CRITERIA FOR DETERMINING TERATOGENICITY
COUNSELING FOR TERATOGEN EXPOSURE
GENETIC AND PHYSIOLOGICAL SUSCEPTIBILITY TO TERATOGENS
KNOWN AND SUSPECTED TERATOGENS
Birth defects are common—2 to 3 percent of all newborns have a major congenital abnormality detectable at birth (Cragan, 2009; Dolk, 2010). By age 5, another 3 percent have been diagnosed with a malformation, and by age 18, another 8 to 10 percent have one or more apparent functional or developmental abnormalities. Importantly, nearly 70 percent of birth defects do not have an obvious etiology, and of those with an identified cause, it is far more likely to be genetic than teratogenic (Schardein, 2000; Wlodarczyk, 2011). The Food and Drug Administration (FDA) (2005b) estimates that less than 1 percent of all birth defects are caused by medications. Examples of medications considered teratogenic are shown in Table 12-1.
TABLE 12-1. Selected Teratogens and Fetotoxic Agents
Angiotensin-converting enzyme inhibitors
Although only a relatively small number of medications have proven harmful effects, there is significant concern surrounding medication use in pregnancy. This is because most pregnant women take medications and for most medications, available safety data are limited. In a review of more than 150,000 pregnancies, 40 percent of women were prescribed a medication other than multivitamins in the first trimester (Andrade, 2004). More recently, data from the National Birth Defects Prevention Study showed that women use an average of 2 to 3 medications per pregnancy and that 70 percent take medication in the first trimester (Mitchell, 2011).
Despite improvements in safety information, data are particularly limited for newer medications. For example, in a review of medications approved by the FDA between 2000 and 2010, the Teratogen Information System (TERIS) expert advisory board deemed the pregnancy risk “undetermined” for more than 95 percent (Adam, 2011).
The study of birth defects and their etiology is termed teratology. The word teratogen is derived from the Greek teratos, meaning monster. Pragmatically, a teratogen may be defined as any agent that acts during embryonic or fetal development to produce a permanent alteration of form or function. Thus, a teratogen may be a drug or other chemical substance, a physical or environmental factor such as heat or radiation, a maternal metabolite such as in phenylketonuria or diabetes, a genetic abnormality, or an infection. Tightly defined, a teratogen causes structural abnormalities, whereas a hadegen—after the god Hades—is an agent that interferes with normal maturation and function of an organ. A trophogen is an agent that alters growth. Substances in the latter two groups typically affect development in the fetal period or after birth, when exposures are often more difficult to document. In most circumstances, teratogen is used to refer to all three types of agents.
Studies in Pregnant Women
The study of medication safety—or teratogenicity—in pregnant women is fraught with complications. Animal studies are considered necessary but insufficient, which is a lesson learned from the safety of thalidomide in several animal species. Rarely are medications approved by the FDA with the specific indication for their use being pregnancy. Between 1996 and 2011, for example, the only medication approved specifically for pregnancy was hydroxyprogesterone caproate for recurrent preterm birth prevention.
Pregnant women are generally considered a special population and excluded from trials. An obvious reason is to protect the embryo and fetus from potentially harmful effects of a medication—its pharmacodynamic effect(s) on the body. Another reason is that pregnancy physiology affects the medication—its pharmacokinetics. Specifically, changes in volume of distribution, cardiac output, gastrointestinal absorption, hepatic metabolism, and renal clearance may each affect drug concentration and thus embryo-fetal exposure (Chap. 4, p. 51).
Case Reports and Series
Several major teratogens were first described by astute clinicians. Congenital rubella syndrome was identified 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 identified through case series include thalidomide and alcohol (Jones, 1973; Lenz, 1962). Unfortunately, teratogens are less likely to come to attention through identification of clinical cases if the exposure is uncommon, if the defects are relatively nonspecific, or if abnormalities occur in only a small proportion of exposed infants. A major limitation of case series is that they lack a control group.
Potentially harmful agents may be monitored by clinicians who prospectively enroll exposed pregnancies in a registry. The FDA maintains a list of ongoing pregnancy registries on their website: www.fda.gov. Included are medication groups used to treat asthma, autoimmune disease, cancer, epilepsy, human immunodeficiency virus (HIV) infection, and transplant rejection. Similar to case series, exposure registries are limited by lack of a control group. To compare the prevalence of an abnormality identified among exposed infants with that expected in the general population, investigators use a birth defect registry. One example is the Metropolitan Atlanta Congenital Defects Program, which is an active surveillance program ongoing since 1967 for fetuses and infants with birth defects.
In these studies, investigators retrospectively assess prenatal exposure to particular substances between affected infants and controls. Birth defect registries are ideal for ascertainment of cases. However, case-control studies have two inherent weaknesses. First, there is potential for recall bias, in which the mother of an affected infant may be more likely to recall exposure. Second, case-control studies can only evaluate associations, rather than causality, and are thus hypothesis-generating. For these reasons, Grimes and Schulz (2012) caution that unless odds ratios in case-control studies are above three- to fourfold, then observed findings may be incorrect.
The National Birth Defects Prevention Study. This population-based case-control study involves 10 states with active birth defects surveillance programs (www.nbdps.org). It represents an important collaborative effort by the Centers for Birth Defects Research and Prevention to evaluate medications as a cause of birth defects. Since 1997, each center has annually enrolled 300 or more cases—including live births, stillbirths, and terminated pregnancies that have one or more of 30 structural birth defects, along with 100 randomly selected controls. Clinical geneticists review each potential case, and standardized telephone interviews are conducted 6 weeks and 24 months after delivery to obtain information regarding medication exposure and medical risk factors (Mitchell, 2011). This large volume has considerable statistical power and permits identification of relatively small associations.
As of 2012, the National Birth Defects Prevention Study (NBDPS) had identified associations between individual birth defects and the following classes of medications: sulfonamides and nitrofurantoin, asthma medications, antiemetics, nonsteroidal antiinflammatory drugs, and opioids (Broussard, 2011; Crider, 2009; Hernandez, 2012; Lin, 2012; Munsie, 2011). For each, the authors discussed the possibility that the observed associations may have been due to chance alone or that the underlying medical disorder for which the drug was given may have caused the abnormality. Based on the degree of risk identified, if any of these medications is eventually deemed teratogenic, it would be considered a low-risk teratogen, as subsequently discussed. Thus, the American College of Obstetricians and Gynecologists (2013b) considers nitrofurantoin and sulfonamides appropriate for first-trimester use if no suitable alternative is available, and they remain the first-line agents for treatment and prevention of urinary infections beyond the first trimester (Chap. 53, p. 1052).
CRITERIA FOR DETERMINING TERATOGENICITY
The guidelines shown in Table 12-2, which were proposed by Shepard (1994) as a framework for discussion, have proven useful for more than 20 years. Although all criteria may not be required to establish teratogenicity, the following tenets must be considered (Shepard, 2002a):
• The defect has been completely characterized. This is preferably done by a geneticist or dysmorphologist because various genetic and environmental factors may produce similar anomalies. It is easiest to prove causation when a rare exposure produces a rare defect, when at least three cases with the same exposure have been identified, and when the defect is severe.
• The agent must cross the placenta. Although almost all drugs cross the placenta, transport must be of sufficient quantity to directly influence embryonic or fetal development or to alter maternal or placental metabolism to exert an indirect effect. Placental transfer depends on maternal metabolism; on specific characteristics of the drug, such as protein binding and storage, molecular size, electrical charge, and lipid solubility; and on placental metabolism such as the cytochrome P450 enzyme systems. In early pregnancy, the placenta also has a relatively thick membrane that slows diffusion.
• Exposure must occur during a critical developmental period:
1. The preimplantation period is the 2 weeks from fertilization to implantation and is known as the “all or none” period. As the zygote undergoes cleavage, an insult damaging a large number of cells typically causes embryonic death. However, if only a few cells are injured, compensation may be possible, with normal development (Clayton-Smith, 1996). Based on animal data, insults that appreciably diminish the cell number in the inner cell mass may produce a dose-dependent diminution in body length or size (Iahnaccone, 1987).
2. The embryonic period is from the second through the eighth week. It encompasses organogenesis and is thus the most crucial period with regard to structural malformations. Critical developmental periods for each organ system are illustrated in Figure 12-1.
3. The fetal period, which is beyond 8 weeks, is characterized by continued maturation and functional development, and during this time, certain organs remain vulnerable. For example, brain development remains susceptible to environmental influences such as alcohol exposure throughout pregnancy.
• A biologically plausible association is supportive. Because birth defects and medication exposures are both common, they may be temporally but not causally related.
• Epidemiological findings must be consistent. Because initial evaluation of teratogen exposure is often retrospective, it may be hampered by recall bias, inadequate reporting, and incomplete assessment of the exposed population. Potential confounding factors include varying dosages, concomitant drug therapy, and maternal disease(s). Familial and environmental factors can also influence development of birth defects. Thus, an important criterion for teratogenicity is that two or more high-quality epidemiological studies report similar findings. Finally, a relative risk of 3.0 or greater is generally considered necessary to support the hypothesis, whereas a lesser risk is interpreted with caution (Khouri, 1992).
• The suspected teratogen causes a defect in animal studies. Human teratogenicity is more likely if an agent produces an adverse effect in different animal species. However, a major lesson was learned from the thalidomide tragedy in that its teratogenicity was not recognized because of reliance on animal data, in which thalidomide produced no defects in several animal species. Not until thousands of infants were affected by thalidomide embryopathy was it realized that this agent was a potent human teratogen.
TABLE 12-2. Criteria for Determining Teratogenicity
1. Careful delineation of clinical cases, particularly if there is a specific defect or syndrome
2. Proof that exposure occurred at critical time during development (see Fig. 12-1)
3. Consistent findings by at least two epidemiological studies with:
a. exclusion of bias,
b. adjustment for confounding variables,
c. adequate sample size (power),
d. prospective ascertainment if possible, and
e. relative risk (RR) of 3.0 or greater, some recommend RR of 6.0 or greater
For a rare environmental exposure associated with a rare defect, at least three reported cases. This is easiest if defect is severe
4. The association is biologically plausible
5. Teratogenicity in experimental animals is important but not essential
6. The agent acts in an unaltered form in an experimental model
Modified from Shepard 1994, 2002a.
FIGURE 12-1 Timing of organogenesis during the embryonic period. (Redrawn from Sadler, 1990, with permission.)
Failure to employ these tenets and criteria has contributed to erroneous conclusions regarding the safety of some widely used drugs. The poster child for this is the medicolegal fiasco surrounding Bendectin. This antiemetic was a combination of doxylamine and pyridoxine that was both safe and effective for nausea and vomiting common in early pregnancy. More than 30 million women used this drug worldwide, and the 3-percent congenital anomaly rate among exposed fetuses was not different from the background rate (McKeigue, 1994). Despite evidence that the drug was not teratogenic, Bendectin was the target of numerous lawsuits, and the financial burden of defending these forced its withdrawal. As a consequence, hospitalizations for hyperemesis doubled (Koren, 1998). Ironically, the combination of doxylamine and pyridoxine has now been recently remarketed under the brand name Diclegis, which was FDA approved in 2013.
COUNSELING FOR TERATOGEN EXPOSURE
Questions regarding medication and illicit drug use should be part of routine preconceptional and prenatal care. Women who request counseling for prenatal drug exposure often have misinformation regarding their level of risk. Not uncommonly, they may underestimate the background risk for birth defects in the general population and exaggerate the potential risks associated with medication exposure. Koren and colleagues (1989) reported that a fourth of women exposed to nonteratogenic drugs thought they had a 25-percent risk for fetal anomalies. Misinformation may be amplified by inaccurate reports in the lay press. Knowledgeable counseling may allay anxiety considerably and in some situations may even avoid pregnancy termination.
The Food and Drug Administration Classification System
This system for evaluating drug safety in pregnancy was developed in 1979. It was designed to provide therapeutic guidance by using five categories—A, B, C, D, or X, shown in Table 12-3, to simplify risk-benefit information. In its present form, the system has important limitations, and these have been acknowledged by the FDA. One is that drugs in categories D and X, and some in category C, may pose similar risks but are in different categories because of different risk-benefit considerations. A higher letter grade does not necessarily confer an increased risk, and even drugs in the same category may have very different risks! And, despite the understanding that medications may affect human and animal development differently, the letter category is often based on animal data.
TABLE 12-3. Food and Drug Administration Categories for Drugs and Medications
Category A: Studies in pregnant women have not shown an increased risk for fetal abnormalities if administered during the first (second, third, or all) trimester(s) of pregnancy, and the possibility of fetal harm appears remote.
Fewer than 1 percent of all medications are in this category. Examples include levothyroxine, potassium supplementation, and prenatal vitamins, when taken at recommended doses.
Category B: Animal reproduction studies have been performed and have revealed no evidence of impaired fertility or harm to the fetus. Prescribing information should specify kind of animal and how dose compares with human dose.
Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus during the first trimester of pregnancy, and there is no evidence of a risk in later trimesters.
Examples include many antibiotics, such as penicillins, most cephalosporins, and macrolides.
Category C: Animal reproduction studies have shown that this medication is teratogenic (or embryocidal or has other adverse effect), and there are no adequate and well-controlled studies in pregnant women. Prescribing information should specify kind of animal and how dose compares with human dose.
There are no animal reproduction studies and no adequate and well-controlled studies in humans.
Approximately two thirds of all medications are in this category. It contains medications commonly used to treat potentially life- threatening medical conditions, such as albuterol, zidovudine, and calcium-channel blockers.
Category D: This medication can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy or if a woman becomes pregnant while taking this medication, she should be apprised of the potential hazard to the fetus.
This category also contains medications used to treat potentially life-threatening medical conditions, for example: corticosteroids, azathioprine, carbamazepine, and lithium.
Category X: This medication is contraindicated in women who are or may become pregnant. It may cause fetal harm. If this drug is used during pregnancy or if a woman becomes pregnant while taking this medication, she should be apprised of the potential hazard to the fetus.
There are a few medications in this category that have never been shown to cause fetal harm but should be avoided nonetheless, such as the rubella vaccine.
From the foregoing, it follows that it may be insufficient or even inappropriate to rely on this classification to make complex therapeutic decisions in pregnant women. Rather than simplifying counseling, the letter classification shifts responsibility to the clinician, who must interpret category information in the context of medication dosage, route and timing of exposure, other medications used, and underlying medical condition(s).
Because of the limitations of its current classification, the FDA (2011b) has proposed a new system for labeling drugs for use by pregnant and lactating women. Letter categories A through X are to be replaced with: (1) a fetal risk summary, (2) a section on clinical considerations—including inadvertent exposure, (3) a section on prescribing decisions for pregnant and lactating women, and (4) a detailed discussion of human and animal data. It is anticipated that this evidence-based rating system may soon become available (Gee, 2014).
The FDA has also expanded the information available on its website: www.fda.gov. The website includes updated, detailed information regarding potentially harmful medications—in the form of drug advisories, registries, and product information. It is an excellent resource for counseling. Current, accurate information is also available through online reproductive toxicity services such as Reprotox and TERIS.
Presenting Risk Information
In addition to potential embryonic and fetal risks from drug exposure, counseling should include a discussion of the risks and/or genetic implications of the underlying condition for which the drug is given, as well as risks associated with not treating the condition. Even the manner in which information is presented affects perception. Jasper and associates (2001) found that women given negative information—such as a 2-percent chance of a malformed infant—are more likely to perceive an exaggerated risk than women given positive information—such as a 98-percent chance of a child without a malformation. Instead of citing an increased odds ratio, it may be helpful to provide the absolute risk for a particular defect or the attributable risk, which is the difference between prevalence in exposed and unexposed individuals (Conover, 2011). The association between oral corticosteroid medications and cleft lip sounds far more concerning when presented as a tripling or 200-percent increase in risk than when presented as an increase from 1 per 1000 to 3 per 1000, or a 99.7-percent likelihood of not developing a cleft following exposure.
With a few notable exceptions, most commonly prescribed drugs and medications can be used with relative safety during pregnancy. All women have an approximate 3-percent chance of having an infant with a birth defect. Although exposure to a confirmed teratogen may increase this risk, the magnitude of the increase is usually only 1 or 2 percent or at most, doubled or tripled. The concept of risk versus benefit is often central to counseling. Some untreated diseases pose a more serious threat to both mother and fetus than medication exposure risks.
There undoubtedly are a number of major teratogens. However, many drugs described in this chapter are low-risk teratogens, which are medications that produce defects in fewer than 10 per 1000 maternal exposures (Shepard, 2002a). Some examples include corticosteroids, lithium, trimethoprim, and methimazole. Because risks conferred by low-risk teratogens are so close to background, they may not be a major factor in deciding whether to discontinue treatment for an important condition (Shepard, 2002b). Obviously, clinicians and patients must carefully weigh risks and benefits in these instances.
GENETIC AND PHYSIOLOGICAL SUSCEPTIBILITY TO TERATOGENS
Teratogens act by disturbing specific physiological processes, which may in turn lead to abnormal cellular differentiation, altered tissue growth, or cell death. Because pathophysiological processes may be induced in various cell types and tissues, exposure may result in multiple effects, and because different teratogens may disturb similar processes, they may produce similar phenotypic abnormalities. But even the most potent teratogen induces birth defects in only a fraction of exposed embryos. Despite the numerous factors that influence exposure, teratogens appear merely to have potential to cause birth defects. The reasons why some infants are affected and others are not remains largely unknown.
In some cases, genetic composition has been linked to susceptibility to teratogenic effects of specific medications. For example, fetuses exposed to hydantoin are more likely to develop anomalies if homozygous for a gene mutation that results in abnormally low levels of epoxide hydrolase (Buehler, 1990). If activity of epoxide hydrolase enzyme is reduced, then hydantoin, carbamazepine, and phenobarbital are metabolized by microsomes to oxidative intermediates that accumulate in fetal tissues (Horning, 1974). These free oxide radicals have carcinogenic, mutagenic, and other toxic effects that are dose related and increase with multidrug therapy (Buehler, 1990; Lindhout, 1984).
Disruption of Folic Acid Metabolism
Fetal neural-tube defects, cardiac defects, and oral clefts can be a result of folic acid metabolic pathway disturbances. Folates are essential for methionine production, which is required for gene methylation and thus production of proteins, lipids, and myelin. Some anticonvulsants—phenytoin, carbamazepine, valproic acid, and phenobarbital—either impair folic acid absorption or act as folic acid antagonists. The resultant low periconceptional folic acid levels in some women with epilepsy may then cause fetal malformations (Dansky, 1987; Hiilesmaa, 1983). In one study of more than 5000 infants with birth defects, exposure to these folic acid antagonists was associated with a two- to threefold increased risk for oral clefts and cardiac abnormalities (Hernandez-Diaz, 2000).
Some congenital heart defects are related to interactions between folate-related genes and environmental or genetic factors. In a case-control study with more than 500 infants with a cardiac defect, maternal polymorphisms in three folate-related genes were found to increase the risk for cardiac anomalies when combined with maternal cigarette smoking, alcohol consumption, or obesity (Hobbs, 2010). Data from the National Down Syndrome Project demonstrated that trisomy 21 fetuses born to women not given periconceptional folic acid supplementation may be more likely to have endocardial cushion defects (Bean, 2011).
In some cases, paternal exposures to drugs or environmental influences may increase the risk of adverse fetal outcome. Proposed mechanisms include induction of a gene mutation or chromosomal abnormality in sperm. Because of the 64 days in which male germ cells mature into functional spermatogonia, drug exposure during the 2 months before conception could cause gene mutations. It may be that epigenetic pathways suppress germ-cell apoptosis or interfere with imprinting (Cordier, 2008). Another possibility is that during intercourse the developing embryo is exposed to a teratogenic agent in seminal fluid.
There is some evidence to support these hypotheses. For example, ethyl alcohol, cyclophosphamide, lead, and certain opiates have been associated with an increased risk of behavioral defects in the offspring of exposed male rodents (Nelson, 1996). In humans, paternal environmental exposure to mercury, lead, solvents, pesticides, anesthetic gases, or hydrocarbons may be associated with early pregnancy loss (Savitz, 1994). In a 20-year study of Swedish university employees, paternal exposure to carcinogenic solvents resulted in offspring with more than a fourfold increase in neural-crest malformations (Magnusson, 2004). Other occupations associated with an increased risk for men to have anomalous offspring include janitors, woodworkers, firemen, printers, and painters (Olshan, 1991; Schnitzer, 1995). Risk attribution is limited because assessment of paternal exposure is often imprecise, and there is potential for simultaneous maternal exposure, particularly for environmental agents such as pesticides (Cordier, 2008).
KNOWN AND SUSPECTED TERATOGENS
The number of medications and other substances strongly suspected or proven to be human teratogens is small, as shown in Table 12-1. With few exceptions, in every clinical situation potentially requiring therapy with a known teratogen, alternative drugs can be given with relative safety. As a general rule, because there are no adequate and well-controlled studies in pregnant women for most medications, and because animal reproduction studies are not always predictive of human response, any medication in pregnancy must be carefully considered and only used if clearly needed.
Ethyl alcohol is a potent and prevalent teratogen. Alcohol is one of the most frequent nongenetic causes of mental retardation as well as the leading cause of preventable birth defects in the United States. According to the Centers for Disease Control and Prevention (CDC)(2012), 8 percent of women report drinking alcohol during pregnancy, and the NBDPS identified a prevalence as high as 30 percent (Ethen, 2009). Between 1 and 2 percent of pregnant women admit to binge drinking.
The fetal effects of alcohol abuse have been recognized since the 1800s. Lemoine (1968) and Jones (1973) and their coworkers are credited with describing the spectrum of alcohol-related fetal defects known as fetal alcohol syndrome (Table 12-4). The Institute of Medicine (1996) has estimated that prevalence of the syndrome ranges from 0.6 to 3 per 1000 births.
TABLE 12-4. Fetal Alcohol Syndrome and Alcohol-Related Birth Defects
Fetal Alcohol Syndrome Diagnostic Criteria—all required
1. Dysmorphic facial features (all 3 are required)
a. Small palpebral fissures
b. Thin vermilion border
c. Smooth philtrum
2. Prenatal and/or postnatal growth impairment
3. Central nervous system abnormalities (1 required)
a. Structural: head size < 10th percentile, significant brain abnormality on imaging
c. Functional: global cognitive or intellectual deficits, functional deficits in at least three domains
Alcohol-Related Birth Defects
1. Cardiac: atrial or ventricular septal defect, aberrant great vessels, conotruncal heart defects
2. Skeletal: radioulnar synostosis, vertebral segmentation defects, joint contractures, scoliosis
3. Renal: aplastic or hypoplastic kidneys, dysplastic kidneys, horseshoe kidney, ureteral duplication
4. Eyes: strabismus, ptosis, retinal vascular abnormalities, optic nerve hypoplasia
5. Ears: conductive or neurosensory hearing loss
6. Minor: hypoplastic nails, clinodactyly, pectus carinatum or excavatum, camptodactyly, “hockey stick” palmar creases, refractive errors, “railroad track” ears
Modified from Bertrand, 2005; Hoyme, 2005.
For every child with fetal alcohol syndrome, many more are born with neurobehavioral deficits from alcohol exposure (American College of Obstetricians and Gynecologist, 2013a). Fetal alcohol spectrum disorder is an umbrella term that includes the full range of prenatal alcohol damage that may not meet the criteria for fetal alcohol syndrome. Prevalence of this disorder is estimated to be as high as 1 percent of births in the United States (Centers for Disease Control, 2012; Guerri, 2009).
Fetal alcohol syndrome has specific criteria, listed in Table 12-4, and which include dysmorphic facial features, pre- or postnatal growth impairment, and central nervous system abnormalities that may be structural, neurological, or functional (Bertrand, 2005). The distinctive facial features are shown in Figure 12-2. Other alcohol-related major and minor birth defects include cardiac and renal anomalies, orthopedic problems, and abnormalities of the eyes and ears. An association has also been reported between periconceptional alcohol use and omphalocele and gastroschisis (Richardson, 2011). There are no established criteria for prenatal diagnosis of fetal alcohol syndrome, although in some cases, major abnormalities or growth restriction may be suggestive (Paintner, 2012).
FIGURE 12-2 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. (From Streissguth, 1985, with permission.)
Fetal vulnerability to alcohol is modified by genetic factors, nutritional status, environmental factors, coexisting maternal disease, and maternal age (Abel, 1995). The minimum amount of alcohol required to produce adverse fetal consequences is unknown. Binge drinking, however, is believed to pose particularly high risk for alcohol-related birth defects and has also been linked to an increased risk for stillbirth (Centers for Disease Control, 2012; Maier, 2001; Strandberg-Larsen, 2008).
Pragmatically, no anticonvulsant drugs are considered truly “safe” in pregnancy. This is because most medications used to treat epilepsy have been proven or suspected to confer an increased risk for fetal malformations. The North American Antiepileptic Drug (NAAED) Pregnancy Registry was established to improve counseling information. Providers are encouraged to enroll pregnant women treated with antiepileptic medication through the FDA website or 1–888–233–2334.
Management of epilepsy in pregnancy, including risks associated with individual anticonvulsants, is discussed in Chapter 60 (p. 1190). Traditionally, women with epilepsy were informed that their risk for fetal malformations was increased two- to threefold. More recent data suggest that the risk may not be as great as once thought, particularly for newer agents. In a recent population-based study involving more than 800,000 pregnancies, exposure to newer anticonvulsants was associated with a 3-percent major malformation risk, compared with a 2-percent risk in unexposed fetuses (Molgaard-Nielsen, 2011). Similarly, the United Kingdom Epilepsy and Pregnancy Registry reported a 3-percent risk for major malformations in pregnancies treated with a single anticonvulsant—monotherapy. This is the same malformation rate as for those with untreated epilepsy (Morrow, 2006). There is one important exception to these findings. Women treated with valproic acid are at significantly increased risk for malformations as subsequently discussed.
The most frequently reported anomalies are orofacial clefts, cardiac malformations, and neural-tube defects (Food and Drug Administration, 2009). Several older anticonvulsants produce a constellation of malformations similar to the fetal hydantoin syndrome (Fig. 12-3). Of agents in current use, valproic acid confers the greatest risk. The NAAED Pregnancy Registry reported that major malformations occurred in 9 percent of fetuses with first-trimester valproate exposure and included a 4-percent risk for neural-tube defects (Hernandez-Diaz, 2012). Moreover, children with in utero exposure to valproic acid are reported to have significantly lower intelligence quotient (IQ) scores at age 3 years compared with scores of those exposed to phenytoin, carbamazepine, or lamotrigine (Meador, 2009). Of the newer agents, topiramate has recently been reported by the NAAED Pregnancy Registry and the NBDPS to confer a risk for orofacial clefts at least fivefold higher than in unexposed pregnancies (Food and Drug Administration, 2011c; Margulis, 2012). Regardless of the anticonvulsant medication used, specialized sonography should be considered.
FIGURE 12-3 Fetal hydantoin syndrome. A. Facial features including upturned nose, mild midfacial hypoplasia, and long upper lip with thin vermilion border. B. Distal digital hypoplasia. (From Buehler, 1990, with permission.)
Angiotensin-Converting Enzyme Inhibitors and Angiotensin-Receptor Blocking Drugs
Angiotensin-converting enzyme (ACE) inhibitors are considered fetotoxic and result in ACE-inhibitor fetopathy. Normal renal development depends on the fetal renal-angiotensin system. ACE-inhibitor medication causes fetal hypotension and renal hypoperfusion, with subsequent ischemia and anuria (Guron, 2000; Pryde, 1993). Reduced perfusion may cause fetal-growth restriction and calvarium maldevelopment, whereas oligohydramnios may result in pulmonary hypoplasia and limb contractures (Barr, 1991). Because angiotensin-receptor blockers have a similar mechanism of action, concerns regarding fetotoxicity have been generalized to include this entire medication class.
The possible embryotoxicity of these two drug classes is less certain. Cooper and colleagues (2006) reported that first-trimester ACE-inhibitor exposure was associated with a two- to threefold increased risk for cardiac and central nervous system abnormalities, but these observations have not been corroborated. It is reasonable to offer specialized sonography for pregnancies with first-trimester exposure. Given the many therapeutic options for treating hypertension during pregnancy, discussed in Chapter 50 (p. 1006), it is recommended that ACE inhibitors and angiotensin receptor-blocking drugs be avoided.
From this class of drugs, fluconazole has been associated with a pattern of congenital malformations resembling the autosomal recessive Antley-Bixler syndrome. Abnormalities include oral clefts, abnormal facies, and cardiac, skull, long-bone, and joint abnormalities. Such findings have been reported only with chronic, high-dose treatment in the first trimester—at doses of 400 to 800 mg daily. In a recent population-based cohort of more than 7000 pregnancies with first-trimester exposure to low-dose fluconazole, a threefold increased risk for tetralogy of Fallot was identified (Molgaard-Nielsen, 2013). However, risks for other birth defects were not increased. The FDA (2011e) lists fluconazole as pregnancy category D, but it states that a single 150-mg dose to treat vulvovaginal candidiasis does not appear to be teratogenic.
Nonsteroidal Antiinflammatory Drugs
This drug class includes both aspirin and traditional “NSAIDs” such as ibuprofen and indomethacin. They exert their effects by inhibiting prostaglandin synthesis. At least 20 percent of pregnant women report use of these drugs in the first trimester. But, based on data from the NBDPS, such exposure does not appear to be a major risk factor for birth defects (Hernandez, 2012). Aspirin is not considered to increase the overall risk for congenital malformations (Kozer, 2002). Low-dose aspirin, 100 mg daily or lower, does not confer an increased risk for constriction of the ductus arteriosus or for adverse infant outcomes (Di Sessa, 1994; Grab, 2000). As with other NSAIDs, however, high-dose aspirin use should be avoided, particularly in the third trimester.
Importantly, NSAIDs may cause adverse fetal effects when taken in late pregnancy (Parilla, 2004; Rebordosa, 2008). Indomethacin may cause constriction of the fetal ductus arteriosus, resulting in pulmonary hypertension. The drug may also decrease fetal urine production and thereby reduce amnionic fluid volume. This is presumed due to an increase in vasopressin levels and vasopressin responsiveness (Rasanen, 1995; van der Heijden, 1994; Walker, 1994). Fetal ductal constriction is more likely when the drug is taken in the third trimester for longer than 72 hours’ duration. In a study of 60 exposed pregnancies, ductal constriction developed in 50 percent and was significantly more likely after 30 weeks (Vermillion, 1997). Fortunately, ductal flow velocity returned to normal in all fetuses following discontinuation of therapy. Other NSAIDs are assumed to confer similar risks.
This is a pyrimidine-synthesis inhibitor used to treat rheumatoid arthritis (Chap. 59, p. 1177). It is considered contraindicated in pregnancy because when given at or below human-equivalent doses in several animal species, it is associated with multiple abnormalities. These include hydrocephalus, eye anomalies, skeletal abnormalities, and embryo death (sanofi-aventis, 2012). The active metabolite of leflunomide is detectable in plasma for up to 2 years following its discontinuation. Women of childbearing potential who discontinue this medication should consider cholestyramine treatment/washout, followed by verification that serum levels are undetectable on two tests performed 14 days apart. Guidelines are also available for cholestyramine treatment/washout for men who discontinue leflunomide and who are contemplating fatherhood (Brent, 2001).
Medications used to treat infections are among those most commonly administered during pregnancy. Over the years, experience has accrued regarding their general safety. With a few exceptions cited below, most of the commonly used antimicrobial agents are considered safe for the embryo/fetus.
Preterm infants treated with gentamicin or streptomycin have developed nephrotoxicity and ototoxicity. Despite theoretical concern for potential fetal toxicity, no adverse effects have been demonstrated, and no congenital defects resulting from prenatal exposure have been identified.
This antimicrobial is not considered teratogenic and is no longer routinely used in the United States. More than 50 years ago, a constellation of findings termed the gray baby syndrome was described in neonates who received the medication. Preterm infants were unable to conjugate and excrete the drug and manifested abdominal distention, respiratory abnormalities, an ashen-gray color, and vascular collapse (Weiss, 1960). Chloramphenicol was subsequently avoided in late pregnancy due to theoretical concerns.
As discussed on page 241, the NBDPS found an association between first-trimester nitrofurantoin exposure and selected birth defects. These include a fourfold increased risk for hypoplastic left heart syndrome and microphthalmia/anophthalmia and a twofold increased risk for clefts and atrial septal defects (Crider, 2009). For postexposure counseling purposes, the absolute risk of these defects remains quite low. For example, a fourfold increased incidence of hypoplastic left heart would result in a prevalence of less than 1 per 1000 exposed infants (Texas Department of State Health Services, 2012). Nitrofurantoin is a proven first-line treatment of urinary infections. The American College of Obstetricians and Gynecologists (2013b) has concluded that first-trimester nitrofurantoin use is appropriate if no suitable alternatives are available.
These drugs are often combined with trimethoprim and used to treat various infections during pregnancy. One example is treatment of methicillin-resistant Staphylococcus aureus (MRSA). The NBDPS found associations between first-trimester sulfonamide exposure and a threefold increased risk for anencephaly and left ventricular outflow tract obstruction, an eightfold increased risk for choanal atresia, and a twofold increased risk for diaphragmatic hernia (Crider, 2009). The American College of Obstetricians and Gynecologists (2013b) considers sulfonamides appropriate for first-trimester use if suitable alternatives are lacking. There are also theoretical concerns that because sulfonamides displace bilirubin from protein binding sites, they may worsen hyperbilirubinemia if given near the time of preterm delivery. However, a recent population-based review of more than 800,000 births from Denmark found no association between receiving sulfamethoxazole in late pregnancy and neonatal jaundice (Klarskov, 2013).
These drugs are no longer commonly used in pregnant women. They are associated with yellowish-brown discoloration of deciduous teeth when used after 25 weeks, although the risk for subsequent dental caries does not appear increased (Billing, 2004; Kutscher, 1966).
Cancer management in pregnancy includes many chemotherapeutic agents generally considered to be at least potentially toxic to the embryo, fetus, or both. For the many novel polyclonal antibody therapies designated as antineoplastics, there are scant data concerning their safety. Some risks associated with cancer treatment with antineoplastic agents are discussed elsewhere—gestational trophoblastic neoplasia in Chapter 20 and cancer chemotherapy in Chapter 63. A few more common agents for which experience in pregnancy has accrued are considered below.
This alkylating agent inflicts a chemical insult on developing fetal tissues and leads to cell death and heritable DNA alterations in surviving cells. Pregnancy loss is increased, and reported malformations include skeletal abnormalities, limb defects, cleft palate, and eye abnormalities (Enns, 1999; Kirshon, 1988). Surviving infants may have growth abnormalities and developmental delays. Environmental exposure among health-care workers is associated with an increased risk for spontaneous abortion (Chap. 18, p. 354).
This folic-acid antagonist is a potent teratogen. It is used for cancer chemotherapy, immunosuppression in conditions such as autoimmune diseases and psoriasis, nonsurgical treatment of ectopic pregnancy, and finally, as an abortifacient. It is similar in action to aminopterin, which is no longer in clinical use, and can cause defects known collectively as the fetal methotrexate-aminopterin syndrome. This includes craniosynostosis with “clover-leaf” skull, wide nasal bridge, low-set ears, micrognathia, and limb abnormalities (Del Campo, 1999). The critical developmental period of these abnormalities is believed to be 8 to 10 weeks, at a dosage of at least 10 mg/week, although this is not universally accepted (Feldcamp, 1993). As discussed in Chapter 19 (p. 384), the standard 50 mg/m2 dose given to treat ectopic pregnancy or to induce elective abortion exceeds this threshold dose. Thus, ongoing pregnancies after treatment with methotrexate—especially if it is used in conjunction with misoprostol—raise serious concerns for fetal malformations (Creinin, 1994; Nurmohamed, 2011).
This nonsteroidal selective estrogen-receptor modulator (SERM) is used as an adjuvant to treat breast cancer (Chap. 63, p. 1231). Although it has not been associated with fetal malformations, it is fetotoxic and carcinogenic in rodents, inducing malformations similar to those caused by diethylstilbestrol (DES) exposure. Consequently, tamoxifen is pregnancy category D. It is recommended that women who become pregnant while either on therapy or within 2 months of its discontinuation be apprised of potential long-term risks of a DES-like syndrome. Exposed offspring should be monitored for carcinogenic effects for up to 20 years (Briggs, 2011).
This is a recombinant monoclonal antibody directed to the human epidermal growth factor receptor 2 (HER2) protein. It is used to treat breast cancers that over express HER2 protein (Chap. 63, p. 1230). This drug has not been associated with fetal malformations, but cases of oligohydramnios, anhydramnios, and fetal renal failure have been described (Beale, 2009; Sekar, 2007; Watson, 2005). Use may result in fetal pulmonary hypoplasia, skeletal abnormalities, and neonatal death.
The number of drugs used to treat viral infections has increased rapidly during the past 20 years. For most, experience in pregnant women is limited.
This nucleoside analogue is a component of therapy for hepatitis C infection, discussed in Chapter 55 (p. 1091). Ribavirin causes birth defects in multiple animal species at doses significantly lower than those recommended for human use. Reported malformations include skull, palate, eye, skeleton, and gastrointestinal abnormalities. The drug has a long half-life and persists in extravascular compartments following discontinuation of therapy. It is recommended that women use two forms of contraception while on therapy and delay childbearing for 6 months following drug discontinuation (Schering Corporation, 2012).
This is a nonnucleoside reverse transcriptase inhibitor used to treat HIV infection (Chap. 65, p. 1279). Central nervous system and ocular abnormalities have been reported in cynomolgus monkeys treated with human-comparable doses. More worrisome are multiple case reports of central nervous system abnormalities following human exposure (Bristol-Meyers Squibb, 2010).
Two endothelin-receptor antagonists—bosentan and ambrisentan—are used to treat pulmonary arterial hypertension (Chap. 49, p. 986). Teratogenic concerns with these drugs stem from the fact that mice deficient in endothelin receptors develop abnormalities of the head, face, and large blood vessels. However, no human data are available (Clouthier, 1998). Bosentan and ambrisentan may be obtained only through restricted programs—the Tracleer Access Program for bosentan and the Letairis Education and Access Program (LEAP) for ambrisentan. Each program has stringent requirements for women, including contraception and monthly pregnancy tests (Actelion Pharmaceuticals, 2012; Food and Drug Administration, 2012).
Some of the functions and effects of male and female hormones on the developing fetus are discussed in Chapter 7 (p. 147). It is intuitive that exposure of female fetuses to excessive male sex hormones—and vice versa—might be detrimental.
Testosterone and Anabolic Steroids
Androgen exposure in reproductive-aged women is typically anabolic steroid use to increase lean body mass and muscular strength. Exposure of a female fetus may cause varying degrees of virilization and may result in ambiguous genitalia similar to that encountered in cases of congenital adrenal hyperplasia (Fig. 7-18A, p. 149). Findings may include labioscrotal fusion with first-trimester exposure and phallic enlargement from later fetal exposure (Grumbach, 1960; Schardein, 1985).
This ethinyl testosterone derivative has weak androgenic activity. It is used to treat endometriosis, immune thrombocytopenic purpura, migraine headaches, premenstrual syndrome, and fibrocystic breast disease. In a review of inadvertent exposure during early pregnancy, Brunskill (1992) reported that 40 percent of exposed female fetuses were virilized. There was a dose-related pattern of clitoromegaly, fused labia, and urogenital sinus malformation.
From 1940 until 1971, between 2 and 10 million pregnant women were given this synthetic estrogen. Subsequently, Herbst and associates (1971) reported a series of eight women exposed to DES in utero who developed an otherwise rare neoplasm, vaginal clear-cell adenocarcinoma. The absolute cancer risk in DES-exposed fetuses was approximately 1 per 1000, with no relationship to dosage. Women with in utero DES exposure also had a twofold increase in vaginal and cervical intraepithelial neoplasia (Vessey, 1989).
Diethylstilbestrol exposure has further been associated with genital tract abnormalities in exposed fetuses of both genders. Women may have a hypoplastic, T-shaped uterine cavity; cervical collars, hoods, septa, and coxcombs; and “withered” fallopian tubes, as described and illustrated in Chapter 3 (p. 42) (Goldberg, 1999; Salle, 1996). Later in life, women exposed in utero have slightly higher rates of earlier menopause and breast cancer (Hoover, 2011). Men may develop epididymal cysts, microphallus, hypospadias, cryptorchidism, and testicular hypoplasia (Klip, 2002; Stillman, 1982).
Some of the immune functions necessary for pregnancy maintenance are discussed in Chapter 5 (p. 97). Given these important interactions, it would be logical that immunosuppressant drugs might affect pregnancy.
These medications include glucocorticoids and mineralocorticoids, which have antiinflammatory and immunosuppressive actions. They are commonly used to treat serious disorders such as asthma and autoimmune disease. Corticosteroids have been associated with clefts in animal studies. In a metaanalysis of case-control studies by the Motherisk program, systemic corticosteroid exposure was associated with a threefold increase in clefts, an absolute risk of 3 per 1000 exposed fetuses (Park-Wyllie, 2000). A 10-year prospective cohort study by the same group, however, did not identify increased risks for major malformations. Based on these findings, corticosteroids are not considered to represent a major teratogenic risk. Unlike other corticosteroids, the active metabolite of prednisone, which is prednisolone, is inactivated by the placental enzyme 11-beta-hydroxysteroid dehydrogenase 2 and does not effectively reach the fetus.
This inosine monophosphate dehydrogenase inhibitor, and a related agent, mycophenolic acid, are potent immunosuppressants used to prevent rejection in organ-transplant recipients. They are also used for treatment of autoimmune disease such as lupus nephritis (Chap. 59, p. 1172). The National Transplantation Pregnancy Registry reported that almost half of exposed pregnancies spontaneously aborted and a fifth of surviving infants had malformations—nearly half of which were ear abnormalities (Food and Drug Administration, 2008). A Risk Evaluation and Mitigation Strategy (REMS) is necessary before mycophenolate is prescribed. Providers receive a brochure detailing associated risks; acceptable protocols for contraception during therapy—because the medication may decrease oral contraceptive efficacy; importance of reporting pregnancies that are conceived while on therapy to the Pregnancy Registry; and finally, a patient-prescriber acknowledgement form.
Radioactive iodine-131 is used in the treatment of thyroid cancer and thyrotoxicosis and for diagnostic thyroid scanning (Chap. 63, p. 1231). 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. It causes irreversible fetal hypothyroidism and may increase the risk for childhood thyroid cancer (Chap. 58, p. 1149).
Prenatal lead exposure is associated with fetal-growth abnormalities and with childhood developmental delay and behavioral abnormalities. According to the CDC (2010), there is no lead exposure level that is considered safe in pregnancy. Care for at-risk pregnancies is discussed in Chapter 9 (p. 183).
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 and leads to a range of defects from developmental delay to microcephaly and severe brain damage (Choi, 1978). The principal concern for prenatal mercury exposure is the consumption of certain species of large fish (Chap. 9, p. 183). Pregnant women are advised to not eat shark, swordfish, king mackerel, or tilefish, and consumption of albacore tuna should be limited to 6 ounces per week (Food and Drug Administration, 2004).
Treatment of psychiatric illness in pregnancy, including a discussion of the risks and benefits of various psychiatric medications, is discussed in Chapter 61 (p. 1204). Selected birth defects and adverse effects associated with specific medications are presented here.
This medication has been associated with Ebstein anomaly, a cardiac abnormality characterized by apical displacement of the tricuspid valve. Ebstein anomaly often results in severe tricuspid regurgitation and marked right atrial enlargement, which confer significant morbidity. Its prevalence in the absence of lithium is approximately 1 per 20,000 births. Although a report from the Lithium Baby Register initially suggested that the risk for Ebstein anomaly was as high as 3 percent, subsequent series have demonstrated that the attributable risk is only 1 to 2 per 1000 exposed pregnancies (Reprotox, 2012; Weinstein, 1977). Fetal echocardiography should be considered for pregnancies exposed to lithium in the first trimester.
Neonatal lithium toxicity from exposure near delivery has been well documented. Findings typically persist for 1 to 2 weeks and may include hypothyroidism, diabetes insipidus, cardiomegaly, bradycardia, electrocardiogram abnormalities, cyanosis, and hypotonia (American College of Obstetricians and Gynecologists, 2012b; Briggs, 2011).
Selective Serotonin- and Norepinephrine- Reuptake Inhibitors
As a class, these medications are not considered major teratogens (American College of Obstetricians and Gynecologists, 2012b; Hviid, 2013). The one exception is paroxetine, which has been associated with increased 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—all identified a similar 1.5- to twofold increased rate of cardiac malformations following first-trimester paroxetine exposure (Bar-Oz, 2007; Food and Drug Administration, 2005a). For these reasons, the American College of Obstetricians and Gynecologists (2012b) recommends that paroxetine be avoided in women planning pregnancy, and that fetal echocardiography be considered for those with first-trimester paroxetine exposure.
Neonatal effects have been associated with prenatal exposure to selective serotonin-reuptake inhibitors (SSRIs) and selective norepinephrine-reuptake inhibitors (SNRIs). Approximately 25 percent of infants exposed to SSRIs in late pregnancy have been found to 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 may include jitteriness, irritability, hyper- or hypotonia, feeding abnormalities, vomiting, hypoglycemia, thermoregulatory instability, and respiratory abnormalities. Fortunately, these neonatal effects are typically mild and self-limited, lasting only about 2 days. Jordan and coworkers (2008) reported that newborns of mothers whose depression was not treated with medication were not more likely to require a higher level of care or extended hospitalization than SSRI-exposed newborns. Rarely, infants exposed to SSRIs in late pregnancy may demonstrate more severe adaptation abnormalities, including seizures, hyperpyrexia, excessive weight loss, or respiratory failure. This has been reported in 0.3 percent and has been compared to manifestations of SSRI toxicity or withdrawal in adults (Levin, 2004).
Another concern with late-pregnancy exposure is the possible association of SSRI medications with persistent pulmonary hypertension of the newborn. Its baseline incidence is 1 to 2 per 1000 term infants and is characterized by high pulmonary vascular resistance, right-to-left shunting, and profound hypoxemia. Chambers and colleagues (2006) identified a sixfold increase in pulmonary hypertension among those infants exposed to SSRIs after 20 weeks. A population-based cohort study involving 1.6 million pregnancies from the five Nordic countries identified a twofold increased risk following late-pregnancy exposure, an attributable risk of approximately 2 per 1000 births (Kieler, 2012). Other investigators have not found any increased risk (Wilson, 2011).
There are no antipsychotic medications that are considered teratogenic. Exposed neonates have manifested abnormal extrapyramidal muscle movements and withdrawal symptoms, including agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, feeding difficulty, and respiratory abnormalities. These findings are nonspecific and transient, similar to the neonatal behavioral syndrome that has been described following SSRI exposure. An FDA (2011a) alert cited 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.
These vitamin A derivatives are among the most potent human teratogens. Three 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 result in a pattern of cranial neural-crest defects—termed retinoic acid embryopathy—that involve the central nervous system, face, heart, and thymus (Fig. 12-4). 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.
FIGURE 12-4 Isotretinoin embryopathy. A. Bilateral microtia or anotia with stenosis of external ear canal. B. Flat, depressed nasal bridge and ocular hypertelorism. (Photograph contributed by Dr. Edward Lammer.)
13-cis-Retinoic acid is a vitamin A isomer that stimulates epithelial cell differentiation 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). The iPLEDGE program is an FDA-mandated REMS for isotretinoin and is found at: www.ipledgeprogram.com. This web-based restricted distribution program requires participation for all patients, physicians, and pharmacies to eliminate embryo-fetal exposure. Although other countries have instituted similar programs, inadvertent exposure remains a global concern (Crijns, 2011).
This retinoid is used to treat severe psoriasis. Acitretin was introduced to replace etretinate, a lipophilic retinoid with such a long half-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, 2011). To obviate exposure, the manufacturer of acitretin has developed a pregnancy risk management program called “Do Your P.A.R.T”–Pregnancy prevention Actively Required during and after Treatment, which is found at: www.soriatane.com. It 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 human-comparable doses, fetuses developed eye and ear abnormalities, cleft palate, and incomplete ossification (Eisai Inc., 2011). To receive this medication, the manufacturer requires two forms of contraception, beginning one month before therapy and continuing for one month after discontinuation, and monthly pregnancy tests during treatment (Eisai Inc., 2011). Males who have partners who could become pregnant are advised to use condoms during sexual intercourse while taking bexarotene and for one month after discontinuing therapy.
These compounds, initially used to treat acne, have become so popular for the treatment of sun damage that they are called cosmeceuticals (Panchaud, 2011). Examples include topical tretinoin and tazarotene. Systemic absorption is low, and this argues against plausible teratogenicity. Still, the manufacturer of tazarotene cautions that application over a sufficient body surface area could be comparable with oral treatment, which causes cranial neural-crest defects in animals (Allergan, 2011). Isolated case reports have described malformations following topical tretinoin. However, a prospective study by the European Network of Teratology Information Services, which included more than 200 pregnancies with first-trimester exposure to topical retinoids, found no differences in the rate of spontaneous abortion or birth defects compared with that of nonexposed pregnancies (Panchaud, 2011).
There are two 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, which has been associated with cranial neural-crest defects when more than 10,000 IU per day were 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 and American College of Obstetricians and Gynecologists, 2012).
Thalidomide and Lenalidomide
The drug thalidomide is likely the most notorious human teratogen. It 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, which results in the hands or feet being attached to the trunk by a small rudimentary bone. Cardiac malformations, gastrointestinal abnormalities, and other limb reduction defects are also common following thalidomide exposure.
Thalidomide was marketed outside the United States from 1956 to 1960, before its teratogenicity was appreciated. The ensuing disaster, with thousands of affected children, was instructive of a number of important teratological principles:
1. The placenta is not a perfect barrier to the transfer of toxic substances from mother to fetus (Dally, 1998).
2. There is extreme variability in species susceptibility to drugs and chemicals. Because thalidomide produced no defects in experimental mice and rats, it had been assumed to be safe for humans.
3. There is a close relationship between exposure timing and defect type (Knapp, 1962). Upper-limb phocomelia developed with thalidomide exposure during days 27 to 30. This coincides with appearance of the upper-limb buds at day 27. Lower-limb phocomelia was associated with exposure during days 30 to 33, gallbladder aplasia at 42 to 43 days, duodenal atresia at 40 to 47 days.
Thalidomide was first approved in the United States in 1999, and currently it is used to treat leprosy and multiple myeloma (Celgene, 2013). The FDA has mandated an REMS for thalidomide called THALOMID REMS, which is found at: www.thalomidrems.com/. This web-based restricted distribution program is required before participation by patients, physicians, and pharmacies.
Lenalidomide is an analogue of thalidomide that is used to treat some types of myelodysplastic syndrome and multiple myeloma. Because of obvious teratogenicity concerns, an REMS has been developed similar to that used for thalidomide, called the Revlimid REMS and is found at: www.revlimidrems.com/.
Like other coumarin derivatives, warfarin is a vitamin K antagonist and a potent anticoagulant. It has a low molecular weight and readily crosses the placenta, causing embryotoxic and fetotoxic effects. Exposure between the 6th and 9th weeks may result in warfarin embryopathy. This is characterized by stippling of the vertebrae and femoral epiphyses and by nasal hypoplasia with depression of the nasal bridge as shown in Figure 12-5 (Hall, 1980). Affected infants may also have choanal atresia, resulting in respiratory distress. The syndrome is a phenocopy of chondrodysplasia punctata, a group of genetic diseases thought to be caused by defects in osteocalcin. In studies conducted before the mid-1980s, warfarin embryopathy was reported in approximately 10 percent of exposed pregnancies (Briggs, 2011). A more recent study by the European Network of Teratology Information Services involving more than 600 pregnancies exposed to vitamin K antagonists found that warfarin embryopathy occurred in less than 1 percent of cases. However, the overall rate of structural abnormalities was increased nearly fourfold (Schaefer, 2006). The risk of embryopathy may be greater in women who require more than 5 mg daily (Vitale, 1999).
FIGURE 12-5 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).
When used beyond the first trimester, warfarin exposure may result in hemorrhage into fetal structures, which can cause abnormal growth and deformation from scarring (Warkany, 1976). Abnormalities may include agenesis of the corpus callosum; cerebellar vermian agenesis, which is the Dandy-Walker malformation; microphthalmia; and optic atrophy (Hall, 1980). Affected infants are also at risk for blindness, deafness, and developmental delays (Briggs, 2011).
Risks associated with various herbal remedies are difficult to estimate because these compounds are not regulated by the FDA. Thus, the identity, quantity, and purity of each ingredient are usually unknown. Because animal studies have not been conducted, knowledge of complications may be limited to reports of acute toxicity (Hepner, 2002; Sheehan, 1998). Given these uncertainties, it seems prudent to counsel pregnant women to avoid these substances. A list of selected herbal compounds and their potential effects is shown in Table 12-5.
TABLE 12-5. Pharmacological Actions and Adverse Effects of Some Herbal Medicines
At least 10 percent of fetuses are exposed to one or more illicit drugs (American Academy of Pediatrics and the American College of Obstetricians and Gynecologists, 2012). Assessment of outcomes attributable to illicit drugs may be confounded by factors such as poor maternal health, malnutrition, infectious disease, and polysubstance abuse. As discussed on page 245, alcohol is a significant teratogen, and because it is legally obtained and ubiquitous, its use also confounds that of illicit drugs. Moreover, illegal substances may contain toxic contaminants such as lead, cyanide, herbicides, and pesticides. Impurities added as diluents may independently have serious adverse perinatal effects. Some examples include fine glass beads, sawdust, strychnine, arsenic, antihistamines, and warfarin.
These sympathomimetic amines are not considered to be major teratogens. Some are used to dilute other illicit drugs. Methamphetamine is prescribed to treat obesity, narcolepsy, and attention deficit disorders. In utero exposure to methamphetamine is associated with fetal-growth restriction and with behavioral abnormalities in both infancy and early childhood. Limited data are available regarding later development (LaGasse, 2011a,b; Little, 1988).
This central nervous system stimulant is derived from the leaves of the Erythroxylum coca tree. Most adverse outcomes associated with cocaine result from its vasoconstrictive and hypertensive effects. It can cause serious maternal complications such as cerebrovascular hemorrhage, myocardial damage, and placental abruption. Studies of congenital abnormalities in the setting of cocaine exposure have yielded conflicting results, but associations have been reported with cleft palate, cardiovascular abnormalities, and urinary tract abnormalities (Chasnoff, 1988; Chavez, 1989; Lipshultz, 1991; van Gelder, 2009). Cocaine use is also associated with fetal-growth restriction and preterm delivery. Children exposed as fetuses are at increased risk for behavioral abnormalities and cognitive impairments (Bada, 2011; Gouin, 2011; Singer, 2002).
As a class, opioids are not considered to be major teratogens. That said, the NBDPS has identified a slightly increased risk for spina bifida, gastroschisis, and cardiac abnormalities in the setting of periconceptional exposure to therapeutic opioid medication (Broussard, 2011).
In contrast, opioid use is strongly associated with adverse fetal and neonatal effects. Heroin-addicted pregnant women are at increased risk for preterm birth, placental abruption, fetal-growth restriction, and fetal death—in part due to the effects of repeated narcotic withdrawal on the fetus and placenta (American College of Obstetricians and Gynecologists, 2012a; Center for Substance Abuse Treatment, 2008). Neonatal narcotic withdrawal, which is called the neonatal abstinence syndrome, may manifest in up to 90 percent of exposed infants (Blinick, 1973; Finnegan, 1975; Zelson, 1973). It is characterized by central nervous system irritability that may progress to seizures if untreated, along with tachypnea, episodes of apnea, poor feeding, and failure to thrive. At-risk neonates are closely monitored using a scoring system, and those severely affected are treated with opioids (Center for Substance Abuse Treatment, 2008; Finnegan, 1975). Data from the Birth Events Records Database from Washington state suggest that the proportion of exposed infants developing neonatal abstinence syndrome has increased in the past decade (Creanga, 2012).
Methadone is a synthetic opioid that has been routinely offered to pregnant heroin users since the 1970s to obviate uncontrolled narcotic withdrawal. It has a half-life of 24 to 36 hours and blocks narcotic cravings without producing intoxication. Women treated with methadone during pregnancy have been reported to be at increased risk for preterm birth and fetal-growth restriction (Cleary, 2010). Neonatal abstinence syndrome may occur in 40 to 70 percent of methadone-exposed infants and may be more protracted than with heroin exposure (Cleary, 2011; Dashe, 2002; Seligman, 2010). There is controversy as to whether a dose-response relationship exists between the maternal methadone dosage and neonatal withdrawal. At Parkland Hospital, pregnant opioid users are offered inpatient hospitalization for controlled methadone taper, with the goal of reducing the likelihood of neonatal abstinence syndrome (Dashe, 2002; Stewart, 2013). The American College of Obstetricians and Gynecologists (2012a) discourages withdrawal from methadone during pregnancy because of high relapse rates.
Marijuana use has not been associated with an increased risk for human fetal anomalies. Its active ingredient, delta-9-tetrahydrocannabinol, is teratogenic when given in high doses to animals. 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. Tolueneis a common solvent used in paints and glue. Occupational exposure is reported to have significant fetal risks (Wilkins-Haug, 1997). It is abused by intentional inhalation, which produces lightheadedness, dizziness, and loss of consciousness. When abused by women in early pregnancy, it is associated with toluene embryopathy, which is phenotypically similar to fetal alcohol syndrome. Abnormalities include pre- and postnatal growth deficiency, microcephaly, and characteristic face and hand findings. These include midface hypoplasia, short palpebral fissures, wide nasal bridge, and abnormal palmar creases (Pearson, 1994). Up to 40 percent of exposed children have developmental delays (Arnold, 1994).
Cigarette smoke contains a complex mixture of nicotine, cotinine, cyanide, thiocyanate, carbon monoxide, cadmium, lead, and various hydrocarbons (Stillerman, 2008). In addition to being fetotoxic, many of these substances have vasoactive effects or reduce oxygen levels. Tobacco is not considered a major teratogen, although selected birth defects have been reported to occur with increased frequency among infants 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 increased twofold (Martinez-Frias, 1999). An increased risk for cardiac anomalies has also been reported and may be dose-related (Alverson, 2011; Malik, 2008). A study using data from the National Vital Statistics System of 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).
The best-documented adverse reproductive outcome from smoking is a dose-response reduction in fetal growth. Newborns of mothers who smoke weigh an average of 200 g less than newborns of nonsmokers (D’Souza, 1981). Smoking doubles the risk of low birthweight and increases the risk of fetal-growth restriction two- to threefold (Werler, 1997). Growth disparity can be detected sonographically between 10 and 20 weeks (Mercer, 2008). Women who stop smoking early in pregnancy generally have neonates with normal birthweights (Cliver, 1995). Cigarette smoking has also been linked to subfertility and spontaneous abortions, to an increased risk for placenta previa and placental abruption, and to preterm delivery.
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