Chapter 8. Teratology, teratogens and Fetotoxic agents
BS. Nguyễn Hồng Anh
Birth deects are common. O all newborns, 2 to 3 percent have a major congenital abnormality detectable at birth (Cragan, 2009; Dolk, 2010). Some medications undoubtedly pose signicant risk to the developing embryo or etus (Table 8-1). However, 80 percent o birth deects do not have an obvious etiology, and o those with an identied cause, nearly 95 percent o cases have chromosomal or genetic origins (Feldkamp, 2017). Te U.S. Food and Drug Administration (FDA) (2018) estimates that <1 percent o all birth deects are caused by medications (Fig. 8-1).
Tat said, signicant concern surrounds medication use in pregnancy. This is because many pregnant women are prescribed medications and because saety data are oten lacking. Investigators rom the National Birth Deects Prevention Study ound that women take an average o two to three medications per pregnancy and that 70 percent use medication in the rst trimester (Mitchell, 2011). A population-based review rom Canada ound that 65 percent o women ll ≥1 prescription during pregnancy (Leong, 2019). Between 2010 and 2019, the FDA approved 290 new drugs, and only 11 percent had human data related to pregnancy (Byrne, 2020).
TERATOLOGY
Te study o birth deects and their etiology is termed teratology, derived rom the Greek teratos, meaning monster. A teratogen may be broadly dened as any agent that acts during embryonic or etal development to produce a permanent alteration o orm or unction. Tus, a teratogen may be a medication or other chemical substance, a physical or environmental actor such as heat or radiation, a maternal metabolite as in diabetes or phenylketonuria, or an inection such as cytomegalovirus.
■ Criteria for Determining
Teratogenicity
Te guidelines shown in Table 8-2 were proposed by Shepard (1994) as a ramework or discussion and have proved useul or nearly 30 years. Although each individual criterion is not required to establish teratogenicity, the ollowing tenets should be considered (Shepard, 2002a):
• e abnormality has been completely characterized. is is preerably done by a geneticist or dysmorphologist because dierent genetic and environmental actors may produce similar deects. It is easiest to prove causation when a rare exposure produces a rare anomaly, when at least three cases with the same exposure have been identied, and when the deect is severe.
• e agent must cross the placenta. Although almost all drugs cross the placenta, transport must be o sucient quantity to directly infuence embryonic or etal development or to alter maternal or placental metabolism to exert an indirect eect.
Placental transer depends on maternal metabolism; on specic characteristics o the drug, such as protein binding and storage, molecular size, electrical charge, and lipid solubility; and on placental metabolism, such as by the cytochrome P450 enzyme system. In early pregnancy, the placenta also has a relatively thick membrane that slows diusion.
• Exposure must occur during a critical developmental period.
Te preimplantation 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 o cells typically causes embryonic death. However, i only a ew cells are injured, compensation may be possible and allow normal development.
Te embryonic period extends rom the second through the eighth week postconception. It encompasses organogenesis and is thus the most crucial period with regard to structural malormations. Critical developmental periods or each organ system are illustrated in Figure 7-2 (p. 122). Te fetal period, which is beyond 8 weeks postconception, is characterized by continued maturation and functional
TABLE 8-2. Criteria for Determining Teratogenicity
FIGURE 8-1 Etiology of birth defects. Known and unknown causes of 5504 birth defects from a population-based review of 270,878 births. development. During this time, certain organs remain vulnerable.
• A biologically plausible association is supportive. Because birth deects and medication exposures are both common, they may be temporally but not causally related.
• Epidemiological ndings must be consistent. Because initial evaluation o teratogen exposure is oten retrospective, it may be hampered by recall bias, inadequate reporting, and146 Preconceptional and Prenatal Care
Section 4 incomplete assessment o the exposed population. Potential conounding actors include varying dosages, concomitant drug therapy, and comorbid maternal disease(s). Familial and environmental variables also can infuence development o birth deects. Tus, an important criterion or teratogenicity is that two or more high-quality epidemiological studies report similar ndings. Last, a relative risk o 3.0 or greater is generally considered necessary to support the hypothesis, whereas a lesser risk is interpreted with caution (Khoury, 1992).
• e suspected teratogen causes a defect in animal studies. Tis criterion is not obligatory, and or litigation purposes, establishment o a causal relationship between an exposure and an outcome in humans requires human data (eratology Society Public Aairs Committee, 2005).
Failure to employ these tenets and criteria has contributed to erroneous conclusions regarding the saety o some widely used drugs. Te poster child or this is the medicolegal asco surrounding Bendectin. Tis antiemetic was a combination o doxylamine and pyridoxine, with or without dicyclomine.
More than 30 million women used this drug worldwide, and it was sae and eective or nausea and vomiting in early pregnancy. Te 3-percent congenital anomaly rate among exposed etuses was not dierent rom the background rate (McKeigue, 1994). Despite considerable evidence that this combination o an antihistamine and a B-vitamin is not teratogenic, Bendectin was the target o numerous lawsuits, and the nancial burden o deending these orced its withdrawal rom the marketplace in 1983. Consequently, hospitalization rates for hyperemesis doubled (Koren, 1998). Ironically, the combination o doxylamine and pyridoxine was subsequently remarketed under the brand name Diclegis and was approved by the FDA in 2013.
■ Studies in Pregnant Women
Te study o medication saety—or teratogenicity—in pregnant women is raught with complications. First, animal studies are necessary but insucient. For example, thalidomide was considered harmless in several 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 or a pregnancy-related indication. Despite the Common Rule’s removal o pregnant women as a vulnerable population, pregnant women are routinely excluded rom research (Health and Human Services, 2017; Spong, 2018). Last, drug concentration and thus embryo-etal exposure are aected by pregnancy physiology. Tis includes changes in volume o distribution, cardiac output, gastrointestinal absorption, hepatic metabolism, and renal clearance.
In the absence o research trials, counseling is based on case reports or series, case-control studies, cohort studies, and pregnancy registry data.
Case Reports and Series
Many major teratogens were rst described by clinicians who observed a rare deect occurring ater a rare exposure. Tis has been termed the “astute clinician model” (Carey, 2009). Congenital rubella syndrome was identied 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 identied through case series include thalidomide and alcohol (Jones, 1973; Lenz, 1962). Shepard (2002a) recommended that establishment o teratogenicity in this way requires proven exposure at a critical time in development and at least three such cases. Unortunately, teratogens are less likely to be identied i the exposure is uncommon, i the deects are relatively nonspecic, or i abnormalities develop in only a small proportion o exposed etuses. A major limitation o case series is their lack o a control group.
Case-control Studies
Tese studies begin with groups o aected inants (cases) and unaected controls and are structured to allow retrospective assessment o prenatal exposure to particular substances. Casecontrol studies are an ecient way to study rare outcomes (Alwan, 2015). Tese permit investigators to evaluate associations and generate useul hypotheses. However, case-control studies have inherent potential or recall bias. Namely, parents o an aected inant are oten more likely to recall exposure than those whose child is not ill. Conounding by indication is another concern, that is, the indication or the medication may be the cause o the birth deect. And importantly, birth deect registries have statistical power to detect small dierences that may not be clinically meaningful. Grimes and Schulz (2012) have cautioned that unless odds ratios in case-control studies are above three- to ourold, the observed associations may not be correct.
The National Birth Defects Prevention Study. Funded by Congress and coordinated by the National Center on Birth Deects and Developmental Disabilities, the National Birth Deects Prevention Study (NBDPS) took place between 1997 and 2013 across ten states with active birth deects surveillance programs. It is an excellent example o a population-based casecontrol study. Te study involved approximately 32,000 cases and nearly 12,000 controls. Live births, stillbirths, and terminated pregnancies were included. Clinical geneticists reviewed each potential case, and standardized telephone interviews were conducted with women whose pregnancies were aected or unaected to obtain inormation regarding medication exposure and risk actors (Mitchell, 2011; Reehuis, 2015).
Te NBDPS identied novel—although oten small—associations between individual birth deects and several classes o medications. Tese include antibiotics, antidepressants, antiemetics, antihypertensives, asthma medications, nonsteroidal antiinfammatory drugs (NSAIDs), and opioids (Ailes, 2016; Broussard, 2011; Fisher, 2018; Hernandez, 2012; Lin, 2012; Munsie, 2011). Pregestational diabetes was signicantly associated with 46 o 50 dierent abnormalities studied (inker, 2020). Te NBDPS also ound associations between birth deects and exposures such as secondhand smoke, pesticides, and nitrogen oxide, which is a marker o trac-related air pollution (Hoyt, 2016; Rocheleau, 2015; Stingone, 2017).
Te NBDPS had several key limitations related to study design. First, interviews were conducted 6 weeks to 2 years ollowing delivery, which raised the likelihood o recall bias. For example, 25 percent o women could not remember which antibiotic they had taken (Ailes, 2016). Additionally, only two thirds o women agreed to participate, and there were dierences in ethnicity and socioeconomic status between cases and controls. Tese actors may have contributed to selection bias (Reehuis, 2015). Further, medical records were not reviewed to veriy dosage, and this precluded assessment o dose-response relationships. Last, a major limitation was that because the NBDPS included only a small number o cases o each birth defect and analyzed them for many dierent maternal exposures, it was not possible to adjust or multiple comparisons. As a result, some o the observed associations were likely due to chance (Alwan, 2015). As one example, the study o antibiotics and birth deects included 43 comparisons and identied our signicant associations, but chance alone predicted that two associations would be identied (Ailes, 2016).
Importantly, the NBDPS was able to identiy statistically signicant odds ratios or which the absolute risk was quite low. Such ndings have the potential to complicate counseling and prenatal management. In many instances, the risk identied by the NBDPS was as low as 1 case per 1000 exposed pregnancies.
Cohort Studies
Tese studies begin with cohorts o pregnant women who are exposed or unexposed to a particular medication. Te percentage o inants or children aected with birth deects is examined in each cohort. Because individual birth deects are rare, cohort studies require a very 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 or conounding variables— such as the indication or which the medication was needed—is an important limitation o this study design.
Pregnancy Registries
Potentially harmul agents may be monitored by clinicians who prospectively enroll exposed pregnancies in a registry. Te FDA (2021) maintains an active webpage of Pregnancy Exposure Registries. As o 2021, this included registries or 115 individual medications and or medication groups used to treat asthma, attention decit hyperactivity disorder, autoimmune diseases, cancer, diabetes, epilepsy, hepatitis B and C, human immunodeciency virus inection, hypercholesterolemia, inborn errors o metabolism, infammatory bowel disease, multiple sclerosis, narcolepsy, psychiatric illness, and transplant rejection. Similar to case series, exposure registries are hampered by lack o a control group. Te prevalence o an abnormality identied through a registry requires knowledge o the baseline prevalence o that anomaly in the population. Investigators typically use a birth deect registry to assess population prevalence. One example is the Metropolitan Atlanta Congenital Deects Program, which is an active surveillance program established in 1967 or etuses and inants with birth deects.
COUNSELING FOR MEDICATION EXPOSURE
Questions regarding medication and illicit drug use should be part o routine preconceptional and prenatal care. Misinormation is common. Individuals tend to underestimate the background risk or birth deects in the general population and exaggerate potential risks associated with medication exposure. In one population-based study o more than 270,000 births rom Utah that included 5500 etuses and inants with major birth deects, only 4 cases were attributed to medication exposure (see Fig. 8-1) (Feldkamp, 2017). And yet, Koren and colleagues (1989) reported that a ourth o women exposed to nonteratogenic drugs thought they had a 25-percent risk or etal anomalies. Misinormation may be amplied by inaccurate reports in the lay press. Knowledgeable counseling may allay anxiety considerably and may even avert pregnancy termination.
Several sources are available to assist providers with accurate and updated risk inormation. With recent changes to the FDA labeling requirements, discussed next, the manuacturer’s prescribing inormation has become increasingly helpul. We recommend using this content or initial counseling. Published research studies can be identied using PubMed, a ree database tool rom the National Center or Biomedical Inormation. Additionally, online databases such as Reprotox, TERIS, and Shepard’s Online Catalog o eratogenic Agents oer detailed reviews o medication risks. Lactmed, a database rom the National Library o Medicine, specically deals with medication use by breasteeding women. Its entries on specic medications describe levels in breast milk and potential eects on the inant.
Ultimately, it is the responsibility o the clinician to interpret risk inormation. Medication dosage and route, timing o exposure during pregnancy, other medications used, and underlying medical condition(s) are considered in this analysis. Last, the risk rom lack o treatment also is weighed.
■ Labeling Requirements
In 1979, the FDA developed a letter classication system (A, B, C, D, X) to provide therapeutic guidance or prescribing medications in pregnancy. Tese letter categories were intended to simpliy risk-benet data using summary statements regarding available evidence rom human or animal studies o embryonic–etal risk. Unortunately, inormation regarding medication risk was oten incomplete and led to an overreliance on the category denition. o address these deciencies, new FDA (2014, 2020b) labeling requirements were created and went into eect in 2015. Te label provides a ramework to aid prescribing decisions by more clearly communicating risks and benets. Inormation about each medication now incorporates a detailed summary o risks, clinical considerations, and available data (Table 8-3). Registry inormation is included when available. For each medication, a lactation subsection is provided, and a section addressing potential risks in emales and males o reproductive potential is presented. In addition to risks associated with specic medications, the label is required to include the background risk o major birth deects and miscarriage in the general population. Because o the level o detail in the new labels, the inormation can be indispensable or counseling.
■ Presenting Risk Information
Counseling should cover not only the embryonic and etal risks rom drug exposure, but also the risks and/or genetic implications o the condition or which the drug is administered. Risks associated with not treating the condition also are described. Even the manner in which information is presented aects perception. For example, women given negative inormation—such as a 2-percent chance o a malormed newborn—are more likely to perceive an exaggerated risk than women given positive inormation—such as a 98-percent chance o an unaected inant (Jasper, 2001). Instead o citing a higher odds ratio, it may be helpul to provide the absolute risk or a particular deect or the attributable risk, which is the dierence between prevalence in exposed and unexposed individuals (Conover, 2011). Te association between oral corticosteroid medications and clet lip sounds ar more concerning when presented as a tripling or 200-percent increase in risk than when described as an increase rom 1 to 3 cases per 1000 or as a 99.7-percent likelihood o no clet development ollowing exposure.
With a ew notable exceptions, most commonly prescribed drugs and medications can be used with relative saety during pregnancy. Many drugs discussed in this chapter are lowrisk teratogens, which are medications that produce deects in ewer than 10 per 1000 maternal exposures (Shepard, 2002a). Because risks conerred by low-risk teratogens are so close to the population background rate o etal anomalies, they may not be a major actor in deciding whether to discontinue treatment or an important condition (Shepard, 2002b). All women have an approximate 3-percent chance o having a etus or newborn with a major anomaly. Although exposure to a conrmed teratogen may elevate this risk, the magnitude o the increase is usually only 1 or 2 percent or at most, doubled or tripled. Te concept o risk versus benet is oten central to counseling. Some untreated diseases pose a more serious threat to both mother and etus than medication exposure risks.
TERATOGENIC AND FETOTOXIC AGENTS
Considering the thousands o compounds available, relatively ew medications and other substances are considered to be major human teratogens or to have signicant etotoxicity. Te most common examples are listed in able 8-1. With ew 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. Detailed sonography is generally indicated i the etus has been exposed to any major teratogen during the embryonic period.
■ Alcohol
Ethanol is a potent and prevalent teratogen. It is considered the leading cause o preventable developmental disabilities
TABLE 8-3. Food and Drug Administration Pregnancy Labeling Requirements Label Subsection Categories Selected Specific Content
In the United States, alcohol use is reported by 10 percent of pregnant women (England, 2020).Nearly 10 percent o such women admit to binge drinking in the rst trimester, and 1 percent report binge drinking in the second and third trimesters. e fetal eects of alcohol abuse have been recognizedsince the 1800s. Lemoine (1968) and Jones (1973) and their coworkers are credited with describing the spectrum o alcoholrelated etal deects known as fetal alcohol syndrome. Criteria are shown in Table 8-4 (Hoyme, 2016). For every child with the syndrome, many more are born with neurobehavioral decits rom alcohol exposure. Fetal alcohol spectrum disorder (FASD) is an umbrella term that includes ve conditions attributed to prenatal alcohol damage: (1) etal alcohol syndrome, (2) partial etal alcohol syndrome, (3) alcohol-related birth deects, (4) alcohol-related neurodevelopmental disorder, and (5) neurobehavioral disorder associated with prenatal alcohol exposure (Williams, 2015). Te prevalence o FASD exceeds 1 percent in 76 countries, and 1 in 13 women who consume alcohol in pregnancy has a child with FASD (Lange, 2017). Te birth prevalence o etal alcohol syndrome is estimated to be as high as 1 percent in the United States (Centers or Disease Control, 2015; Guerri, 2009). Further, studies o school-aged children have identied FASD in 2 to 5 percent (May, 2009, 2014).
Criteria
Fetal alcohol syndrome has specic criteria (see able 8-4). Tese include central nervous system (CNS) abnormalities, pre- or postnatal growth impairment, and a characteristic pattern o minor acial abnormalities (Fig. 8-2). Similar criteria have been established or the other conditions that make up FASD (Hoyme, 2016). Prenatal alcohol exposure criteria also are available to assist with assessment.
Alcohol-related birth deects include cardiac and renal anomalies, orthopedic problems, and abnormalities o the eyes and ears (see able 8-4). An association has urther been reported between periconceptional alcohol use and omphalocele and gastroschisis (Richardson, 2011). Tere are no established sonographic criteria or prenatal diagnosis o etal alcohol syndrome. At Parkland Hospital, we reserve detailed sonography or pregnancies that have met the exposure criteria listed in able 8-4. Tird-trimester assessment o etal growth also should be considered.
Fetal vulnerability to alcohol is modied by genetic and environmental actors, nutritional status, coexisting maternal disease, and maternal age (Abel, 1995). Binge drinking, however, is believed to pose particularly high risk or alcohol-related birth
TABLE 8-4. Criteria for Prenatal Alcohol Exposure, Fetal Alcohol Syndrome, and Alcohol-Related Birth Defects
FIGURE 8-2 Fetal alcohol syndrome. A. At 2½ 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 10-year follow-up of eleven patients, Lancet. 1985 Jul 13;2(8446):85–91.)
deects and has also been linked to a greater risk or stillbirth (Centers or Disease Control, 2015; Strandberg-Larsen, 2008).
Te American College o Obstetricians and Gynecologists, Centers or Disease Control and Prevention (CDC), and the American Academy o Pediatrics have stressed that no amount o alcohol can be considered sae in pregnancy (American College o Obstetricians and Gynecologists, 2020a; Williams, 2015).
■ Antiepileptic Medications
raditionally, women with epilepsy requiring treatment with medication were inormed that their risk or etal malormations was increased. More recent data suggest that the risk may not be as great as once thought, particularly or newer agents. Te most requently reported anomalies are oroacial clets, cardiac malormations, and neural-tube deects.
O agents in current use, valproic acid coners the highest risk (Vajda, 2016). Te North American Antiepileptic Drug (NAAED) Pregnancy Registry reported that major malformations developed in 9 percent o etuses with rst-trimester valproate exposure. Tis included a 4-percent risk or neural-tube defects (Hernandez-Diaz, 2012). School-aged children with prior in utero exposure to valproic acid have poorer cognitive development—including signicantly lower intelligence quotient (IQ) scores—than children exposed to other antiepileptic drugs (Bromley, 2014; Meador, 2009).
Regarding other specic anticonvulsants, one metaanalysis identied increased malormation rates among exposed children compared with rates among children born to women with untreated epilepsy. Rates were twoold higher among children exposed to carbamazepine or phenytoin, threefold higher among those exposed to phenobarbital, and ourold higher among those exposed to topiramate as monotherapy (Weston, 2016). Te risk or etal malormations is approximately doubled i multiple agents are required (Vajda, 2016). Several older anticonvulsants may produce a constellation o ndings similar to the fetal hydantoin syndrome. e syndrome is characterized by distinctive eatures such as hypertelorism, low nasal bridge, and midace hypoplasia; hypoplasia o the distal phalanges and nails; growth impairment; and intellectual disability.
Importantly, evidence to date suggests that these risks do not appear to hold or the newer agents levetiracetam and lamotrigine (Mølgaard-Nielsen, 2011; Weston, 2016). A review o 208 pregnancies with rst-trimester lamotrigine exposure rom the Israeli eratology Inormation Service ound no increase in the rate o major malormations and no case o oral clet (DiavCitrin, 2017). Similarly, the International Lamotrigine Pregnancy Registry ollowed more than 1500 pregnancies with rst trimester exposure and observed no eect on the rate o major malormations (Cunnington, 2011). Te Motherisk Program reviewed eight studies o levetiracetam and concluded that monotherapy was associated with a 2-percent major malormation rate, no dierent rom that or the general population (Chaudhry, 2014). More recently, a review o 465 pregnancies reported to the Levetiracetam Pregnancy Registry ound no evidence o teratogenicity (Scheuerle, 2019).
Providers are encouraged to enroll pregnant women treated with antiepileptic medication in the NAAED Pregnancy Registry. Management o epilepsy in pregnancy is discussed in Chapter 63 (p. 1128).
■ Angiotensinconverting Enzyme Inhibitors and Receptor Blocking Drugs
Tese medications may result in angiotensin-converting enzyme (ACE)-inhibitor fetopathy. Normal renal development depends on the fetal renin-angiotensin system. ACE-inhibitor medication may cause etal hypotension and renal hypoperusion, with subsequent ischemia and anuria (Guron, 2000; Pryde, 1993). Reduced perusion can result in etal-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 o action, concerns regarding etotoxicity have been generalized to include this entire medication class. A recent review o nearly 200 pregnancies rom teratology inormation services ound a 30-percent etopathy risk with angiotensin-receptor blockers compared with a 3-percent risk with ACE-inhibitor exposure beyond 20 weeks’ gestation (Weber-Schoendorer, 2020).
Concerns about ACE-inhibitor embryotoxicity have largely been disproven. In 2006, a review o 29,000 inants rom the ennessee Medicaid database identied a two- to threeold greater risk or neonatal cardiac and CNS abnormalities among the 209 that had prenatal ACE-inhibitor exposure (Cooper, 2006). Subsequent larger studies have not corroborated these observations. In a retrospective cohort study o more than 460,000 pregnancies, risks or birth deects were not higher with ACE inhibitors than with other antihypertensive medications (Li, 2011). Similarly, a review o 1.3 million pregnancies rom the Medicaid Analytic eXtract ound no increased risk for any malformation with ACE-inhibitor exposure after adjusting or conounding actors such as diabetes (Bateman, 2017). Tus, women with inadvertent rst-trimester exposure to these medications may be reassured. Importantly, given the many therapeutic options or treating hypertension during pregnancy, discussed in Chapter 53 (p. 949), ACE inhibitors and angiotensin receptor-blocking drugs should be avoided in pregnancy.
■ Antifungal Medications
From this class of drugs, uconazole has been associated with a pattern o congenital malormations resembling the autosomal recessive Antley-Bixler syndrome. Abnormalities include oral clets, abnormal acies, and cardiac, skull, long-bone, and joint abnormalities. Such ndings have been reported only with chronic, rst-trimester, high-dose treatment at doses o 400 to 800 mg daily.
Regarding low-dose treatment o vulvovaginal candidiasis, the Motherisk Program conducted a systematic review o pregnancies with rst-trimester oral uconazole exposure of 150 or 300 mg in total (Alsaad, 2015). Te overall risk or birth deects was not greater, although a small increase in rates o cardiac malormations could not be excluded. A populationbased cohort study rom Denmark identied a threeold greater risk or tetralogy o Fallot ollowing exposure to low-dose fuconazole (Mølgaard-Nielsen, 2013). e birth prevalence of tetralogy o Fallot rose rom 3 to 10 cases per 10,000. Notably, investigators did not identiy increased risks or 14 other birth defects previously associated with exposure to high-dose azole antiungal agents (Mølgaard-Nielsen, 2013). A subsequent review o more than 37,000 pregnancies with rst-trimester fuconazole exposure did not identify an association with cardiac abnormalities (Zhu, 2020). Based on reported risks, we do not perorm detailed sonography or etal echocardiography ollowing low-dose uconazole exposure.
■ Antiinflammatory Agents
Nonsteroidal Antiinflammatory Drugs
Tis drug class includes both aspirin and traditional NSAIDs such as ibuproen and indomethacin. Tey exert their eects by inhibiting prostaglandin synthesis. In a report rom the NBDPS, at least 20 percent o pregnant women recall rst-trimester NSAID use, particularly ibuproen and aspirin, and such exposure is not a major risk factor for birth defects (Hernandez, 2012).
When taken in late pregnancy, however, indomethacin may cause constriction o the etal ductus arteriosus and subsequent pulmonary hypertension. Fetal ductal constriction is more likely with third trimester use that exceeds 72 hours. Te drug also may decrease etal urine production and amnionic fuid volume (Rasanen, 1995; van der Heijden, 1994; Walker, 1994). In one systematic review, indomethacin tocolysis was associated with a 1.5-old risk or bronchopulmonary dysplasia, intraventricular hemorrhage, and necrotizing enterocolitis (Hammers, 2015a,b).
Based on a review o 35 cases o oligohydramnios or neonatal kidney problems reported to the FDA Adverse Event Reporting System database, the FDA recommends that pregnant women ≥20 weeks’ gestation avoid NSAID use (Food and Drug Administration, 2020a). I NSAIDs are needed or more than 48 hours, ultrasound evaluation o amnionic fuid should be considered. Oligohydramnios usually resolves within 6 days o discontinuing NSAIDs, but there are cases in which inants have died o renal ailure.
With aspirin, a low dosage o 100 mg daily or less does not coner a greater risk or constriction o the ductus arteriosus or or adverse inant outcomes (Grab, 2000). As with other NSAIDs, however, high-dose aspirin use should be avoided, particularly in the third trimester.
Leflunomide
Tis is a pyrimidine-synthesis inhibitor used to treat rheumatoid arthritis. Lefunomide is considered contraindicated in pregnancy. In rats and rabbits, lefunomide results in hydrocephalus, eye anomalies, skeletal anomalies, and embryo death when given at or below human-equivalent doses (Sano-Aventis, 2016). Te active metabolite, terifunomide, is detectable in plasma or up to 2 years ollowing discontinuation o the medication. Women who become pregnant while taking lefunomide, and even those o childbearing potential who have discontinued it, are recommended to undergo an accelerated drug elimination procedure with either cholestyramine or activated charcoal (Sano-Aventis, 2016). Reassuringly, studies o exposed human pregnancies have not conrmed these teratogenic eects (Berard, 2018; Chambers, 2010). In a cohort o 60 women with rst-trimester lefunomide exposure who completed cholestyramine washout, the rate o birth deects was not increased (Chambers, 2010).
A recent review o more than 500 exposed pregnancies ound that the rate o major birth deects was 3 percent, similar to the general population (Henson, 2020). Te rate o spontaneous abortion also was not increased.
■ Antimicrobial and Antiviral Drugs
Medications used to treat inections are among those most requently administered during pregnancy. Over the years, experience has accrued regarding their general saety. With ew exceptions, commonly used antimicrobial agents are without embryo-etal saety concerns.
Nitrofurantoin
From NBDPS results, rst-trimester nitrourantoin exposure is linked to a twoold risk or clet lip (Ailes, 2016). Considering that the birth prevalence o clets approximates 1 case per 1000, the likelihood that a nitrourantoin-exposed etus would not have a clet would thus be 998 per 1000. For other birth deects, initial associations with this antibiotic did not persist in the nal NBDPS cohort (Ailes, 2016).
In one systematic review o nitrourantoin exposure in pregnancy, results o cohort and case-control studies diered (Goldberg, 2015). Five cohort studies included 9275 exposed pregnancies and nearly 1.5 million unexposed pregnancies, and the review ound no higher risk or any malormation. However, among three case-control studies that had nearly 40,000 cases matched with 130,000 controls, the rate o hypoplastic let heart syndrome was threeold greater (Goldberg, 2015). For context, this increase in risk would result in a birth prevalence o ewer than 1 case per 1000 exposed inants. Nitrourantoin is considered contraindicated in pregnant women with known or suspected glucose-6-phosphate dehydrogenase (G6PD) de- ciency because o risk or hemolytic anemia and other hematologic abnormalities. In the absence o G6PD deciency, the Tere are no concerns with second- or third-trimester nitrourantoin use, and rst-trimester use is appropriate i no suitable alternatives are available.
Sulfonamides
Tese drugs are oten combined with trimethoprim and used to treat inections during pregnancy. One indication is treatment o methicillin-resistant Staphylococcus aureus (MRSA) inection. Te NBDPS, which included 107 pregnancies with periconceptional trimethoprim-sulfamethoxazole exposure and birth deects, identied a veold greater risk to have ospring with esophageal atresia or diaphragmatic hernia (Ailes, 2016). Similar to ndings with nitrourantoin exposure, this degree o increase would coner a risk o approximately 1 case per 1000 exposed inants or these selected birth deects. However, these ndings have not been corroborated by other reports. One review rom the Medication Exposure in Pregnancy Risk Evaluation Program included more than 7500 inants with rst-trimester exposure to trimethoprim-sulfamethoxazole (Hansen, 2016). Compared with either unexposed inants or those exposed to penicillins or cephalosporins, no higher risk or any congenital abnormality was identied. Given this reassuring data, we consider sulonamides appropriate or rst-trimester use i suitable alternatives are lacking.
Sulonamides are considered contraindicated in pregnant women with known or suspected G6PD deciency because o risk or hemolytic anemia and other hematologic abnormalities. Additionally, sulonamides displace bilirubin rom proteinbinding sites. Tus, i given near the time o preterm delivery, these agents theoretically might worsen neonatal hyperbilirubinemia. However, a population-based review o more than 800,000 births rom Denmark ound no association between exposure to sulfamethoxazole in late pregnancy and neonatal jaundice (Klarskov, 2013).
Tetracyclines
Tese drugs are not commonly used in pregnant women. Tey have been associated with yellowish-brown discoloration o the deciduous teeth when used ater 25 weeks’ gestation. Te risk or subsequent dental caries is not increased (Billings, 2004; Kutscher, 1966). Doxycycline has a reduced ability to chelate calcium orthophosphate compared with other tetracyclines and is preerred i needed. A systematic review o doxycyclineexposed pregnancies identied no higher rates o either birth deects or staining o deciduous teeth (Cross, 2016).
Ribavirin
Tis antiviral nucleoside analogue is a component o therapy or hepatitis C inection, discussed in Chapter 58 (p. 1038). Ribavirin causes birth deects in multiple animal species at doses signi- cantly lower than those recommended or human use. Reported malormations include skull, palate, eye, skeleton, and gastrointestinal abnormalities. Te drug has a hal-lie o 12 days and persists in extravascular compartments ollowing therapy discontinuation. reated women must use two orms o contraception and have monthly pregnancy tests while on therapy and or 6 months ollowing drug discontinuation (Merck, 2020). Ribavirin use is also contraindicated in men whose partners are pregnant.
■ Antineoplastic Agents
Cancer management in pregnancy includes many chemotherapeutic agents generally considered to be at least potentially toxic to the embryo, etus, or both. For the many novel polyclonal antibody therapies designated as antineoplastics, there is little inormation concerning saety. Te National oxicology Program (2013) conducted a review o 300 pregnancies with rst-trimester exposure and identied major malormations in 14 percent. reatment o cancer in pregnancy is discussed in Chapter 66 (p. 1163). Risks associated with selected agents or which experience in pregnancy has accrued are considered next.
Cyclophosphamide
Tis alkylating agent inficts a chemical insult on developing etal tissues and leads to cell death and heritable DNA alterations in surviving cells. Pregnancy loss rates are greater, and reported etal abnormalities include skeletal anomalies, limb deects, clet palate, and eye abnormalities (Enns, 1999; Kirshon, 1988). e risk or a major abnormality is estimated to be 18 percent (National oxicology Program, 2013). Surviving inants may have growth abnormalities and developmental delays. Environmental exposure among health-care workers is associated with a higher risk or spontaneous abortion.
Methotrexate
Tis olic-acid antagonist is a potent teratogen. It is used or cancer chemotherapy, immunosuppression o autoimmune diseases and psoriasis, nonsurgical treatment o ectopic pregnancy, and medical abortion. It acts similarly to aminopterin, which is no longer used clinically, and can cause deects known collectively as the etal methotrexate-aminopterin syndrome. Associated cranioacial abnormalities include craniosynostosis with a “clover-lea” skull, wide nasal bridge, low-set ears, and micrognathia (Del Campo, 1999). Exposure has also been linked to central nervous system abnormalities, cardiac deects, and limb anomalies (Cumberland Pharmaceuticals, 2020). Intellectual impairment has been described. Te embryo is thought to be most vulnerable at 8 to 10 weeks postconception and at dosages o at least 10 mg/week. However, this is not universally accepted (Feldkamp, 1993). Because o its distribution, methotrexate can remain in the body or prolonged periods. Tus, preconceptional exposure is not without risk.
Te standard 50-mg/m2 dose given to treat ectopic pregnancy or to induce abortion exceeds the 10-mg/week threshold dose. Reports describe cardiac anomalies, particularly conotruncal deects, in intrauterine pregnancies inadvertently treated with methotrexate or suspected ectopic pregnancy (Dawson, 2014; Hyoun, 2012).
Tamoxifen
is nonsteroidal selective estrogen-receptor modulator (SERM) is used as an adjuvant to treat breast cancer. In animal studies, tamoxien has been associated with malormations similar to those caused by diethylstilbestrol (DES) exposure in rodents, including vaginal adenosis. One review o 167 pregnancies reported a fetal abnormality in 13 percent but emphasized that evidence was limited (Schuurman, 2019). Abnormalities have included ambiguous genitalia and cranioacial anomalies.
Trastuzumab
Tis is a recombinant monoclonal antibody directed to the human epidermal growth factor receptor 2 (HER2) protein. Used to treat breast and gastric cancers that express HER2 protein, this drug has not been associated with etal malormations. However, postmarketing surveillance identied cases o oligohydramnios sequence resulting in pulmonary hypoplasia, renal ailure, skeletal abnormalities, and neonatal death (Genentech, 2020). Surveillance or these complications is recommended or exposed pregnancies and or 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. Tese warnings also apply to those treated with ado-trastuzumab emtansine.
■ Endothelinreceptor Antagonists
Bosentan, ambrisentan, and macitentan are three endothelin-receptor antagonists used to treat pulmonary arterial hypertension (Chap. 52, p. 930). Te endothelin-receptor signaling pathway is important or neural-crest development. Mice decient in endothelin receptors develop neural-crest cell deects that include cranioacial and cardiac outfow tract abnormalities (de Raaf, 2015). Each of these three agents has been ound to cause similar birth deects in multiple animal species (Janssen, 2019a,b). No human data are available. Endothelinreceptor antagonists may be obtained only through restricted access programs, each o which has stringent requirements that include contraception and monthly pregnancy testing (Gilead, 2019; Janssen, 2019a,b).
■ Immunosuppressant Medications
Selected autoimmune diseases and their treatment are reviewed in Chapter 62 (p. 1109).
Corticosteroids
Glucocorticoids and mineralocorticoids have antiinfammatory and immunosuppressive actions. Tey are used to treat serious disorders such as asthma and autoimmune disease. Corticosteroids have been associated with oroacial clets in animal studies, but the absolute risk is small. In a metaanalysis o casecontrol studies by the Motherisk Program, systemic corticosteroid exposure was associated with a threeold rate increase, conerring an absolute risk o 3 clets per 1000 exposed etuses (Park-Wyllie, 2000). A 10-year prospective cohort study by the same group, however, did not identiy an increased overall risk or major malormations. Based on these ndings, corticosteroids are not considered to represent a major teratogenic risk.
Potential risks associated with prednisone or methylprednisolone are considered to be lower than those with other corticosteroids. Prednisolone, the active metabolite o prednisone, is itself metabolized and rendered inactive by the placental enzyme 11β-hydroxysteroid dehydrogenase 2 (Murphy, 2007). Tus, it is thought to reach the etus less eectively.
Mycophenolate Mofetil
Tis inosine monophosphate dehydrogenase inhibitor, and a related agent, mycophenolic acid, are immunosuppressants. Tey are used to prevent rejection in organ-transplant recipients and to treat autoimmune disease (Chap. 62, p. 1112). Mycophenolate is a potent teratogen. From the National ransplantation Pregnancy Registry, o pregnancies in which mycophenolate was not discontinued until ater the rst trimester, birth deects complicated 30 percent, and another 30 percent spontaneously aborted (King, 2017). One prospective review by the European Network of Teratology Information Services similarly identied a spontaneous loss rate o nearly 30 percent in exposed pregnancies. More than 20 percent o liveborn infants had major anomalies (Hoeltzenbein, 2012).
Many aected inants have a pattern o deects termed mycophenolate embryopathy. Tis includes microtia, auditory canal atresia, clets, coloboma and other eye anomalies, short ngers with hypoplastic nails, and cardiac deects (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 benets o a given drug.
■ Lead
Lead crosses the placenta via passive diusion. Prenatal lead exposure is associated with etal-growth impairment and with childhood neurodevelopmental delays. According to the CDC (2010), no level o lead exposure is considered sae in pregnancy. Although routine testing is not recommended, risk actors should be assessed in all pregnancies (American College o Obstetricians and Gynecologists, 2019a). Care and testing or at-risk pregnancies is discussed in Chapter 10 (p. 188).
■ Mercury
Te developing nervous system is particularly susceptible to mercury. In the 1950s and early 1960s, children born near Minamata Bay, Japan were ound to have congenital Minamata disease—severe neurological abnormalities rom methylmercury exposure in utero (Yoriuji, 2020). Prenatal exposure causes disturbances in neuronal cell division and migration.
Tis leads to a range o deects rom microcephaly to intellectual disability, choreo-athetoid movement abnormalities, motor delays, and behavioral abnormalities (Grandjean, 2011). Te principal concern or prenatal mercury exposure is the consumption o certain species o large sh and seaood (Chap. 10, p. 188). Methylmercury cannot be eliminated by cooking. It crosses the placenta and can accumulate in the etus. Te FDA (2019) advises that pregnant women and breasteeding mothers avoid consumption o king mackerel, marlin, orange roughy, shark, swordsh, tilesh, and bigeye tuna.
■ Psychiatric Medications
reatment o psychiatric illness in pregnancy, including a discussion o the risks and benets o various psychiatric medications, is described in Chapter 64 (p. 1142).
Antipsychotic Medications 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, agitation, somnolence, respiratory abnormalities, and eeding diculty. Such ndings are nonspecic and transient. An FDA (2017) alert cited all medications in this class. Included are older medications like haloperidol and chlorpromazine and newer medications such as aripiprazole, olanzapine, quetiapine, and risperidone.
Lithium
is medication has been associated with Ebstein anomaly, a rare cardiac abnormality that otherwise complicates only 1154 per 20,000 births. Ebstein anomaly is characterized by apical displacement o the tricuspid valve, oten resulting in severe tricuspid regurgitation and marked right atrial enlargement. A report rom the Lithium Baby Registry initially suggested that the risk for Ebstein anomaly was as high as 3 percent. However, subsequent series have identied an attributable risk for Ebstein anomaly and co-occurring right-sided cardiac anomalies o only 1 to 4 cases per 1000 exposed pregnancies (Patorno, 2017; Yacobi, 2008). Te NBDPS ound that just 1 o 135 cases o Ebstein anomaly occurred in the setting of lithium exposure (Downing, 2019).
Neonatal lithium toxicity stems rom exposure near delivery. Te manuacturer recommends that i possible, the dosage should be decreased or drug discontinued 2 to 3 days prior to delivery to reduce this risk (West-Ward, 2020). Findings may persist or up to 2 weeks and may include cardiac arrhythmias, hypoglycemia, nephrogenic diabetes insipidus, and a “foppy inant syndrome” (American College o Obstetricians and Gynecologists, 2019). Te latter may include hypotonia, respiratory distress or apnea, bradycardia, cyanosis, and eeding diculties (West-Ward, 2020).
Selective Serotonin- and Norepinephrine-reuptake Inhibitors
Tese medications have been studied more than almost any other, apart rom Bendectin (p. 146). As a class, they are not considered major teratogens (American College o Obstetricians and Gynecologists, 2019). Te one exception is paroxetine, which has been associated with a slightly higher risk or cardiac anomalies, particularly atrial and ventricular septal deects. Metaanalyses have identied a pooled odds ratio o just 1.3 or paroxetine and cardiac abnormalities (Berard, 2016; Wurst, 2010). However, a review o nearly 1 million pregnancies rom the nationwide Medicaid Analytic eXtract identied no signicant association between paroxetine use in the rst trimester and etal cardiac abnormalities (Huybrechts, 2014). Te American College o Obstetricians and Gynecologists (2019) recommends that women planning pregnancy avoid paroxetine. Fetal echocardiography should be considered or those with rst-trimester paroxetine exposure.
Neonatal eects have been associated with prenatal exposure to selective serotonin-reuptake inhibitors (SSRIs) and selective norepinephrine-reuptake inhibitors (SNRIs). Approximately 25 percent o neonates exposed to SSRIs in late pregnancy maniest one or more nonspecic ndings considered to represent poor neonatal adaptation (Costei, 2002; Jordan, 2008). Collectively termed the neonatal behavioral syndrome, ndings can include jitteriness, irritability, hyper- or hypotonia, eeding abnormalities, vomiting, hypoglycemia, thermoregulatory instability, and respiratory abnormalities. Fortunately, these neonatal behaviors are typically mild and sel-limited and last approximately 2 days. Jordan and coworkers (2008) reported that aected newborns were not more likely to require a higher level o care, to experience respiratory abnormalities, or to have prolonged hospitalization.
Rarely, neonates exposed to SSRIs in late pregnancy have demonstrated more severe adaptation abnormalities (Ornoy, 2017). Another concern with late-pregnancy exposure is the possible association o SSRI medications with persistent pulmonary hypertension of the newborn (PPHN). Te baseline incidence approximates 2 cases per 1000 term newborns. PPHN is characterized by elevated pulmonary vascular resistance with right-to-let shunting and resultant hypoxemia. wo population-based cohort studies—together involving more than 5 million pregnancies—identied an attributable risk o only 1 to 2 cases per 1000 births (Huybrechts, 2015; Kieler, 2012). Moreover, cases o PPHN associated with SSRI medication have not been severe (Ornoy, 2017).
■ Retinoids
Vitamin A derivatives are among the most potent human teratogens. By inhibiting neural-crest cell migration during embryogenesis, they create a pattern o cranial neural-crest deects—termed retinoic acid embryopathy—that involve the CNS, ace, heart, and thymus (Fig. 8-3). Specic anomalies may include ventriculomegaly, maldevelopment o the acial bones or cranium, microtia or anotia, micrognathia, clet palate, conotruncal heart deects, and thymic aplasia or hypoplasia.
Acitretin
Tis retinoid is used to treat severe psoriasis. It was introduced to replace etretinate, a lipophilic retinoid with such a long hal- lie (120 days) that birth deects resulted more than 2 years ater therapy was discontinued. Although acitretin has a short half-life, it is metabolized to etretinate, and thus remains in the body or prolonged periods (Stieel Laboratories, 2017). o obviate exposure, the manuacturer o acitretin has developed a pregnancy risk management program. Called “Do Your P.A.R.”—pregnancy prevention actively required during and ater treatment, this program promotes a delay o conception or at least 3 years ollowing therapy discontinuation.
Bexarotene
Tis retinoid is used to treat reractory cutaneous -cell lymphoma. When given to rats in doses comparable to those or human therapy, etuses developed eye and ear abnormalities, clet palate, and incomplete ossication. For a woman to receive bexarotene, the manuacturer requires two orms o contraception that are initiated 1 month beore therapy and continued
FIGURE 8-3 Retinoic acid embryopathy. A. Bilateral microtia or anotia with stenosis of external ear canal. B. Flat, depressed nasal bridge and ocular hypertelorism. (Reproduced with permission from permission from Dr. Edward Lammer.)
or 1 month ater it is discontinued. Tis is coupled with monthly pregnancy testing during treatment (Bausch Health, 2020). Males who have partners who could become pregnant are advised to use condoms during sexual intercourse while taking bexarotene and or 1 month ater discontinuing therapy.
Isotretinoin
13-cis-Retinoic acid is a vitamin A isomer that stimulates epithelial cell dierentiation. It is primarily used to treat recalcitrant nodular acne. First-trimester exposure is associated with a high rate o pregnancy loss, and up to a third o inants have malormations (Lammer, 1985). e iPLEDGE program is an FDA-mandated REMS for isotretinoin and is found at www.ipledgeprogram. com. Tis web-based, restricted-distribution program requires participation or all patients, physicians, and pharmacies to help eliminate embryo–etal exposure. Other countries have instituted similar programs, however, inadvertent exposure remains a global concern (Autret-Leca, 2010; Crijns, 2011).
Topical Retinoids
Tese compounds, initially used to treat acne, have become so popular or sun-damage treatment that they are called cosmeceuticals (Panchaud, 2012). Te most commonly used topical agents are tretinoin, isotretinoin, and adapalene. Systemic absorption is low, and this argues against plausible teratogenicity. Isolated case reports have described malormations ollowing 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 o eratology Inormation Services ound no higher rates o birth deects or spontaneous losses, and no case o retinoid embryopathy (Panchaud, 2012). A systematic review o 635 pregnancies exposed to topical retinoids identied no higher risk or congenital malormations, spontaneous abortion, stillbirth, low birthweight, or preterm delivery (Kaplan, 2015). Notably, the manufacturer of tazarotene cautions that application over a sucient body surace area could be comparable to oral treatment. Accordingly, its use in pregnancy is not recommended (Allergan, 2019).
Vitamin A
Tere are two natural orms o vitamin A. First, provitamin A carotenoids, which include beta-carotene, alpha-carotene, and beta-cryptoxanthin, are precursors ound in ruits and vegetables. Te body converts carotenoids into vitamin A. Tey have never been shown to cause birth deects (Oakley, 1995).
Second, preformed vitamin A, also called retinol, has been associated with cranial neural-crest deects when more than 10,000 IU per day is consumed in the rst trimester (Rothman, 1995). Preormed vitamin A is present in liver, sh oils, milk, eggs, and in vitamin pills and dietary supplements. It seems reasonable to avoid doses o preormed preparations that exceed the recommended 3000 IU daily allowance (American Academy o Pediatrics, 2017).
■ Sex Hormones
Selected unctions and eects o male and emale hormones on the developing etus are reviewed in Chapter 3 (p. 31). Androgen exposure may cause varying degrees of virilization in emale etuses and may result in ambiguous genitalia (Fig. 3-3, p. 34).
■ Thalidomide and Analogues
Possibly the most notorious human teratogen, thalidomide causes malormations in 20 percent o etuses exposed between 34 and 50 days menstrual age. Te characteristic malormation is phocomelia—an absence or underdevelopment o one or more long bones. As a result, hands or eet may attach to the trunk, occasionally by a small rudimentary bone. Cardiac deects, gastrointestinal abnormalities, external ear and eye mal- ormations, and other limb-reduction deects also are common ollowing thalidomide exposure. Te manuacturer reports that up to 40 percent o aected newborns do not survive the neonatal period (Celgene, 2021). Talidomide was marketed outside the United States rom 1956 to 1960, beore its teratogenicity was appreciated. Te ensuing disaster, with thousands o aected children, was instructive o several important teratological principles. First, the placenta is not an eective barrier to the transer o toxic substances rom mother to embryo (Dally, 1998). Second, dierent species maniest considerable variability in their susceptibility to drugs and chemicals.
Namely, thalidomide produced no deects in multiple rodent species and was assumed to be sae or humans. Last, timing o exposure may be closely related to the type o deect (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. Talidomide was rst approved in the United States in 1999 and currently is used to treat erythema leprosum nodosum and multiple myeloma (Celgene, 2021). Te FDA has mandated a web-based, restricted-distribution program or thalidomide, called THALOMID REMS, which is required before patients, physicians, and pharmacies can access the medication.
Lenalidomide and pomalidomide are analogues o thalidomide. Both cross the placenta in animal species. Lenalidomide is used to treat some types o myelodysplastic syndrome and multiple myeloma. It has been ound to cause thalidomide-like limb abnormalities in monkeys (Celgene, 2019). Pomalidomide is used to treat reractory multiple myeloma and acquired immunode- ciency syndrome (AIDS)-related Kaposi sarcoma. It is teratogenic in rats and rabbits (Celgene, 2020). Restricted-distribution programs similar to those used or thalidomide have been developed or these analogues.
■ Thyroid Medications
Methimazole
Tis thionamide drug is used to treat hyperthyroidism. Methimazole has been associated with a 2-fold increased risk for aplasia cutis congenita, as well as choanal atresia and esophageal atresia (Yoshihara, 2012). Tis constellation o ndings has been termed methimazole embryopathy. Aplasia cutis is a rare abnormality characterized by a full-thickness skin defect, usually the scalp, occasionally with a deect o underlying bone. In a study o more than 1000 methimazole-treated pregnancies, Yoshihara and colleagues (2015) identied the embryopathy in 1 to 2 percent. reatment o hyperthyroidism in pregnancy is reviewed in Chapter 61.
Radioiodine
Radioactive iodine-131 is used or treatment o thyroid cancer and thyrotoxicosis and or diagnostic thyroid scanning. It is also a component o iodine-131 tositumomab therapy, which is employed to treat a type o non-Hodgkin lymphoma. Radioiodine is contraindicated during pregnancy because it readily crosses the placenta and is concentrated in the etal thyroid gland by 12 weeks’ gestation. It may cause severe or irreversible etal and neonatal hypothyroidism, which can lead to decreased mental capacity and delayed skeletal maturation. Pregnancy testing should be perormed beore administration o radioiodine-131, and it is recommended that pregnancy be avoided or 6 to 12 months ollowing treatment (Haugen, 2016). A review o more than 3000 pregnancies in which women delayed conception or at least 6 months ater receiving radioactive iodine treatment identied no increase in pregnancy losses or congenital malormations (Kim, 2020). Concerns or the breasteeding mother stem rom breast exposure to the radioisotope.
■ Warfarin
Tis anticoagulant is a vitamin K antagonist with a long hal- lie. Because o its low molecular weight, it readily crosses the placenta and may cause embryotoxic and etotoxic eects. It is considered contraindicated in pregnancy with one important exception. As discussed in Chapter 52 (p. 922), wararin is used to treat women with mechanical heart valves who are at high risk or thromboembolism (Bristol-Myers Squibb, 2019). Warfarin embryopathy is characterized by stippled epiphyses and nasal hypoplasia (Fig. 8-4). In one review o 63 cases attributed to wararin exposure, 80 percent displayed characteristic ndings, which include depressed nasal bridge with nasal hypoplasia and choanal atresia, along with stippled epiphyses o the emur, humerus, calcanei, and distal phalanges (Van Driel, 2002). Te embryopathy may result rom exposure between 6 and 9 weeks’ gestation (Hall, 1980). Prevalence ollowing exposure during this critical period is estimated to be 6 percent. One metaanalysis o cases in which the wararin dosage was ≤5 mg/d identied embryopathy in 1 percent o exposed etuses. Tis suggests that risk may be dose dependent (Hassouna, 2014).
I used beyond the rst trimester, wararin may lead to hemorrhage into etal structures, which can cause abnormal growth and deormation rom scarring (Warkany, 1976). Nearly 50 percent o reported embryopathy cases also have CNS anomalies (van Driel, 2002). Abnormalities can include agenesis o the corpus callosum; cerebellar vermian agenesis, which is the Dandy-Walker malormation; microphthalmia; and optic atrophy. Aected inants are also at risk or blindness, deaness, and developmental delays.
■ Tobacco
Cigarette smoking is the leading preventable cause o perinatal mortality. At least 7 percent o women report smoking cigarettes during pregnancy (Drake, 2018). Cigarette smoke contains a complex mixture o nicotine, cotinine, cyanide, thiocyanate, carbon monoxide, cadmium, lead, and various hydrocarbons (Stillerman, 2008). In addition to being etotoxic, many o these substances have vasoactive eects or reduce oxygen levels.
Although tobacco is not considered a major human teratogen, selected birth deects have been reported to occur with greater requency ollowing exposure. Cigarette smoking and exposure to second-hand smoke have been associated with up to a 1.5-old risk or oroacial clets (Kummet, 2016; Sabbagh, 2015). Tis equates to an attributable risk o approximately 1 case per 2000 births. It is plausible that the vasoactive properties o tobacco smoke could produce congenital deects related to vascular disturbances. For example, the prevalence o Poland sequence, which is caused by an interruption in the vascular supply to one side o the etal chest and ipsilateral arm, has been reported to occur two times more commonly among cigarette smokers (Martinez-Frias, 1999). Te NBDPS similarly ound an association between active or passive cigarette smoking and limb reduction deects, and an overall increase in risk o 25 percent (Caspers, 2013). A small increased risk or etal cardiac anomalies also has been reported and may be dose related (Alverson, 2011; Malik, 2008; Sullivan, 2015). Te most prevalent obstetrical complication rom smoking is a dose-dependent reduction in etal growth. Newborns o mothers who smoke weigh on
FIGURE 8-4 Warfarin embryopathy or fetal warfarin syndrome: nasal hypoplasia and depressed nasal bridge seen in a fetal sonographic image (A) and in the same newborn (B). average 200 g less than newborns of nonsmokers (D’Souza, 1981).
Smoking doubles the risk o low birthweight and raises the risk o etal-growth restriction two- to threeold (Werler, 1997). As such, cigarette smoking accounts or 15 percent o lowbirthweight neonates (Dietz, 2010). Even secondhand smoke increases the risk or low birthweight. Other adverse pregnancy outcomes associated with cigarette smoking include preterm birth, prelabor rupture o membranes, placenta previa, and placenta abruption (American College o Obstetricians and Gynecologists, 2020b). Approximately one third o cases o sudden inant death syndrome have been attributed to cigarette smoking (Anderson, 2019; Dietz, 2010). Risks of childhood asthma and obesity also are increased.
When inquiring about tobacco use, providers should include alternative nicotine delivery products. All orms o nicotine cross the placenta. None is considered sae in pregnancy. Vaping or e-cigarette products heat an “e-liquid” containing nicotine— and oten additional contaminants—along with a favoring agent. Nicotine is associated with adverse eects on etal brain and lung development (American College o Obstetricians and Gynecologists, 2020b; Spindel, 2016). In adults, vaping has been linked to serious lung injury known as EVALI— e-cigarette or vaping-associated lung injury (Krishnasamy, 2020). Animal studies o hookah use, in which tobacco smoke is ltered through a water bowl, demonstrate lower birthweight and increased markers o cardiac stress (Khabour, 2016).
Smoking cessation should be strongly encouraged. Counseling includes avoidance o secondhand smoke and all nicotinereplacement products, such as patches, gum, and lozenges. A hotline is available rom the Centers o Disease Control and Prevention and can be accessed by calling 1-800-QUI-NOW. Te U.S. Preventive Services ask Force has recommended that behavioral interventions be oered at the initial visit and continued throughout pregnancy (Siu, 2015).
■ Herbal Medicinal Products
In large survey studies from North America and Europe, 30 to 60 percent o women report using herbal remedies during pregnancy (Kennedy, 2016; Pallivalapila, 2015). Tese products are not regulated by the FDA, and there is a paucity o controlled studies assessing their saety and ecacy. Te identity, quantity, and purity o each ingredient are usually unknown. Authors o a recent systematic review that included more than 1 million pregnancies concluded that in the absence o more saety data, the use o herbal medicinal products in pregnancy should be discouraged (Munoz Balbontin, 2019). Selected herbal remedies and their reported adverse eects are shown in Table 8-5.
■ Drugs of Abuse
Substance abuse is not uncommon in pregnancy. Assessment o outcomes attributable to illicit drug use is oten conounded by actors such as poor maternal health, malnutrition, and inectious disease. Polysubstance abuse urther complicates assessment o outcomes associated with any one drug. Moreover, illegal substances may contain toxic contaminants such as lead, cyanide, herbicides, and pesticides. Impurities added as diluents may independently have serious adverse perinatal eects. As noted on page 149, alcohol is a signicant teratogen. Because it is legally obtained and ubiquitous, its use conounds the study o illicit drug teratogenicity. Similarly, tobacco use conounds the eect o drugs on etal growth.
Cocaine
With this CNS stimulant, most adverse outcomes result rom its vasoconstrictive and hypertensive eects. Serious potential maternal complications are cerebrovascular hemorrhage, myocardial damage, and placental abruption. Studies o congenital abnormalities and cocaine exposure have yielded conficting results, but associations with clet palate, cardiovascular abnormalities, and urinary tract anomalies have been reported (Chasno, 1988; Lipshultz, 1991; van Gelder, 2009). Cocaine use is also associated with etal-growth restriction and preterm delivery. Children exposed as etuses have risks or behavioral abnormalities and cognitive impairments (Bada, 2011; Gouin, 2011).
Marijuana
Tis is the recreational drug most commonly used in pregnancy (American College o Obstetricians and Gynecologists, 2019b). Based on data rom the National Survey on Drug Use and Health, nearly 4 percent o pregnant women reported using marijuana in 2014 (Brown, 2017). Among women diagnosed with nausea and vomiting o pregnancy, the prevalence o marijuana use increased rom 7 to 11 percent rom 2009 to 2016 (Young-Wol, 2019). O concern is that the increase in prevalence is related to perceived saety and ecacy. In a study o 400 cannabis dispensaries, nearly 70 percent advised a caller posing as a pregnant woman with nausea at 8 weeks’ gestation to use marijuana (Dickson, 2018). However, no data support ecacy o marijuana or nausea and vomiting o pregnancy, and there are indeed safety concerns (Metz, 2018).
Cannabinoids are not considered to be major teratogens, but they cross the placenta, and endogenous cannabinoids play key roles in brain development. In animals, cannabinoids are involved in neuronal prolieration, migration, and dierentiation (Campolongo, 2011). Adverse developmental outcomes reported in exposed children include decreased attention span and lower scores on tests o visual problem solving and visual-motor coordination (Fried, 2003; Willord 2010).
Pregnancy outcome data are somewhat limited by the con- ounding risks o concomitant tobacco use. In one metaanalysis o nearly 8000 exposed pregnancies, only those with concomitant tobacco use had increased rates o preterm birth and lowbirthweight neonates (Conner, 2016). Te American College o Obstetricians and Gynecologists (2019b) has stated that the eects o marijuana may be as serious as those o cigarette smoking or alcohol consumption. Because o neurodevelopmental concerns, women who are pregnant or contemplating pregnancy should avoid marijuana use.
Methamphetamine
Tis sympathomimetic amine is derived rom dextroamphetamine. It enhances dopamine release and blocks its reuptake. Methamphetamine is prescribed to treat attention decit hyperactivity disorder and narcolepsy. Abuse has been rising in the United States since the late 1980s (American College o Obstetricians and Gynecologists, 2019c). Methamphetamine is not considered teratogenic. However, use in pregnancy is consistently associated with small-or-gestational age newborns, and children are at risk or developmental delays and behavioral abnormalities (Derauf, 2012; Eze, 2016; Gabrhelik, 2021; O’Connor, 2020). Behavioral abnormalities have been described in both infants and school-aged children (Eze, 2016). Hypertensive complications, placental abruption, preterm birth, and stillbirth are other associated adverse outcomes (Gorman, 2014).
Opioids
Te dramatic rise in narcotic use among nonpregnant and pregnant individuals has been aptly termed an epidemic. Opioids are not major teratogens. However, the NBDPS did identiy a slightly greater risk or spina bida, gastroschisis, and cardiac abnormalities with periconceptional opioid exposure (Broussard, 2011). Te American College o Obstetricians and Gynecologists (2019d) stresses that this potential, small increase in birth deects with maintenance therapy should be weighed against the risks associated with uncontrolled opioid abuse. Heroin addiction is associated with adverse pregnancy outcomes rom the eects o repeated narcotic withdrawal on the etus and placenta. Tese include preterm birth, placental abruption, etal-growth restriction, and etal death.
Neonatal narcotic withdrawal, called the neonatal abstinence syndrome, may maniest in 40 to 90 percent o exposed newborns (Blinick, 1973; Creanga, 2012; Dashe, 2002; Zelson, 1973). As discussed in Chapter 33 (p. 605), CNS irritability may progress to seizures if untreated and may be accompanied by tachypnea, apneic episodes, poor eeding, and ailure to thrive. At-risk neonates are closely monitored using a scoring
TABLE 8-5. Pharmacological Actions and Adverse Effects of Some Herbal Medicines Herb and Common Name Potential Pharmacological Effects Concerns
Te American College o Obstetricians and Gynecologists (2019d) 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. reatment includes either buprenorphine, which may be given in an oce-based setting by a licensed buprenorphine prescriber, or methadone, usually through a licensed outpatient opioid treatment program. A multidisciplinary treatment program is recommended to reduce the likelihood o additional opioid abuse while on maintenance therapy. Withdrawal rom methadone during pregnancy is discouraged because o high relapse rates (American College o Obstetricians and Gynecologists, 2019d). At Parkland Hospital, pregnant opioid users who decline maintenance therapy are oered inpatient hospitalization for controlled methadone taper. e goal is to reduce the likelihood o neonatal abstinence syndrome (Dashe, 2002; Stewart, 2013).
Miscellaneous Drugs
Phencyclidine (PCP) or angel dust is not associated with congenital anomalies. More than hal o 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 signicant etal risks (Wilkins-Haug, 1997). When abused by women in early pregnancy, it is associated with toluene embryopathy, which is phenotypically similar to etal alcohol syndrome. Abnormalities include pre- and postnatal growth deciency, microcephaly, midace hypoplasia, short palpebral ssures, and wide nasal bridge (Pearson, 1994). Up to 40 percent o exposed children have developmental delays (Arnold, 1994)
Nhận xét
Đăng nhận xét