. Accordingly, its use in pregnancy is not recommended (Allergan, 2017).


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Obstentrics_Williams. There are wo natural forms of vitamin A. Beta-carotene, which is a precursor of provitamin A, is found in fruits and vegetables and has never been shown to cause birth defects (Oakley, 1995). Retinol is preformed vitamin A, ear canal. B. Flat, depressed nasal bridge and ocular hypertelorism. (Used with permission from Dr. Edward Lammer.) and after Ireatment, this program promotes a delay of conception for at least 3 years following therapy discontinuation.


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Obstentrics_Williams. Dr. Edward Lammer.) and after Ireatment, this program promotes a delay of conception for at least 3 years following therapy discontinuation. This retinoid is used to treat cutaneous T-cell lymphoma. When given to rats in doses comparable to those for human therapy, fetuses developed eye and ear abnormalities, cleft palate, and incomplete ossification. For a woman to receive this medication, the manufacturer requires two forms of contraception that are initiated 1 month before therapy and are continued for 1 month after bexarotene discontinuation. This is coupled with monthly pregnancy testing during treatment (Valeant Pharmaceuticals, 2015). Males who have partners who could become pregnant are advised to use condoms during sexual intercourse while taking bexarotene and for 1 month after discontinuing therapy.


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Obstentrics_Williams. These compounds, initially used to treat acne, have become so popular for the treatment of sun damage that they are called cosmeceuticals (Panchaud, 2012). The most commonly used topical agents are tretinoin, isotretinoin, and adapalene. Systemic absorption is low, and this argues against plausible teratogenicity.


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Obstentrics_Williams. Isolated case reports have described malformations following topical tretinoin, and it is unknown whether this is due to variability in absorption or perhaps potential individual susceptibility (Kaplan, 2015). A prospective study by the European Network of Teratology Information Services found no higher rates of birth defects or spontaneous losses, and no case of retinoid embryopathy (Panchaud, 2012). One systematic review by the Motherisk Program included 635 pregnancies with exposure to topical retinoids. Investigators similarly identified no higher risk for congenital malformations, spontaneous abortion, stillbirth, low birthweight, or preterm delivery cranial neural-crest defects when more than 10,000 IU per day is consumed in the first trimester (Rothman, 1995). It seems reasonable to avoid doses of preformed preparations that exceed the recommended 3000 IU daily allowance (American Academy of Pediatrics, 2017).


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Obstentrics_Williams. Possibly the most notorious human teratogen, thalidomide causes malformations in 20 percent of fetuses exposed between 34 and 50 days menstrual age. The characteristic malformation is phocomelia-an absence of one or more long bones. As a result, hands or feet are attached to the trunk, occasionally by a small rudimentary bone. Cardiac malformations, gastrointestinal abnormalities, external ear malformations, eye anomalies, and other limb-reduction defects are also common following thalidomide exposure. The manufacturer reports that up to 40 percent of afected newborns do not survive the neonatal period (Celgene, 2017 a).


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Obstentrics_Williams. Thalidomide was marketed outside the United States from 1956 to 1960, before its teratogenicity was appreciated. The ensuing disaster, with thousands of afected children, was instructive of several important teratological principles. First, the placenta is not an efective barrier to the transfer of toxic substances from mother to embryo (Dally, 1998). Second, diferent species show extreme variability in their susceptibility to drugs and chemicals. Namely, thalidomide produced no defects in multiple rodent species and was assumed to be safe for humans. Last, exposure timing and defect type are often closely related (Vargesson, 2015). For example, upper-limb amelia may develop with thalidomide exposure during days 24 to 30 postconception, upper-limb phocomelia with exposure during days 24 to 33, and lower-limb phocomelia with exposure during days 27 to 33.


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Obstentrics_Williams. halidomide was irst approved in the United States in 1999 and currently is used to treat erythema leprosum nodosum and multiple myeloma (Celgene, 2017a). The FDA has mandated a web-based, restricted-distribu tion program for thalidomide, called THALOMID REMS, which is required before patients, physicians, and pharmacies can access the medication. Lenalidomide is an analogue of thalidomide that is used to treat some types of myelodys myeloma. It crosses the placenta in multiple animal species, and gene, 2017b). Because of obvi ous teratogenicity concerns, a similar to that used for thalido mide has been developed.


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Obstentrics_Williams. his anticoagulant is a vitamin K antagonist with a long halflife. Because of its low molecular weight, it readily crosses the placenta and may cause embryotoxic and fetotoxic efects. Warfarin analogues, such as Coumadin, are considered contraindicated in pregnancy. An exception, as discussed in Chapter 49 (p. 954), is treatment of women with mechanical heart valves who are at high risk for thromboembolism (Bristol-Myers Squibb,i2017a).


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Obstentrics_Williams. Waarin embryopathy is characterized by stippled epiphyses and nasal hypoplasia (Fig. 12-6). In one review of 63 cases attributed to warfarin exposure, 80 percent displayed characteristic indings, which include depressed nasal bridge with nasal hypoplasia and choanal atresia, along with stippled epiphyses of the femur, humerus, calcanei, and distal phalanges (Van Driel, 2002). It may result from exposure between the 6th and 9th weeks' gestation (Hall, 1980). he prevalence of the warfarin embryopathy following exposure during this critical period is estimated to be 6 percent (van Driel, 2002). One metaanalysis of cases in which the warfarin dosage was ; 5 mg/ d identiied embryopathy in 1 percent of exposed fetuses. his suggests that risk may be dose dependent (Hassouna, 2014).


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Obstentrics_Williams. If used beyond the first trimester, warfarin may lead to hemorrhage into fetal structures, which can cause abnormal growth and deformation from scarring (Warkany, 1976). Nearly 50 percent of reported embryopathy cases also have CNS anomalies (van Driel, 2002). Abnormalities can include agenesis of the corpus callosum; cerebellar vermian agenesis, which is the Dandy-Walker malformation; microphthalmia; and optic atrophy (Hall, 1980). Afected infants are also at risk for blindness, deafness, and developmental delays. With various herbal remedies, associated risks are more challenging to estimate because studies are few and because these compounds are not FDA-regulated. he European Committee of Herbal Medicinal Products provides assessment reports and Teratology, Teratogens, and Fetotoxic Agents 247 FIGURE 12-6 Warfarin embryopathy or fetal warfarin syndrome: nasal hypoplasia and depressed nasal bridge seen in a fetal sonographic image (A) and in the same newborn (8).


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Obstentrics_Williams. FIGURE 12-6 Warfarin embryopathy or fetal warfarin syndrome: nasal hypoplasia and depressed nasal bridge seen in a fetal sonographic image (A) and in the same newborn (8). monographs on selected herbal substances and preparations, but safety data are generally limited (Wiesner, 2017). Animal studies have not been conducted, and thus knowledge of complications often derives from reports of acute toxicity (Hepner, 2002; Sheehan, 1998). Further, the identity, quantity, and purity of each ingredient are usually unknown. Given these uncertainties, it seems prudent to counsel pregnant women to avoid these substances. A list of selected herbal compounds and their potential efects is shown in Table 12-5.


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Obstentrics_Williams. Not uncommonly, fetuses are exposed to one or more illicit drugs. Assessment of outcomes attributable to these drugs may be confounded by factors such as poor maternal health, malnutrition, infectious disease, and polysubstance abuse. Moreover, illegal substances may contain toxic contaminants such as lead, cyanide, herbicides, and pesticides. Impurities added as diluents may independently have serious adverse perinatal efects. As noted on page 239, alcohol is a significant teratogen. Because it is legally obtained and ubiquitous, its use also confounds the study of illicit drug teratogenicity.


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Obstentrics_Williams. hese sympathomimetic amines are not considered to be major teratogens. Methamphetamine enhances dopamine release and blocks its reuptake. It is prescribed to treat attention-deicit/ hyperactivity disorder and narcolepsy. Methamphetamine abuse has been rising in the United States since the late 1980s (American College of Obstetricians and Gynecologists, 2017b). In utero exposure has been consistently associated with higher rates of small-for-gestational age newborns (Gorman, 2014; Smith, 2006). Hypertensive complications, placental abruption, preterm birth, and stillbirth are other associated complications (Gorman, 2014). Behavioral abnormalities have been described in both infants and school-aged children (Eze, 2016). TABLE 12-5. Pharmacological Actions and Adverse Effects of Some Herbal Medicines Echinacea: purple coneflower root Ephedra: ma huang Garlic: ajo Kava: awa, intoxicating pepper, kawa Valerian: all heal, garden heliotrope, vandal root Yohimbe


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Obstentrics_Williams. Echinacea: purple coneflower root Ephedra: ma huang Garlic: ajo Kava: awa, intoxicating pepper, kawa Valerian: all heal, garden heliotrope, vandal root Yohimbe Contains linoleic acids, a prostaglandin precursor Cyclooxygenase inhibitor, thromboxane synthetase inhibitor Lowers blood glucose; inhibition of platelet aggregation Sedation, anxiolysis Data from Ang-Lee, 2001; Briggs, 2015; Hall, 2012; Wiesner, 2017.


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Obstentrics_Williams. Lowers blood glucose; inhibition of platelet aggregation Sedation, anxiolysis Data from Ang-Lee, 2001; Briggs, 2015; Hall, 2012; Wiesner, 2017. With this CNS stimulant, most adverse outcomes result from its vasoconstrictive and hypertensive efects. Serious potential maternal complications are cerebrovascular hemorrhage, myocardial damage, and placental abruption. Studies of congenital abnormalities and cocaine exposure have yielded conflicting results, but associations with cleft palate, cardiovascular abnormalities, and urinary tract anomalies have been reported (Chasnof, 1988; Lipshultz, 1991; van Gelder, 2009). Cocaine use is also associated with fetal-growth restriction and preterm delivery. Children exposed as fetuses have risks for behavioral abnormalities and cognitive impairments (Bada, 2011; Gouin, 2011).


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Obstentrics_Williams. The dramatic rise in narcotic use among non-pregnant and pregnant individuals has been aptly termed an epidemic. Opioids are not considered to be major teratogens. he NBDPS did identiY a slightly greater risk for spina biida, gastroschisis, and cardiac abnormalities with periconceptional opioid exposure (Broussard, 2011). The American College of Obstetricians Allergic reactions; decreases immunosuppressant efectiveness; possible immunosuppression with long-term use arrhythmias, myocardial ischemia, stroke; depletes endogenous catecholamines; lifethreatening interaction with monoamine oxidase inhibitors Possible complications if used for labor induction Risk of bleeding, especially when combined with other platelet aggregation inhibitors Increased risk of bleeding Risk of bleeding; interferes with monoamine oxidase inhibitors Hypoglycemia; hypertension; risk of bleeding


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Obstentrics_Williams. Increased risk of bleeding Risk of bleeding; interferes with monoamine oxidase inhibitors Hypoglycemia; hypertension; risk of bleeding Sedation; hepatotoxicity, benzodiazepine-like acute withdrawal Hypertension, arrhythmias and Gynecologists (2017 c) stresses that this potential, small increase in birth defects with maintenance therapy should be weighed against the risks associated with uncontrolled opioid abuse. Heroin addiction is associated with adverse pregnancy outcomes from the efects of repeated narcotic withdrawal on the fetus and placenta (American College of Obstetricians and Gynecologists, 2017 c). These include preterm birth, placental abruption, fetal-growth restriction, and fetal death.


Obstentrics_Williams

Obstentrics_Williams. Neonatal narcotic withdrawal, called the neonatal abstinence syndrome, may manifest in 40 to 90 percent of exposed newborns (Blinick, 1973; Creanga, 2012; Dashe, 2002; Zelson, 1973). As discussed in Chapter 33 (p. 625), CNS irritability may progress to seizures if untreated and may be accompanied by tachypnea, apneic episodes, poor feeding, and failure to thrive. At-risk neonates are closely monitored using a scoring system, and those severely afected are treated with opioids (Finnegan, 1975). he proportion of exposed newborns developing neonatal abstinence syndrome has risen significantly in recent years (Creanga, 2012; Lind, 2015).


Obstentrics_Williams

Obstentrics_Williams. he American College of Obstetricians and Gynecologists (2017 c) recommends that pregnant women with opioid-use disorder be maintained on opioid-agonist therapy to reduce the risks associated with illicit opioid abuse and associated behaviors. Treatment includes either methadone, usually through a licensed outpatient opioid treatment program, or buprenorphine, which may be given in an oice-based setting by a licensed buprenorphine prescriber. A multidisciplinary treatment program is recommended to reduce the likelihood of additional opioid abuse while on maintenance therapy. he College (2017 c) discourages withdrawal from methadone during pregnancy because of high relapse rates. At Parkland Hospital, pregnant opioid users who decline maintenance therapy are ofered inpatient hospitalization for controlled methadone taper, with the goal of reducing the likelihood of neonatal abstinence syndrome (Dashe, 2002; Stewart, 2013).


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Obstentrics_Williams. This is the illicit drug most commonly used in pregnancy (American College of Obstetricians and Gynecologists, 2017a). Based on data from the National Survey on Drug Use and Health, the prevalence of marijuana use in pregnancy was nearly 4 percent in 2014 (Brown, 2017). Cannabinoids are not considered to be major teratogens, but there is concern because endogenous cannabinoids play key roles in human brain development. In one metaanalysis of nearly 8000 exposed pregnancies, adverse outcomes such as preterm birth and low birthweight were increased only in the presence of concomitant tobacco use (Conner, 2016).


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Obstentrics_Williams. Phencyclidine (PCP) or angel dust is not associated with congenital anomalies. More than half of exposed newborns, however, experience withdrawal symptoms characterized by tremors, jitteriness, and irritability. Toluene is a common solvent used in paints and glue. Occupational exposure is reported to have signiicant fetal risks (Wilkins-Haug, 1997). When abused by women in early pregnancy, it is associated with toluene embyopathy, which is phenotypically similar to fetal alcohol syndrome. Abnormalities include pre-and postnatal growth deficiency, microcephaly, midface hypoplasia, short palpebral fissures, and wide nasal bridge (Pearson, 1994) . Up to 40 percent of exposed children have developmental delays (Arnold, 1994).


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Obstentrics_Williams. Cigarette smoke contains a complex mixture of nicotine, cotinine, cyanide, thiocyanate, carbon monoxide, cadmium, lead, and various hydrocarbons (Stillerman, 2008). In addition to being fetotoxic, many of these substances have vasoactive efects or reduce oxygen levels. Tobacco is not considered a major teratogen, although selected birth defects have been reported to occur with greater frequency among newborns of women who smoke. It is plausible that the vasoactive properties of tobacco smoke could produce congenital defects related to vascular disturbances. For example, the prevalence of Poland sequence, which is caused by an interruption in the vascular supply to one side of the fetal chest and ipsilateral arm, is twofold greater in smokers (Martinez-Frias, 1999). A small increased risk for cardiac anomalies has also been reported and may be dose related (Alverson, 2011; Malik, 2008; Sullivan,


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Obstentrics_Williams. Teratology, Teratogens, and Fetotoxic Agents 249 2015). One study analyzing more than 6 million births found an association between maternal smoking and hydrocephaly, microcephaly, omphalocele, gastroschisis, cleft lip and palate, and hand abnormalities (Honein, 2001). Electronic nicotine delivery systems are not considered safe, as nicotine may have adverse efects on fetal brain and lung development (American College of 0bstetricians and Gynecologists, 2017 d).


Obstentrics_Williams

Obstentrics_Williams. he best-documented adverse reproductive outcome from smoking is a dose-response reduction in fetal growth. Newborns of mothers who smoke weigh on average 200 g less than newborns of nonsmokers (D'Souza, 1981). Smoking doubles the risk of low birthweight and raises the risk of fetal-growth restriction two-to threefold (Werler, 1997). Even secondhand smoke increases the risk for low birthweight (Hegaard, 2006). Women who stop smoking early in pregnancy may have neonates with normal birthweights (Cliver, 1995). Other adverse outcomes associated with cigarette smoking include preterm birth, placenta previa, placenta abruption, spontaneous abortion, and sudden infant death syndrome (American College of Obstetricians and Gynecologists, 2017d). Risks of childhood asthma and obesity are also increased. Abel EL, Hannigan ]H: Maternal risk factors in fetal alcohol syndrome: provocative and permissive inluences. Neurotoxicol Teratolo17(4):445, 1995


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Obstentrics_Williams. Abel EL, Hannigan ]H: Maternal risk factors in fetal alcohol syndrome: provocative and permissive inluences. Neurotoxicol Teratolo17(4):445, 1995 Actelion Pharmaceuticals: Opsumit (Macitentan) prescribing information, 2017. Available at: http://www.opsumit.com/opsumit-prescribing-information. pd. Accessed September 24, 2017 Actelion Pharmaceuticals: T racleer (Bosentan) prescribing information, 2016. Available at: www.tracleer.com/assets/PD Rs/T racleer_Full_Prescribin� Information. pdf. Accessed September 24, 2017 Adam MP, Polifka ]E, Friedman ]M: Evolving knowledge of the teratogenicity of medications in human pregnancy. Am] Med Genet C Semin Med Genet 157(3):175,o2011 Ailes EC, Gilboa SM, Gill SK, et al: Association between antibiotic use among pregnant women and urinary tract infections in the irst trimester and birth defects, National Birth Defects Prevention Study 1997 to 2011. Birth Defects Res A Clin Mol Teratol 106(1o1):940, 2016


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Obstentrics_Williams. Allergan: Tazorac (Tazarotene) prescribing information, 2017. Available at: https:/ /www.allergan.com/assets/pdfltazorac_cream_pi.pd. Accessed September 24, 201o7 Alsaad AM, Kaplan YC, Koren G: Exposure to luconazole and risk of congenital malformations in the ofspring: a systematic review and meta-analysis. Reprod Toxicol 52:78, 2015 Alverson q, Strickland M], Gilboa SM, et al: Maternal smoking and congenital heart defects in the Baltimore-Washington Infant Study. Pediatrics 12 (3):e647,o2011 Alwan S, Chambers CD: Findings from the National Birth Defects Prevention Study: interpretation and translation for the clinician. Birth Defects Res A Clin Mol Teratolo103(8):721, 2015 American Academy of Pediatrics and American College of Obstetricians and Gynecologists: Guidelines for Perinatal Care, 8th ed. Elk Grove Village, AAP,o2017


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Obstentrics_Williams. American Academy of Pediatrics and American College of Obstetricians and Gynecologists: Guidelines for Perinatal Care, 8th ed. Elk Grove Village, AAP,o2017 American College of Obstetricians and Gynecologists: At-risk drinking and alcohol dependence: obstetric and gynecologic implications. Committee Opinion No. 496, August 2013 American College of Obstetricians and Gynecologists: Use of psychiatric medications during pregnancy and lactation. Practice Bulletin No. 92, April 2008, Reairmed 2016 American College of Obstetricians and Gynecologists: Marijuana use during pregnancy and lactation. Committee Opinion No. 722, October 20 17a American College of Obstetricians and Gynecologists: Methamphetamine abuse in women of reproductive age. Committee Opinion No. 479, March 2011, Reairmed 2017b American College of Obstetricians and Gynecologists: Opioid use and opioid use disorder in pregnancy. Committee Opinion No. 71o1, August 2017c


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Obstentrics_Williams. American College of Obstetricians and Gynecologists: Opioid use and opioid use disorder in pregnancy. Committee Opinion No. 71o1, August 2017c American College of Obstetricians and Gynecologists: Smoking cessation during pregnancy. Committee Opinion No. 721, October 20o17 d American College of Obstetricians and Gynecologists: Sulfonamides, nitrofurantoin, and risk of birth defects. Committee Opinion No. 717, September 2017e Anderka MT, Lin AE, Abuelo ON, et al: Reviewing the evidence for mycophenolate mofetil as a new teratogen: case report and review of the literature. Am J Med Genet A 149A( 6): 1241, 2009 Ang-Lee MK, Moss J, Yuan CS: Herbal medicines and perioperative care. JAMA 286(2):208,o2001


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Obstentrics_Williams. Salle B, Sergeant P, Awada A, et al: Transvaginal ultrasound studies of vascular and morphological changes in uteri exposed to diethylstilbestrol in utero. Hum Reprod 11(11):2531, 1996 Sanofi-Aventis: Arava (Lelunomide) prescribing information, 20o16. Available at: http://products.sanoi.us/arava/arava.htmll. Accessed September 24, 2017 Schardein JL: Congenital abnormalities and hormones during pregnancy: a clinical review. Teratology 22(3):251,o1980 Sebela Pharmaceuticals: Pexeva (Paroxetine) prescribing information, 2017. Available at: ww.pexeva.com/pdf/Pexeva_20140728_ver .pd. Accessed September 24, 2017 Sheehan DM: Herbal medicines, phytoestrogens and toxicity: risk:beneit considerations. Proc Soc Exp BioI Med 21 (3):379, 1998 Shepard TH: Annual commentary on human teratogens. Teratology 66(6):275, 2002a Shepard TH: Letters: "proof' of human teratogenicity. Teratology 50(2):97, 1994


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Obstentrics_Williams. Shepard TH: Annual commentary on human teratogens. Teratology 66(6):275, 2002a Shepard TH: Letters: "proof' of human teratogenicity. Teratology 50(2):97, 1994 Shepard TH, Brent L, Friedman JM, et al: Update on new developments in the study of human teratogens. Teratology 65(4): 153, 2002b Smith LM, LaGasse LL, Derauf C, et al: he infant development, environment, and lifestyle study: efects of prenatal methamphetamine exposure, polydrug exposure, and poverty on intrauterine growth. Pediatrics 118(3): 1149,2006 Stewart D, Nelson DB, Adhikari EH, et al: he obstetrical and neonatal impact of maternal opioid detoxification in pregnancy. Am J Obstet Gynecol 209(3):267, 2013 Stiefel Laboratories Soriatane (acitretin) prescribing information. 2015. Available at: https:/ Iwww.gsksource.com/pharma/ con tentl dam I G laxoSmi thKline/USI en/P rescribin�Informationl Soriatanel pdfl SO RIA T ANEPI-MG. PDF. Accessed September 24,o2017


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Obstentrics_Williams. Available at: https:/ Iwww.gsksource.com/pharma/ con tentl dam I G laxoSmi thKline/USI en/P rescribin�Informationl Soriatanel pdfl SO RIA T ANEPI-MG. PDF. Accessed September 24,o2017 Stillerman KP, Mattison DR, Giudice LC, et al: Environmental exposures and adverse pregnancy outcomes: a review of the science. Reprod Sci 15(7):631, 2008 Stillman RJ: In utero exposure to diethylstilbestrol: adverse efects on the reproductive tract and reproductive performance in male and female ofspring. Am J Obstet Gynecol 142(7):905, 1982 Stingone JA, Luben TJ, Carmichael SL, et al: Maternal exposure to nitrogen dioxide, intake of methyl nutrients and congenital heart defects in ofspring. AmoJ EpidemioIo186(6):719, 2017 Stothard KJ, Tennant PWG, Bell R, et al: Maternal overweight and obesity and the risk of congenital anomalies: a systematic review and meta-analysis. JAMA 301(6):636,o2009


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Obstentrics_Williams. Strandberg-Larsen K, Nielsen NR, Gf0nbaek M, et al: Binge drinking in pregnancy and risk of fetal death. Obstet Gynecol III(3):602, 2008 Streissguth AP, Clarren SK, Jones L: Natural history of fetal alcohol syndrome: a 10-year follow-up of eleven patients. Lancet 2:85, 1985 Sullivan PM, Dervan A, Reiger S, et al: Risk of congenital heart defects in the ofspring of smoking mothers: a population-based study. J Pediatr 166(4):978,o2015 Teratology Society Public Afairs Committee: Causation in teratology-related litigation. Birth Def Res A Clin Mol Teratol 3(6):421,o2005 Vajda FJ, O'Brien TJ, Lander CM, et al: Antiepileptic drug combinations not involving valproate and the risk of fetal malformations. Epilepsia 57(7):1048,o2016


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Obstentrics_Williams. Vajda FJ, O'Brien TJ, Lander CM, et al: Antiepileptic drug combinations not involving valproate and the risk of fetal malformations. Epilepsia 57(7):1048,o2016 Valeant Pharmaceuticals: Tagretin (Bexarotene) prescribing information, 2015. Available at: http://ww.valeant.com/Portals/25/PDF/TargretinCapsulesP1.pd?ver=2016-05-1o1-044521-020. Accessed September 24,o2017 van der Heijden BJ, Carlus C, Narcy F, et al: Persistent anuria, neonatal death, and renal microcystic lesions after prenatal exposure to indomethacin. Am J Obstet GynecoIo171(3):617, 1994 Van Driel D, Wesseling J, Sauer PJ, et al: Teratogen update: fetal efects after in utero exposure to coumarins overview of cases, follow-up findings, and pathogenesis. Teratology 66(3):127,o2002 Van Gelder MM, Reehuis J, Caton R, et al: Maternal periconceptional illicit drug use and the risk of congenital malformations. Epidemiology 20:60, 2009 Vargesson N: halidomide-induced teratogenesis: history and mechanisms.


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Obstentrics_Williams. Birth Defects Res C Embryo Today 105(2):140, 2015 Vessey MP: Epidemiological studies of the efects of diethylstilbestrol. IARC Sci Pub1o335, 1989 Walker MP, Moore TR, Brace A: Indomethacin and arginine vasopressin interaction in the fetal kidney. A mechanism of oliguria. Am J Obstet Gynecol 171(5):1234, 1994 Waller DK, Shaw GM, Rasmussen SA, et al: Prepregnancy obesity as risk factor for structural birth defects. Arch Pediatr Adolesc Med 161(8):745,2007 Warkany J: Warfarin embryopathy. Teratology 14(2):205, 1976 Weiss CF, Glazko AJ, Weston JK: Chloramphenicol in the newborn infant: a physiologic explanation of its toxicity when given in excessive doses. N Engl J Med 262:787, 1960 Werler MM: Teratogen update: smoking and reproductive outcomes. Teratology 55(6):382, 1997 Weston J, Bromley R, Jackson CF, et al: Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database Syst Rev 11 :CDO 1 0224, 2016


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Obstentrics_Williams. Weston J, Bromley R, Jackson CF, et al: Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database Syst Rev 11 :CDO 1 0224, 2016 West-Ward Pharmaceuticals: Lithium prescribing information, 20o16. Available at: https:/ Idailymed.nlm.nih.gov/dailymed/fda/fdaDruXsl.cfm?setid =a226a88d-eb5 7 -4c96-afda-93980 1 bcaOa9&type=display. Accessed September 24, 2017 Wiesner J, Knoss W: Herbal medicinal products in pregnancy-which data are available? Reprod Toxicol 72:142, 201 Wilkins-Haug L: Teratogen update: toluene. Teratology 55(2):145, 1997 Williams JF, Smith VC, American Academy of Pediatrics Committee on Substance Abuse: Fetal alcohol spectrum disorders. Pediatrics 136(5):e1395, 2015 Yacobi S, Ornoy A: Is lithium a real teratogen? What can we conclude from the prospective versus retrospective studies? A review. Isr J Psychiatry Relat Sci 45(2):95, 2008


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Obstentrics_Williams. Yacobi S, Ornoy A: Is lithium a real teratogen? What can we conclude from the prospective versus retrospective studies? A review. Isr J Psychiatry Relat Sci 45(2):95, 2008 Zelson C, Lee SJ, Casalino M: Neonatal narcotic addiction: comparative efects of maternal intake of heroin and methadone. N Engl J Med 289(23):1216, 1973 GENOMICS IN OBSTETRICSe. . . . . . . . . . . . . . . . . . . . . . . 253 ABNORMALITIES OF CHROMOSOME NUMBER .e.e. .e. 254 ABNORMALITIES OF CHROMOSOME STRUCTURE .... 260 CHROMOSOMAL MOSAICISM .. .e. .e.... .e.. ... . . 263 MODES OF INHERITANCE .. .e... ..e...e. ..e.e. .e. ..e. 264 CYTOGENETIC ANALYSIS . . . . . . . . . . . . . . . . . . . . . . . . 270 CHROMOSOMAL MICROARRAY ANALYSIS . .e.. .e. .e... 271 WHOLE GENOME AND WHOLE EXOME SEQUENCINGe.. 272 FETAL DNA IN THE MATERNAL CIRCULATION ...e. .e. 273


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Obstentrics_Williams. CHROMOSOMAL MICROARRAY ANALYSIS . .e.. .e. .e... 271 WHOLE GENOME AND WHOLE EXOME SEQUENCINGe.. 272 FETAL DNA IN THE MATERNAL CIRCULATION ...e. .e. 273 Foetal death may be due to abnormalities in the ovum itsef or due to some disease on the part of the mother, and now and again of the ather. The death of the oetus is frequenty due to abnormalities in the development of the embyo which are inconsistent with oetal le. -J. Whitridge Williams (1903) In Williams' irst edition of Obstetrics, he rarely referenced inherited conditions that Gregor Mendel had described 50 years earlier. Fast-forward to 2017, when the science of genetics is a major obstetrical discipline.


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Obstentrics_Williams. Genetics is the study of genes, heredity, and the variation of inherited characteristics. Medical genetics deals with the etiology and pathogenesis of human diseases that are at least partially genetic in origin, along with their prediction and prevention. Thus, it is closely linked to genomics, which is the study of gene function and interaction. In addition to chromosomal, mendelian, and nonmendelian genetic conditions reviewed in this chapter, medical genetics includes prenatal and preimplantation genetic diagnosis, as well as newborn genetic screening, which are discussed in Chapters 14 and 32, respectively.


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Obstentrics_Williams. Genetic disease is common. Between 2 and 3 percent of newborns have a recognized structural defect. In another 3 percent of individuals, a defect is diagnosed by age 5, and another 8 to 10 percent of persons are discovered by age 18 to have one or more functional or developmental abnormalities. Advances in genomics are used increasingly to provide information regarding susceptibility to genetic diseases, and every indication suggests that this ield will reshape prenatal diagnosis.


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Obstentrics_Williams. Completed in 2003, the Human Genome Project identiied more than 25,000 human genes and led to rapid expansion of genomic research to better understand disease biology (McKusick, 2003). More than 99 percent of our DNA is identical. However, genetic code varies every 200 to 500 base pairs, usually as a single-nucleotide polymorphism. The human genome contains more than 80 million such genetic variants, and understanding their potential role in disease requires not only sophisticated interpretation but also integration of resources (Rehm, 2015).


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Obstentrics_Williams. The National Center for Biotechnology Information (NCB!) maintains genetic and genomic databases that are freely accessible to clinicians and researchers. Several of these databases are particularly useful in obstetrics and maternal-fetal medicine practice. he GeneReviews database provides in-depth clinical information for nearly 700 genetic conditions, including diagnostic criteria, management, and genetic counseling considerations (National Center for Biotechnology Information, 2017a). The Genetic Testing Registry (GTR) database contains information regarding the beneits and limitations of available tests for a given disorder. It lists more than 48,000 genetic tests and instructions for specimen collection and transport to individual laboratories throughout the world (National Center for Biotechnology Information, 2017b). Another database, Online Mendelian Inheritance in Man (OMIM), is a comprehensive catalog of human genes and phenotypes that allows clinicians to search for


Obstentrics_Williams

Obstentrics_Williams. for Biotechnology Information, 2017b). Another database, Online Mendelian Inheritance in Man (OMIM), is a comprehensive catalog of human genes and phenotypes that allows clinicians to search for syndromes based on particular traits or abnormalities. As of early 2017, OMIM included more than 15,000 genes and nearly 5000 mendelian and mitochondrial conditions with a known molecular basis Oohns Hopkins University, 2017). The National Library of Medicine (2017) has also established a database of genetic information intended for patients-one that trainees may find especially helpful-the Genetics Home Reerence (GHR). his database contains data on more than 2400 genetic conditions and genes, including resources for families.


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Obstentrics_Williams. Chromosomal abnormalities igure prominently in genetic disease. Aneuploidy accounts for more than 50 percent of irst-trimester miscarriages, approximately 20 percent of second-trimester losses, and 6 to 8 percent of stillbirths and early-childhood deaths (Reddy, 2012; Stevenson, 2004; Wou, 2016). In the European Surveillance of Congenital Anomalies (EUROCAT) network of population-based registries, chromosomal abnormalities were identiied in 0.4 percent of births (Wellesley, 2012). Of recognized pregnancies with aneuploidy, trisomy 21 composes just more than half of all cases. Trisomy 18 accounts for almost 15 percent, and trisomy 13 for 5 percent (Fig. Karyotypes are described using the International System for Human Cytogenomic Nomenclature (McGowan-Jordan, Trisomy 21 (23:10,000) 0 45,X (3:10,000) Trisomy 18 (6: 1 0,000) o 47,XXX; 47,XXY; 47,XYY (2:1e0,000) o Trisomy 13 (2:10,000) o Other (23: 10,000)


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Obstentrics_Williams. Trisomy 21 (23:10,000) 0 45,X (3:10,000) Trisomy 18 (6: 1 0,000) o 47,XXX; 47,XXY; 47,XYY (2:1e0,000) o Trisomy 13 (2:10,000) o Other (23: 10,000) FIGURE 13-1 Prevalence and relative proportion of selected chromosomal abnormalities from EUROCAT (European Surveillance of Congenital Anomalies) population-based registries that included > 10,000 aneuploid live births, fetal deaths, and pregnancy terminations, 2000-2006. (Data from Wellesley, 2012.) 2016). Abnormalities fall into two broad categories-those of chromosome number, such as trisom)i, and those of chromosome structure, such as a deletion or translocation. Each chromosome has a short arm, termed the "p" or petit arm, and a long arm, known as the "q" arm, selected because it is the next letter in the alphabet. The two arms are separated by the centromere.


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Obstentrics_Williams. When reporting a karyotype, the total number of chromosomes is listed irst, corresponding to the number of centro meres. This is followed by the sex chromosomes, X or Y, and then by a description of any structural variation. Speciic abnormalities are indicated by standard abbreviations, such as del (deletion) and inv (inversion). he afected region or bands of the p or q arms are then designated, so that the reader will know the exact abnormality location and type. Examples are shown in Table


Obstentrics_Williams

Obstentrics_Williams. Terminology is similar for fluorescence in situ hybridization. Described on page 270, this technique is used to rapidly identiy of a specific chromosome abnormality and veriy suspected microdeletion or microduplication syndromes. The report begins with the designation ish for in situ hybridization performed on metaphase cells and nuc ish for hybridization performed on interphase nuclei. If no abnormality is identified, this is followed by the probe's specific chromosomal region, such as 22q 11i.2, and then the name of the probe and the number of signals visualized-for example, HIRAx2. If a deletion is identified, del is included before the chromosomal region, and the name of the probe is followed by a minus sign (HIRA-), as shown in Table 13-1. The 22q 11.2 microdeletion syndrome is discussed on page 260.


Obstentrics_Williams

Obstentrics_Williams. A recent addition to the standard nomenclature is terminology to represent copy number variants identiied by chromosomal microarray anaysis, which is discussed on page 271. Copy number variant is another term for a microdeletion or microduplication of DNA too small to be visualized with a standard karyotype. The array designation begins with the abbreviation arr and the version of the genome build to which the nucleotide designations are aligned, such as GRCh38 for Genome Reference Consortium human build 38. his is followed by the number of the chromosome on which the abnormality is identified, by the p or q arm, and by the speciic bands in question. Array reports next include the afected base pair coordinates, thus conveying the exact size and location within the genome for every abnormality identiied-including copy number variants of uncertain signiicance . • Abnormalities of Chromosome Number


Obstentrics_Williams

Obstentrics_Williams. • Abnormalities of Chromosome Number The most easily recognized chromosomal abnormalities are numerical. Aneuploidy is inheritance of either an extra chromosome-resulting in trisomy, or loss of a chromosomemonosomy. These difer from poyploidy, which is an abnormal number of haploid chromosome sets, such as triploidy. The estimated incidence of various numerical chromosomal abnormalities is shown in Figure 13-1. These account for approximately half of all chromosomal abnormalities. In most cases, trisomy results from nondisjunction,


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Obstentrics_Williams. TABLE 13-1. Examples of Karyotype Designations Using the 2016 International System for Human Cytogenetic Nomenclature 46,XX Normal female chromosome constitution 47,XY,+21 Male with trisomy 21 47,XX,+21/46,XX Female who is a mosaic of trisomy 21 cells and cells with normal constitution 46,XY,del(4)(p 14) Male with terminal deletion (del) of the short arm of chromosome 4 at band p 14 46,XX,dup(5)(p 14p 15.3) Female with duplication (dup) of the short arm of chromosome 5 from band p14 to band p15.3 45,XY,derCi 3;14)(q 1 O;q 10) Male with balanced robertsonian translocation (der) of the long arms of chromosomes 13 and 14-the karyotype now has one normal 13, one normal 14, and the translocation chromosome. reducing the normal 46 chromosome complement to 45 46,XX,t(11 ;22)(q23;q 11l.2) Female with a balanced reciprocal translocation (t) between chromosomes 11 and 22, with breakpoints at 11 q23 and 22q 11l.2 46,XY,inv(3)(p21 q 13) Male with inversion (inv) of chromosome 3 that extends from


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Obstentrics_Williams. with a balanced reciprocal translocation (t) between chromosomes 11 and 22, with breakpoints at 11 q23 and 22q 11l.2 46,XY,inv(3)(p21 q 13) Male with inversion (inv) of chromosome 3 that extends from p21 to q 13-a pericentric inversion because it includes the centromere 46,X,r(X)(p22.1 q27) Female with one normal X and one ring (r) X chromosome, with the regions distal to p22.1 and q27 deleted from the ring 46,X,i(X)(q 10) Female with one normal X chromosome and an isochromosome (i) of the long arm of the ish 22q11l.2(HIRAx2) FISH of metaphase cells using a probe for the HIRA locus of the 22q 11l.2 region, with 2 signals identified (no evidence of microdeletion) ish del(22)(q 11.2q 11l.2) (HIRA-) FISH of metaphase cells using a probe for the HIRA locus of the 22q11l.2 region, with only one signal identified, consistent with the microdeletion arr[GRCh38] 18p 11.32q23 Microarray analysis (arr), genome build GRCh38, showing a single copy gain on (102328_79093443)x3 chromosome 18 from


Obstentrics_Williams

Obstentrics_Williams. one signal identified, consistent with the microdeletion arr[GRCh38] 18p 11.32q23 Microarray analysis (arr), genome build GRCh38, showing a single copy gain on (102328_79093443)x3 chromosome 18 from band p11.32 to band q23 (essentially the entire chromosome), consistent with trisomy 18 arr[GRCh38] 4q32.2q35.1 Microarray analysis (arr), genome build GRCh38, showing a copy loss on the long arm of (163146681_183022312)x1 chromosome 4 at bands q32.2 through q35.1 (19.9 Mb) arr[GRCh38] 15q 11l.2q26 SNP microarray analysis (arr), genome build GRCh 38, showing homozygosity for the entire (23123715_101888908)x2 long arm of chromosome 15 cycle regulator; SNP = single nucleotide pleomorphism.


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Obstentrics_Williams. Used with permission from Dr. Kathleen S. Wilson. which is failure of normal chromosomal pairing and separation during meiosis. Nondisjunction may occur if the chromosomes: (1) fail to pair up, (2) pair up properly but separate prematurely, or (3) fail to separate.


Obstentrics_Williams

Obstentrics_Williams. he risk of any autosomal trisomy rises steeply with maternal age, particularly after age 35 (Fig. 13-2). Oocytes are suspended in midprophase of meiosis I from birth until ovulation, in some cases for 50 years. Following completion of meiosis at ovulation, nondisjunction results in one gamete having two copies of the afected chromosome, leading to trisomy if fertilized. he other gamete, receiving no copy of the afected chromosome, will be monosomic if fertilized. It is estimated that 10 to 20 percent of oocytes are aneuploid secondary to meiotic errors, compared with 3 to 4 percent of sperm. lthough each chromosome pair is equally likely to have a segregation error, programs in the United States, 2006-2010, which included live it is rare for trisomies other than 21, 18, or 13 to result in a births, stillbirths, and pregnancy terminations. (Data from Mai, 2013. term pregnancy, and most fetuses with trisomies 18 and 13 die Redrawn with permission from Dashe JS: Aneuploidy screening.


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Obstentrics_Williams. in a births, stillbirths, and pregnancy terminations. (Data from Mai, 2013. term pregnancy, and most fetuses with trisomies 18 and 13 die Redrawn with permission from Dashe JS: Aneuploidy screening. before term. Obstet GynecoIo128(1):181, 2016.) 6 10 11'.13 14 16 19


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Obstentrics_Williams. FIGURE 13-3 Abnormal male karyotype with trisomy 21, consistent with Down syndrome (47,XY,+21). (Used with permission from Dr. Frederick Elder.) Mter a pregnancy with an autosomal trisomy, the risk for any autosomal trisomy in a future pregnancy approximates 1 percent until the woman's age-related risk exceeds this. Accordingly, prenatal diagnosis with chorionic villus sampling or amniocentesis is ofered in these subsequent pregnancies (Chap. 14, p. 292). Parental chromosomal studies are not indicated unless the afected pregnancy was caused by an unbalanced translocation or other structural rearrangement.


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Obstentrics_Williams. Trisomy 21-Down Syndrome. In 1866, ]. L. H. Down described a group of intellectually disabled children with distinctive physical features. Nearly 100 years later, Lejeune (1959) demonstrated that Down syndrome is caused by an autosomal trisomy (Fig. 13-3). Trisomy 21 causes 95 percent of Down syndrome cases, whereas 3 to 4 percent of cases are due to a robertsonian translocation, described later (p. 262). he remaining 1 to 2 percent results from an isochromosome or from mosaicism. he nondisjunction that yields trisomy 21 occurs during meiosis I in approximately 75 percent of cases, and the remaining events are during meiosis II. Down syndrome is the most common nonlethal trisomy.


Obstentrics_Williams

Obstentrics_Williams. Down syndrome is the most common nonlethal trisomy. Its approximate prevalence is 1 in 500 recognized pregnancies. However, fetal losses and pregnancy terminations yield an estimated prevalence of 13.5 in 10,000 births in the United States-1 per 740 (Mai, 2013; Parker, 2010). he fetal death rate beyond 20 weeks' gestation approximates 5 percent (Loane, 2013). Coinciding with the older maternal age distribution during the past four decades, the prevalence of Down syndrome has risen approximately 33 percent (Loane, 2013; Parker, 2010; Shin, 2009). Notably, adult women with Down syndrome are fertile, and a third of their ofspring will have Down syndrome (Scharrer, 1975). Males with Down syndrome are almost always sterile because of markedly reduced spermatogenesis.


Obstentrics_Williams

Obstentrics_Williams. Approximately 30 percent of second-trimester fetuses with Down syndrome have a major malformation that can be identified sonographically (Hussamy, 2017; Vintzileos, 1995). As discussed in Chapter 14 (p. 286), when both major anomalies and minor aneuploidy markers are considered, an estimated 50 to 60 percent of Down syndrome pregnancies can be detected sonographically (American College of Obstetricians and Gynecologists, 2016d). Approximately half of liveborn neonates with Down syndrome are found to have cardiac defects, particularly ventricular septal defects and endocardial cushion defects (Figs. 10-29 and 10-30, p. 202) (Bergstrom, 2016; Freeman, 2008). Gastrointestinal abnormalities are identiied in 12 percent and include esophageal atresia, Hirschsprung disease, and duodenal atresia (Fig. 10-38, p. 207) (Bull, 2011). Characteristic features of Down syndrome are shown in


Obstentrics_Williams

Obstentrics_Williams. Characteristic features of Down syndrome are shown in Figure 13-4. Typical indings include brachycephaly; epicanthaI folds and up-slanting palpebral issures; Brushield spots, which are grayish spots on the periphery of the iris; a lat nasal bridge; and hypotonia. Infants often have loose skin at the nape of the neck, short ingers, a single palmar crease, hypoplasia of the middle phalanx of the fifth finger, and a prominent space or "sandal-toe gap" between the irst and second toes. Some of these indings are prenatal sonographic markers for Down syndrome, reviewed in Chapter 14 (p. 286). Health problems common in children with Down syndrome include hearing loss in 75 percent, severe optical refractive


Obstentrics_Williams

Obstentrics_Williams. Health problems common in children with Down syndrome include hearing loss in 75 percent, severe optical refractive FIGURE 13-4 Trisomy 21-Down syndrome. A. Characteristic facial appearance. B. Redundant nuchal tissue. C. Single transverse palmar crease. (Used with permission from Dr. Charles P. Read and Dr. Lewis Waber.) errors in 50 percent, cataracts in 15 percent, obstructive sleep apnea in 60 percent, thyroid disease in 15 percent, and a higher incidence of leukemia (Bull, 2011). The degree of mental impairment is usually mild to moderate, with an average intelligence quotient (IQ) score of 35 to 70. Social skills in afected children are often higher than predicted by their IQ scores.


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Obstentrics_Williams. Data suggest that approximately 95 percent of liveborn infants with Down syndrome survive the irst year. The 10-year survival rate is at least 90 percent overall and is 99 percent if major malformations are absent (Rankin, 2012; Vendola, 2010). Several organizations ofer education and support for prospective parents faced with prenatal diagnosis of Down syndrome. These include the March of Dimes, National Down Syndrome Congress (ww.ndsccenter.org), and National Down Syndrome Society (ww.ndss.org).


Obstentrics_Williams

Obstentrics_Williams. Trisomy l8-Edwards Syndrome. he association between this constellation of abnormalities and an autosomal trisomy was irst described by Edwards (1960). In population-based series, prevalence of trisomy 18 approximates 1 in 2000 recognized pregnancies-including abortuses, stillbirths, and live births, and approximately 1 in 6600 liveborn neonates (Loane, 2013; Parker, 2010). he diference in prevalence is explained by the high in-utero lethality of the condition and the termination of many afected pregnancies. Perhaps not surprisingly, survival of liveborn neonates is likewise bleak. .10re than half die within the irst week, and the I-year survival rate approximates only 2 percent (Tennant, 2010; Vendola, 2010). The syndrome is three-to fourfold more common in females (Lin, 2006; Rosa, 2011) . Unlike Down and Patau syndromes, which involve acrocentric chromosomes and thus may stem from a robertsonian translocation, Edwards syndrome uncommonly results from a chromosomal rearrangement.


Obstentrics_Williams

Obstentrics_Williams. Virtually every organ system can be afected by trisomy 18. Common major anomalies include heart defects in more than 90 percent-particularly ventricular septal defects, as well as cerebellar vermian agenesis, myelomeningocele, diaphragmatic hernia, omphalocele, imperforate anus, and renal anomalies such as horseshoe kidney (Lin, 2006; Rosa, 2011; Yeo, 2003). Sonographic images of several of these are shown in Chapter 10.


Obstentrics_Williams

Obstentrics_Williams. Sonographic images of several of these are shown in Chapter 10. Cranial and extremity abnormalities are also frequent and include a prominent occiput, posteriorly rotated and malformed ears, micrognathia, clenched hands with overlapping digits, radial aplasia with hyperflexion of the wrists, and rockerbottom or clubbed feet (Fig. 13-5). A "strawberry-shaped" cranium is noted in approximately 40 percent of cases, abnormally wide cavum septum pellucidum in more than 90 percent, and choroid plexus cysts in up to 50 percent (Abele, 2013; Yeo, 2003). Importantly, isolated choroid plexus cysts are not associated with trisomy 18. These cysts only raise the risk for trisomy 18 if fetal structural abnormalities or an abnormal aneuploidy screening test result is also present (Reddy, 2014).


Obstentrics_Williams

Obstentrics_Williams. Pregnancies with trisomy 18 that reach the third trimester often develop fetal-growth restriction, and the mean birthweight is <2500 g (Lin, 2006; Rosa, 201l). Because abnormal fetal heart rate tracings are common during labor, mode of delivery and management of heart rate abnormalities should be discussed in advance. In older reports, more than half of undiagnosed fetuses underwent cesarean delivery for "fetal distress" (Schneider, 1981). Trisomy l3-Patau Syndrome. This constellation of fetal abnormalities and their association with an autosomal trisomy was irst described by Patau and colleagues (1960). The prevalence of trisomy 13 approximates 1 in 12,000 live births and 1 in 5000 recognized pregnancies, which includes abortuses and stillbirths (Loane, 2013; Parker, 2010). As with trisomy 18, trisomy 13 is highly lethal, and most afected fetuses are lost or terminated.


Obstentrics_Williams

Obstentrics_Williams. Approximately 80 percent of pregnancies with Patau syndrome result from trisomy 13. The remainder is caused by a robertsonian translocation involving chromosome 13. The most frequent structural chromosomal rearrangement is a translocation between chromosomes 13 and 14, der(l3; 14) (q 1 O;q 10). This translocation is carried by approximately 1 in 1300 individuals, although the risk of an afected liveborn neonate is less than 2 percent (Nussbaum, 2007). FIGURE 13-5 Trisomy 18-Edwards Syndrome. A. This transventricular sonographic view shows fetal choroid plexus cysts and an angulated "strawberry-shaped" skull. B. Radial clubhand is manifested as a single forearm bone (radius), with the hands in a fixed, hyperflexed position at right angles to the forearms. C. This three-dimensional (3-�) sonographic image shows the characteristic hand position of clenched fists with overlapping digits. D. 3-D sonographic image displays a rockerbottom foot.


Obstentrics_Williams

Obstentrics_Williams. Trisomy 13 is associated with abnormalities of virtually every organ system. One characteristic finding is holoprosencephaly (Fig. 10-15, p. 195). his is present in approximately two thirds of cases and may be accompanied by microcephaly, hypotelorism, and nasal abnormalities that range from a single nostril to a proboscis. Cardiac defects are found in up to 90 percent of fetuses with trisomy 13 (Shipp, 2002). Other abnormalities that suggest trisomy 13 include neural-tube defectsparticularly cephalocele, microphthalmia, cleft lip-palate, omphalocele, cystic renal dysplasia, polydactyly, rockerbottom feet, and areas of skin aplasia (Lin, 2007). For the fetus or newborn with a cephalocele, cystic kidneys, and polydactyly, the diferential diagnosis includes trisomy 13 and the autosomalrecessive Meckel-Gruber syndrome. Sonographic images of several of these are shown in Chapter 10 (p. 192).


Obstentrics_Williams

Obstentrics_Williams. Few fetuses with trisomy 13 survive until birth. Of those that do, the I-week survival rate approximates 40 percent, and I-year survival rate is only about 3 percent (Tennant, 2010; Vendola, 2010). Counseling regarding prenatal diagnosis and management options is similar to that described for trisomy 18. Unlike other aneuploidies, fetal trisomy 13 confers risk to the pregnant woman. Hyperplacentosis and preeclampsia develop in up to half of pregnancies with trisomy 13 carried beyond the second trimester (Tuohy, 1992). Chromosome 13 contains the gene for soluble fms-like tyrosine kinase-1 (sFlt-l), which is an anti angiogenic protein associated with preeclampsia (Chap. 40, p. 716). Investigators have documented overexpression of the slt-1 protein by trisomic 13 placentas and in serum of women with preeclampsia (Bdolah, 2006; Silasi, 2011).


Obstentrics_Williams

Obstentrics_Williams. Other Trisomies. In the absence of mosaicism, discussed later (p. 263), other autosomal trisomies rarely yield a liveborn neonate. Case of live births with trisomy 9 and with trisomy 22 have been noted (Kannan, 2009; Tinkle, 2003). Trisomy 16 is the most common trisomy found with first-trimester losses and accounts for 16 percent of these losses. However, it is not identiied later in gestation. Trisomy 1 has never been reported. Nondisjunction creates an equal number of nullisomic and disomic gametes. As a rule, missing chromosomal material is more devastating than extra chromosomal material, and almost all monosomic conceptuses are lost before implantation. he one exception is monosomy for the X chromosome (45,X), Turner syndrome, which is discussed subsequently. Despite the strong association between maternal age and trisomy, maternal age and monosomy are not linked.


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Obstentrics_Williams. This is an abnormal number of complete haploid chromosomal sets. Polyploidy accounts for approximately 20 percent of spon taneous abortions but is rare in later gestations.


Obstentrics_Williams

Obstentrics_Williams. Triploid pregnancies have three haploid sets-69 chromosomes. One parent must contribute two sets, and the phenotypic presentation difers according to the parent of origin. With diandric triploidy, also known as type I triploidy, the extra chromosomal set is paternal, resulting from fertilization of one egg by two sperm or by a single diploid-and thus abnormal-sperm. Diandric triploidy produces a partial molar pregnancy, discussed in Chapter 20 (p. 389). Diandric triploidy accounts for most triploid conceptions, but their first-trimester loss rate is extremely high. As a result, two thirds of triploid pregnancies identified beyond the first trimester are caused instead by diynic triploidy Q auniaux, 1999). With a digynic triploid pregnancy, also known as type II triploidy, the extra chromosomal set is maternal, and the egg fails to undergo the irst or second meiotic division before fertilization. Digynic triploid placentas do not develop molar changes. However, the fetus usually


Obstentrics_Williams

Obstentrics_Williams. chromosomal set is maternal, and the egg fails to undergo the irst or second meiotic division before fertilization. Digynic triploid placentas do not develop molar changes. However, the fetus usually displays asymmetrical growth restriction.


Obstentrics_Williams

Obstentrics_Williams. he prevalence of recognized triploid pregnancies approximates 1 in 5000 pregnancies (Zalel, 2016). Triploidy is a lethal aneuploidy, and more than 90 percent of fetuses with either the diandric or digynic form have multiple structural anomalies. hese include central nervous system defects-particularly involving the posterior fossa, as well as cardiac, renal, and extremity anomalies Qauniaux, 1999; Zalel, 2016). Counseling, prenatal diagnosis, and delivery options are similar to those for trisomies 18 and 13. he recurrence risk for a woman whose triploid fetus survived past the first trimester is 1 to 1.5 percent, and thus prenatal diagnosis is ofered in future pregnancies (Gardner, 1996). Tetraploid pregnancies have four haploid sets of chromosomes, resulting in either 92,XXor 92,YY. This suggests a postzygotic failure to complete an early cleavage division. The conceptus invariably succumbs, and the recurrence risk is minimal.


Obstentrics_Williams

Obstentrics_Williams. 45, X-Turner Syndrome. First described by Turner (1938), this syndrome later was found to be caused by monosomy X (Ford, 1959). he prevalence of Turner syndrome is approximately 1 in 2500 liveborn girls (Cragan, 2009; Dolk, 2010). The missing X chromosome is paternally derived in 80 percent of cases (Cockwell, 1991; Hassold, 1990). Screening for Turner syndrome with cell-free DNA is discussed in Chapter 14 (p. 284). Turner syndrome is the only monosomy compatible with life, but it is also the most common aneuploidy in first-trimester losses, accounting for 20 percent. his is explained by the wide range in phenotype. Approximately 98 percent of afected conceptuses are so abnormal that they abort early in the first trimester. Of the remainder, many manifest large, septated cystic hygromas in the late irst or early second trimester (Fig. 10-22, p. 198). When cystic hygromas are accompanied by hydrops fetalis, fetuses nearly always die in utero (Chap 15, p. 309).


Obstentrics_Williams

Obstentrics_Williams. Less than 1 percent of pregnancies with Turner syndrome yield a liveborn neonate. And, only half of these actually have monosomy X. Approximately a fourth have mosaicism, such as 45,X/46,XX or 45,Xl46,XY, and another 15 percent have isochromosome X, that is, 46,X,i(Xq) (Milunsky, 2004; Nuss baum, 2007).


Obstentrics_Williams

Obstentrics_Williams. Abnormalities associated with Turner syndrome include left sided cardiac defects-such as coarctation of the aorta, hypo plastic left heart syndrome, or bicuspid aortic valve-in 30 to 50 percent; renal anomalies, particularly horseshoe kidney; and hypothyroidism. Other features are short stature, broad chest with widely spaced nipples, congenital lymphedema-pui ness over the dorsum of hands and feet, and a "webbed" pos terior neck resulting from cystic hygromas. Intelligence scores are generally in the normal range, but afected individuals are at risk for diiculties with visual-spatial organization, nonver bal problem solving, and interpretation of social cues Q ones, 2006). Growth hormone is typically administered in childhood to ameliorate short stature (Kappelgaard, 201i1). More than 90 starting just before adolescence. An exception is mosaicism involving the Y chromosome, as this confers risk for germ cell neoplasm-regardless of whether the child is phenotypically male or female.


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Obstentrics_Williams. starting just before adolescence. An exception is mosaicism involving the Y chromosome, as this confers risk for germ cell neoplasm-regardless of whether the child is phenotypically male or female. Accordingly, eventual prophylactic bilateral gonadectomy is indicated (Cools, 2011; Schorge, 2016).