Chapter 20Teratogenesis and Environmental Exposure Christina Chambers, PhD, MPH, and Carl P. Weiner, MD, MBAA teratogenic agent is deﬁned as one that has the potential to interfere lidomide, a sedative-hypnotic drug, was associated with a dramaticwith the normal functional or structural development of an embryo increase in risk for a characteristic pattern of limb reduction anomaliesor fetus. A teratogenic exposure occurs when a pregnant woman is and other defects.3,4 Although the drug had undergone premarketexposed to an agent that increases risk. Although teratogenic exposures testing in rodents, it had not shown any evidence of adverse outcomesare generally thought of as those that increase the risk for major con- in these species. The subsequent recognition that therapeutic agentsgenital anomalies, in the broader sense, teratogenic exposures also could induce malformations was a major stimulus for the implementa-increase the risk for a spectrum of adverse pregnancy outcomes, tion of the Kefauver-Harris Amendment to the Food, Drug andincluding spontaneous abortion, stillbirth, minor structural anoma- Cosmetic Act in the United States, which expanded the role of the Foodlies, shortened gestational age, growth restriction, and behavioral or and Drug Administration (FDA) as a regulatory agency charged withcognitive deﬁcits. However, excess risks for these latter events are much ensuring both the efﬁcacy and the safety of products.5more difﬁcult to recognize. Although the thalidomide experience raised public awareness of the The currently known teratogenic exposures comprise a wide range potential risks of prenatal exposures, it was accompanied by misun-of agents, including some prescription and over-the-counter medica- derstandings about how to differentiate exposures that actually causetions, recreational drugs and alcohol, chemicals, physical agents, and birth defects from coincidental exposures occurring in women whosematernal diseases. Although studies speciﬁcally evaluating human tera- pregnancy outcome is abnormal for other, unrelated reasons. A classictogenicity are lacking for most environmental agents, including pre- example is doxylamine succinate and pyridoxine hydrochloride withscription medications, it is generally estimated that at least 10% of or without dicyclomine hydrochloride (Bendectin®), a once popularmajor birth defects are attributable to environmental exposures and antiemetic medication used by as many as 30% of American womentherefore are, to some extent, preventable.1 As a result, the possible for the treatment of nausea and vomiting of pregnancy. In 1983, thisteratogenicity of agents to which a woman may be exposed during agent was voluntarily withdrawn from the market after anecdotal con-pregnancy is of great concern to the general public and requires that cerns for teratogenicity triggered on onslaught of litigation, despiteclinicians develop expertise in evaluating these risks on behalf of their voluminous scientiﬁc evidence to the contrary.6patients. Within the last 40 years, research in the ﬁeld of teratology has advanced, and several new human teratogens have been identiﬁed, including several anticonvulsants, selected antineoplastic agents,Historical Perspective inhibitors of enzymes in the angiotensinogen-angiotensin pathway, methylmercury, cocaine, alcohol, hyperthermia, tetracycline, warfarin,Before the 1940s, it was somewhat naively thought that the placenta and isotretinoin.7 Work continues to better deﬁne the range of adverseprovided a protective barrier for the developing embryo and fetus, so outcomes associated with these exposures, the magnitude of the riskthat agents to which the mother was exposed could not interfere with for a given dose at a speciﬁc gestational age, and the subpopulationsnormal prenatal development. The revolutionary concept that a mater- of mothers and infants who may be at particularly increased risknal exposure could pose a risk to the developing embryo or fetus was because of their genotype. However, major knowledge gaps exist forﬁrst raised, not by a scientist or an obstetrician, but rather by an Aus- most agents—few of which have been adequately evaluated in humantralian ophthalmologist, Norman Gregg, who observed in his own pregnancy.8clinical practice an unusual number of children diagnosed with con- Concerns regarding the inadequacy of accurate information forgenital cataracts shortly after a rubella epidemic. Gregg’s work led to the developmental effects of a majority of therapeutic and over-the-investigations that identiﬁed additional features of a variable but char- counter agents are critical. Studies indicate that drug exposure duringacteristic pattern of developmental abnormalities associated with fetal pregnancy is extremely common: in one U.S. health care system samplerubella infection, including congenital heart defects, hearing deﬁcits, of 98,182 deliveries, 64% of women were prescribed at least one medi-and endocrine abnormalities, all of which came to be known as the cation during their pregnancy other than a vitamin or mineral supple-congenital rubella syndrome.2 ment.9 In another U.S. population–based sample of women, more than In the early 1960s, an Australian obstetrician and a German geneti- 70% reported the use of one or more over-the-counter medicationscist independently recognized that ﬁrst-trimester maternal use of tha- during pregnancy.10 Therefore, a theoretical and practical framework
348 CHAPTER 20 Teratogenesis and Environmental Exposureis necessary to aid clinicians in advising patients, who are likely to have portion of the ﬁrst trimester, whereas later gestational exposure isexperienced several exposures by the time their pregnancy is recog- associated with central nervous system (CNS) effects.18 The formernized, and to help support evidence-based clinical decision making abnormality likely reﬂects a vitamin K deﬁciency, the latter a complica-in the common situations in which pregnancy exposures can be tion of fetal bleeding.anticipated. Consistent with these concepts, very early gestational exposure, limited in general to the ﬁrst 2 weeks after conception, is thought to pose little potential for teratogenicity. This is true in part because ofPrinciples of Teratology the limited biologic availability to the embryo of an agent that is taken and eliminated by the mother before the completion of placentation.Wilson and Fraser11 outlined the basic principles of teratology in the Further, pluripotent cells of the early embryo may be resilient in recov-early 1970s to aid in identifying those agents with teratogenic potential ering from a teratogenic insult, or, alternatively, they may be particu-and to provide a basis for establishing causality. Appreciation of these larly vulnerable to a teratogenic exposure, resulting in spontaneousprinciples can help clinicians place into context research ﬁndings from abortion before the clinical recognition of pregnancy.11the literature as well as individual patient histories. The principles The principle of dose response suggests that, for those agentsdiscussed here are species speciﬁcity, genetic susceptibility, gestational that are teratogenic, there is a threshold dose below which no effect istiming, dose response, route of administration, spectrum of outcomes, detected, and higher doses produce stronger effects relative to lowerand speciﬁc mechanisms leading to pathogenesis. doses, with the highest doses being lethal. For example, when the The principle of species speciﬁcity, in combination with the concept anticonvulsant valproic acid is ingested by a pregnant woman duringof genetic susceptibility, holds that agents that are teratogenic in one the critical window for neural tube closure, the risk for that defectspecies may not be so in another. Similarly, the manifestations of a increases by approximately 10- to 20-fold, from a baseline risk of 0.1%teratogenic exposure may differ across susceptible species, and, even to a risk of 1% to 2% . However, there is evidence that the risk is dose-within species, certain strains or individuals may be at higher risk than related, because valproate-treated mothers who deliver infants withothers. spina biﬁda on average have taken signiﬁcantly higher doses than val- These two principles have implications for the predictive value of proate-treated mothers of normal newborns.19preclinical animal reproductive toxicity studies; for example, thalido- The principle of route of administration is closely linked to themide was not teratogenic in the species initially tested, and only after principle of dose response from the standpoint of inﬂuencing theits recognition as a human teratogen was the most sensitive animal effective dose that is biologically available to the embryo or fetus. Thisspecies identiﬁed.12 Variability in susceptibility is also evident within is a critical element in the design of animal reproductive and develop-species, including humans, where no teratogenic agent at typical doses mental toxicity studies in terms of their comparability to human preg-has been demonstrated to produce adverse effects in 100% of concep- nancy exposures. This principle can be applied to studies regarding thetuses. Even potent, known human teratogens such as thalidomide and relative toxicity of human exposures resulting from oral dosing versusisotretinoin affect fewer than 50% of exposed infants. In some cases, topical application. For example, retinoids as a class have been identi-this variability in susceptibility has been linked to speciﬁc genetic ﬁed as human teratogens with effects that depend on the dose andpolymorphisms that interact with the agent to create a particularly timing of exposure in gestation. Isotretinoin taken as an oral medica-susceptible subgroup of mothers or fetuses. tion is one of the most potent known human teratogens. Exposure to For example, women with infants who have cleft lip with or without isotretinoin limited to as little as a few days in early pregnancy resultscleft palate or isolated cleft palate are approximately twice as likely to in an approximate 20% risk of a pattern of brain, heart, ear, andreport heavy ﬁrst-trimester tobacco use than are mothers of normal thymus abnormalities and mental deﬁciency in liveborn children.20 Innewborns; however, women who have a certain transforming growth contrast, topical retinoids, when used sparingly in the ﬁrst trimesterfactor-α (TGF-α) polymorphism and who smoke heavily have a 3 to for blemishes or to reduce signs of skin aging, have not been associated11 times higher risk of having a child with an oral cleft, suggesting a with a measurably increased risk for the same pattern of adversegene-environment interaction. Furthermore, this risk appears to be effects.21,22 These ﬁndings do not rule out the teratogenic potential oflessened by maternal multivitamin use.13,14 Similarly, a low level of topical retinoids but simply suggest that the maternal blood levels ofepoxide hydrolase enzyme activity inﬂuenced by epoxide hydrolase retinoids delivered via skin absorption may represent a teratogenic riskpolymorphisms has been implicated as a risk factor for fetal hydantoin that is so low as to be undetectable without very large sample sizes.syndrome in children whose mothers have taken phenytoin for the The principle of spectrum of outcomes indicates that, depending ontreatment of a seizure disorder during pregnancy.15 dose and timing in gestation, adverse outcomes associated with a given The principle of gestational timing, or critical developmental teratogen may encompass effects ranging from spontaneous abortionwindows of exposure, requires that the exposure occur during the stage or stillbirth to major and minor structural defects, prenatal or postna-in development when the maturational process is most susceptible. For tal growth deﬁciency, preterm delivery, and functional deﬁcits or learn-example, the critical window for an agent that interferes with closure ing disabilities. For example, moderate to heavy maternal alcoholof the neural tube in the human embryo is approximately the ﬁrst intake, particularly if consumed in a “binge” pattern, has been demon-3 weeks after conception. Carbamazepine, an anticonvulsant linked strated to increase the risks for spontaneous abortion, stillbirth, ato a 10-fold increased risk for neural tube defects, does not produce characteristic pattern of minor craniofacial abnormalities, selectedthe defect if maternal exposure occurs after the second month of speciﬁc major structural defects including heart defects and oral clefts,pregnancy.16,17 prenatal and postnatal growth deﬁciency, deﬁcits in global IQ, and A corollary to this principle is that, depending on the precise ges- speciﬁc behavioral and learning abnormalities.23 Animal and humantational timing of teratogenic exposure, a range of adverse outcomes studies consistently support the notion that the entire spectrum ofmay be induced. For example, coumarin-derived anticoagulants are outcomes associated with alcohol may not be manifested in any singleassociated with a pattern of nasal hypoplasia and skeletal abnormalities affected pregnancy; rather, the results vary by dose and pattern ofwhen prenatal exposure occurs during a critical window in the latter drinking, differ with gestational timing of exposure, and are inﬂuenced
CHAPTER 20 Teratogenesis and Environmental Exposure 349by genetic susceptibility and other modifying factors such as maternal potential for human teratogenicity. For almost all known humannutrition. teratogens, there is an animal model; however, animal studies are not Finally, the principle of speciﬁc mechanisms leading to pathogenesis completely predictive of human pregnancy outcomes due to speciesspeciﬁes that teratogenic agents do not increase the risk of all adverse sensitivity and differences in dosing and exposure timing.outcomes; rather, they act on speciﬁc targets to produce a characteristicpattern of effects. This principle underlies the methods by which manyhuman teratogens have been recognized; that is, a pattern of abnor- Adverse Case Reportsmalities associated with a particular teratogenic exposure helps to When new medications are marketed in the United States, initialidentify that exposure as a cause of the outcome. For example, the reports of pregnancy exposures with adverse outcomes may appear ascharacteristic pattern of abnormalities comprising the fetal alcohol case reports in the literature, or through safety data provided to thesyndrome includes minor craniofacial features (short palpebral ﬁs- FDA by manufacturers, or in voluntary reports by clinicians or patients.sures, smooth philtrum, and thin vermilion of the upper lip) accom- Although individual adverse outcome reports have the potential topanied by microcephaly, growth deﬁciency, and cognitive and generate a hypothesis regarding teratogenicity—especially if thebehavioral deﬁcits. The prenatal effects of alcohol, although pervasive, outcome reported is an unusual pattern of malformation—these datanevertheless represent a constellation or pattern of features that is sources lack critical information about the number of exposed preg-unlikely to randomly occur without exposure to alcohol in substantial nancies with normal outcomes and therefore can confuse the processdoses and during certain gestational weeks. of determining whether the adverse event reports represent an excess It therefore appears likely that there are a few general mechanisms risk over the baseline for that event.that lead to abnormal development. For example, a teratogenic agentcan interact with a receptor, bind to DNA or protein, degrade cellmembranes or proteins, inhibit an enzyme, or modify proteins. These Pregnancy Registriesmechanisms ultimately manifest as one or more types of abnormal Additional sources of pregnancy safety information on new drugsembryogenesis, including excessive or reduced cell death, failed cell sometimes include pregnancy registries. Registries typically collectinteractions, reduced biosynthesis, impeded morphogenetic move- data regarding exposures to a speciﬁc drug or class of drugs, bothment, or mechanical disruption of tissues. For this reason, several retrospectively and prospectively. The outcome of primary interest inspeciﬁc teratogens may have the same end result on development by traditional pregnancy registries is major birth defects. Registry data areacting through a common pathway. For example, some anticonvul- periodically summarized and reviewed for possible “signals” that mightsants, trimethoprim, and triamterine may increase the risk for neural lead to recommendations for initiation of a hypothesis-testing study.tube defects via folate antagonism.24 Angiotensin I–converting enzyme Strengths of registries include their potential for gathering early infor-(ACE) inhibitors such as enalapril and lisinopril may induce the mation about a new drug and the possibility of identifying a uniquerisk for ACE-inhibitor fetopathy, which consists of renal tubular pattern of malformation that is associated with exposure to the drugdysplasia and hypocalvarium, possibly through the mechanism of interest. However, traditional registries lack formal comparisonof drug-induced fetal hypotension leading to hypoperfusion and groups and typically have outcome data on relatively small numbersoligohydramnios.25 of pregnancies. As a result, they usually have insufﬁcient sample size to detect increased frequencies of speciﬁc and relatively rare birth defects.26 Nevertheless, collaborative registry designs such as the Antiepileptic Drugs in Pregnancy Registry have demonstrated successSources of Safety Data on in identifying signals or establishing higher than expected rates forExposures in Pregnancy major birth defects after selected exposures.27In the ideal world, clinicians would have access to complete informa-tion about the human teratogenic potential of all environmental expo- Observational Cohort Studiessures, including medications, recreational drugs, nutrients and nutrient Another source of pregnancy safety data originates from observationalsupplements, occupational exposures, toxic exposures or poisonings, cohort studies that are initiated with the goal of testing a speciﬁchousehold chemicals and cosmetics, environmental contaminants or hypothesis. These include prospectively designed exposure cohortpollutants, and physical agents such as heat and radiation. Unfortu- studies in which women with and without the exposure of interest arenately, for many if not most exposures, reliable information is limited. enrolled during pregnancy and followed to outcome. Such studies haveSufﬁcient human data are commonly lacking for even prescription the ability to evaluate a spectrum of outcomes, including major andmedications whose safety is monitored by the FDA. In one study minor malformations, and to collect early information on a new drug.reviewing the human safety data for prescription medications mar- They also have the advantage of including a comparison group orketed in the United States over the previous 20 years, Lo and Friedman8 groups, allowing for the control of key factors that may be confound-concluded there were insufﬁcient data to conﬁrm or rule out terato- ers, such as maternal age, socioeconomic status, and alcohol or tobaccogenicity for more than 80% of these agents. use. Such a study design was successful identifying carbamazepine as There are many reasons for this situation, some inherent to the a human teratogen.28 One disadvantage of this approach is that thedifﬁculty of conducting pregnancy outcome research and some related sample sizes are typically too small to rule out anything but the mostto the lack of a standard surveillance system for studying agents to dramatically increased prevalence of speciﬁc major birth defects.which women of reproductive age are likely to be exposed. Clinicaltrials for prescription medications are not typically conducted inhuman pregnancy, and the pharmaceutical industry has no incentive Database Cohortsto do so even when there is an apparent clinical need. Animal repro- A variation of the observational cohort involves construction of anductive and developmental toxicity studies are used to estimate the historical cohort using archived information in existing databases. For
350 CHAPTER 20 Teratogenesis and Environmental Exposureexample, health maintenance organization claims data and records TABLE 20-1 FDA PREGNANCY CATEGORIESfrom government-supported healthcare agencies are increasingly beinganalyzed for information on pregnancies with or without speciﬁc Category Deﬁnitionmedication exposures. The strengths of this approach include the A Adequate and well-controlled studies have failed topotential cost savings for collecting data for a given number of preg- demonstrate a risk to the fetus in the ﬁrst trimesternancies, but the limitations include sample sizes that are too small to of pregnancy (and there is no evidence of risk indetect increased risks for many, if not most, speciﬁc birth defects. In later trimesters).addition, because database studies rely on information not collected B Animal reproduction studies have failed toprimarily for research purposes, validation of exposure and outcome, demonstrate a risk to the fetus and there are noas well as data on some key potential confounders, may be difﬁcult or adequate and well-controlled studies in pregnantimpossible to obtain. Nevertheless, database cohorts have been used, women.for example, to identify a possible link between paroxetine and con- C Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate andgenital heart defects.29 well-controlled studies in humans, but potential beneﬁts may warrant use of the drug in pregnant women despite potential risks.Case-Control Studies D There is positive evidence of human fetal risk basedIn case-control study designs, pregnancies are retrospectively selected on adverse reaction data from investigational orfor having a speciﬁc outcome, such as a particular birth defect. The marketing experience or studies in humans, butfrequency of exposure to an agent of interest among mothers of potential beneﬁts may warrant use of the drug inaffected infants is compared with the frequency among mothers whose pregnant women despite potential risks.pregnancies did not result in that birth defect. A major strength of X Studies in animals or humans have demonstrated fetalcase-control studies is that, with proper numbers of cases and controls, abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction datathey can provide sufﬁcient power to detect increased risks for rare from investigational or marketing experience, andoutcomes. In addition, because they include a comparison group, they the risk involved in use of the drug in pregnantcan collect information on important potential confounding variables women clearly outweighs potential beneﬁts.such as age, socioeconomic status, and alcohol and tobacco use. Thecase-control approach was used successfully to identify the associationof misoprostol (used to induce abortion) with a very high risk for arare congenital facial nerve paralysis, Möbius syndrome.30 Limitations associated with prescription drugs. However, this category system isto case-control studies include the lag time inherent in collecting infor- frequently misunderstood by health care providers and patients alike.mation on a new drug, especially if it is infrequently used by pregnant The categories are summarized in Table 20-1.women. Another limitation is the inability to evaluate an agent for In practice, the FDA category assigned to a medication often mis-a spectrum of outcomes that are as yet unidentiﬁed as part of represents or oversimpliﬁes the actual evidence. For example, thethe anomaly pattern. Finally, it is possible that women who are category assignments do not take into consideration factors such asalready aware of a negative outcome of their pregnancy may recall exposure timing in gestation or dose and route of administration.exposures more carefully (or incorrectly) than those who had a normal Although several drugs assigned to category X (i.e., contraindicated inoutcome. pregnancy) are indeed known human teratogens (e.g., isotretinoin), others, such as ribavirin and the “statins,” were assigned to that cate- gory based on theoretical concerns or animal data without conclusiveSummary of Data Sources human data to establish a teratogenic risk.32 Further, incorporation ofIn summary, the strengths and weaknesses of the methodologies that new data into the label and classiﬁcation updates is often slow.are available to evaluate for potential teratogenicity reveal that no Communication of potential risk to a woman regarding a categorysingle approach is sufﬁcient. From the clinical perspective, this means X exposure that has already taken place varies substantially from thatthat conclusions drawn from one type of study must be interpreted for an exposure that is anticipated. An example is the communicationwith caution until they are either conﬁrmed or refuted by other types of information regarding risk from an exposure to ribavirin (to treatof studies. This is especially important in recognizing high-risk expo- hepatitis C) that occurred during an unplanned pregnancy comparedsures (and perhaps even more so for identifying agents that are not with the communication of concern if the clinician and patient areteratogenic), so that appropriate treatment decisions can be made. prospectively determining whether ribavirin is an appropriate medica-From a public health perspective, a combination of complementary tion to use. Such nuances are not reﬂected in the category statements.study designs is required, one that ideally is initiated in a coordinated, In recognition of these limitations and weaknesses, the FDA has workedsystematic fashion so as to provide clinicians and patients with the best with an advisory committee to develop recommended revisions to theand earliest possible information.31 category system and the label format.33 Other sources of information readily available to the clinician include a number of print resources, each with different approaches to providing summary information. Some of these references are avail-Risk Assessments able in hard copy, compact disk (CD-ROM), and personal digital assis-and Resources tant (PDA) versions.34,35 Online databases that provide summary statements prepared by experts in the ﬁeld of teratology and updatedThe U.S. FDA established a widely used pregnancy safety category on a frequent basis include TERIS and REPROTOX (available atsystem that is incorporated into the product label with the intent of http://www.micromedex.com/reprorisk [accessed January 14, 2008]).informing clinicians and pregnant women of the teratogenic risks In addition, the Organization of Teratology Information Specialists
CHAPTER 20 Teratogenesis and Environmental Exposure 351(OTIS) provides individualized information to clinicians as well as the radiographs, and growth restriction. Central nervous system (CNS)public via toll-free telephone access (see http://otispregnancy.org and eye abnormalities including microcephaly, hydrocephalus, Dandy-[accessed January 14, 2008]). Clinicians or patients who are interested Walker malformation, agenesis of the corpus callosum, optic atrophy,in pregnancy registries that are open for enrollment can locate a cataracts, and mental retardation occur occasionally.36,37 The criticalcurrent list at the FDA’s Ofﬁce of Women’s Health Web site (avail- period for the warfarin embryopathy appears to be between 6 and 9able at http://www.fda.gov/womens/registries [accessed January 14, weeks’ gestation. A systematic review of 17 studies involving a total of2008]). 979 exposed pregnancies estimated a 6% incidence of warfarin embry- opathy. In addition, 22% of exposed pregnancies ended in spontaneous abortion, 4% in stillbirth, and 13% in preterm delivery.38 A largeSelected Human Teratogens multicenter study of 666 pregnancies with exposure to vitamin K antagonists reported a signiﬁcant increase in the rate of major birthTable 20-2 presents the potential effects of selected human teratogens, defects overall, relative to unexposed healthy comparison womensome of which are discussed further in the following sections. (odds ratio [OR], 3.86; 95% conﬁdence interval [CI], 1.76 to 8.00). In that study, only 2 infants (0.6%) were thought to have warfarin embry- opathy. In addition, the rate of preterm delivery was increased (16.0%Vitamin K Antagonists versus 7.6%; OR, 2.61; CI, 1.76 to 3.86); the mean birth weight of termA speciﬁc pattern of congenital anomalies referred to as the fetal war- infants was signiﬁcantly lower (3166 versus 3411 g); and the rate offarin syndrome has been identiﬁed in some children born to mothers spontaneous abortion was signiﬁcantly higher (42% versus 14%; OR,who use medications such as phenprocoumon, acenocoumarol, ﬂuin- 3.36; CI, 2.28 to 4.93) with exposure.18dione, warfarin, and phenindione, which are vitamin K antagonists. In one study of 71 pregnancies occurring in 52 women with pros-The features include nasal hypoplasia, stippled epiphyses visible on thetic heart valves who were being treated with warfarin, the risk for TABLE 20-2 EFFECTS OF SELECTED TERATOGENS Drug Potential Effects Comments ACE inhibitors Calvarial hypoplasia, renal dysgenesis, oligohydramnios, IUGR, Risk seen with use in second and third and neonatal renal failure trimester Alcohol Syndrome: prenatal and postnatal growth restriction, Risk not limited to ﬁrst trimester; late microcephaly, craniofacial dysmorphology (1-4/1000 live pregnancy use is associated with IUGR and births); renal, cardiac, and other major malformations developmental delay; incidence is 4-44% increased among “heavy drinkers” Antidepressants (SSRIs) Possible cardiac defects, NTDs, omphalocele; neonatal — pulmonary hypertension and withdrawal syndrome Aminopterin and Syndrome: calvarial hypoplasia, craniofacial abnormalities, limb Syndrome associated with methotrexate methotrexate defects; possible developmental delay >10 mg/wk Androgens and Masculinization of external female genitalia Labioscrotal fusion can occur with exposure; norprogesterones as many as 50% of those exposed are affected Carbamazepine NTDs (1%); possible facial hypoplasia and developmental delay — Corticosteroids Cleft lip/palate increased threefold to sixfold; IUGR increased — with high doses Diethylstilbestrol Clear cell adenocarcinoma of the vagina, vaginal adenosis, — abnormalities of the cervix and uterus, testicular abnormalities, male/female infertility Isotretinoin Syndrome: CNS malformations, microtia/anotia, micrognathia, — thymus abnormalities, cleft palate, cardiac abnormalities, eye anomalies, limb reduction defects (28%); miscarriage (22%), developmental delay (47%) Lithium Small increase in Ebstein cardiac anomaly — Penicillamine Cutis laxa with chronic use — Phenytoin Syndrome: IUGR, microcephaly, facial hypoplasia, hypertelorism, Full syndrome in 10%; up to 30% exhibit prominent upper lip (10%); possible developmental delay some features Streptomycin Hearing loss, eighth nerve damage — Tetracycline Discoloration of deciduous teeth and enamel hypoplasia Risk only in second and third trimester Tobacco Oral clefts: relative risk, 1.22-1.34; IUGR, IUFD, abruption — Trimethadione Syndrome: oral clefts, craniofacial abnormalities, developmental — delay (80%) Valproic acid NTDs (1-2%); facial hypoplasia, possible developmental delay — Warfarin Syndrome: nasal hypoplasia, stippled epiphyses, growth Greatest risk is at 6-9 wk restriction (6%); also increased microcephaly, Dandy-Walker syndrome, IUGR, preterm birth, mental retardation ACE, angiotensin-converting enzyme; CNS, central nervous system; IUGR, intrauterine growth restriction; NTD, neural tube defect.
352 CHAPTER 20 Teratogenesis and Environmental Exposureadverse outcome was found to be signiﬁcantly greater with doses Carbamazepinegreater than 5 mg/day.39 A review of 85 pregnancies involving exposure Similar to valproic acid, carbamazepine has been associated with anto a coumarin drug only after the ﬁrst trimester reported that 1 preg- increased risk for spina biﬁda (approximately 1%) with exposure innancy ended in stillbirth, 3 in spontaneous abortion, and 19 in preterm the early ﬁrst trimester.16 It has also been linked to a pattern of minorbirths; 1 infant had a CNS anomaly, and none had the warfarin embry- craniofacial abnormalities, including upslanting palpebral ﬁssures, aopathy.38 In addition, in one large study that evaluated the cognitive long philtrum, and nail hypoplasia, as well as growth deﬁciency andperformance of 307 children prenatally exposed to warfarin, compared microcephaly.28 Although some small studies have suggested develop-with that of nonexposed children, mean IQ scores did not differ mental delay after prenatal exposure to carbamazapine,57 others havesigniﬁcantly, but low intelligence scores (IQ < 80) occurred more not.58,59frequently in those children whose exposure was limited to the secondand third trimester.40 Other Antiepileptic Drugs A number of newer antiepileptic medications have been introduced into practice over the past several years, including lamotrigine, gaba-Antiepileptic Drugs pentin, and topiramate. Although these agents are currently beingAs a group, most older drugs used to treat seizure disorders are as- studied, insufﬁcient information has been collected to rule out orsociated with an increase in the risk of congenital malformations.41,42 identify risks similar to those seen with older anticonvulsants. Further-This has been suggested to indicate that the underlying disease is the more, speciﬁc risks associated with the use of older- and newer-teratogenic cause. Newer studies have challenged this concept42-44; generation anticonvulsants for other indications, such as treatmenthowever, it is difﬁcult to separate the effects of the disease from those of mood disorders, has not been well studied.of treatment, especially for more severe epilepsy, which is unlikely tobe untreated during pregnancy. The use of multiple anticonvulsantmedications (polytherapy) as opposed to a single drug (monotherapy)is associated with greater risk of structural defects.43,45,46 It is unclear Chemotherapeutic andwhether this is a result of drug-drug interactions, more severe disease Immunosuppressive Agentsin women requiring treatment with polytherapy, or a combination ofthe two. Cyclophosphamide Eight case reports documenting a unique pattern of malformation inDiphenylhydantoin infants prenatally exposed to cyclophosphamide have been published.60Phenytoin as a treatment for seizure disorders has been associated with Features include growth deﬁciency, craniofacial anomalies, and absentan increased risk for oral clefts and for a pattern of anomalies known ﬁngers and toes. In three of these cases, the infant survived and devel-as the fetal hydantoin syndrome. This pattern is estimated to occur in opmental information was available; signiﬁcant delays were noted in10% of infants with prenatal exposure and includes prenatal or post- all three. The magnitude of the risk is unknown.natal growth restriction, microcephaly, hypoplasia of the digits andnails, and craniofacial abnormalities (i.e., short nose with low nasal Methotrexatebridge, ocular hypertelorism, abnormal ears, and a wide mouth with Both aminopterin and its methyl derivative, methotrexate, havea prominent upper lip).47-49 Initial reports suggested that mental deﬁ- been associated with a speciﬁc pattern of malformation that includesciency was also a common feature of fetal hydantoin syndrome.50 prenatal-onset growth deﬁciency, severe lack of calvarial ossiﬁcation,However, the limited subsequently published data suggest that neu- hypoplastic supraorbital ridges, small low-set ears, micrognathia, limbrobehavioral effects may be more mild.51 For example, Scolnik and abnormalities, and, in some cases, developmental delay.61,62 The major-colleagues52 reported that average IQ scores were 10 points lower in ity of affected infants have been born to women treated with high-dosechildren exposed to phenytoin monotherapy, compared with unex- methotrexate for psoriasis or neoplastic disease or as an abortifacient.posed children born to mothers who were matched on age and socio- Although the magnitude of the risk is unknown, it has been suggestedeconomic status. that the dose necessary to produce the aminopterin/methotrexate syn- drome is greater than 10 mg/wk.63,64Valproic AcidStudies over the last 2 decades have associated early ﬁrst-trimesterexposure to valproic acid with an increased risk for neural tube defects,speciﬁcally spina biﬁda. The estimated risk is about 1% to 2%, with Adrenal Corticosteroidshigher doses thought to be associated with higher risk.19,53 It has been Among four recent case-control studies, three concluded that systemicestimated that the overall risk for major birth defects is increased by corticosteroid use in the ﬁrst trimester appears to be associated with afourfold to sevenfold after valproate monotherapy, with increased risks threefold to sixfold increased risk for cleft lip with or without cleftfor speciﬁc cardiovascular, limb, and genital anomalies noted in some palate and possibly cleft palate alone.65-68 It is unclear to what extentreports.27 As with other anticonvulsants, a pattern of minor malforma- this association was caused by the various underlying maternal diseasestions and growth deﬁciency has also been identiﬁed for valproic acid; involved in these studies. If only the positive studies are considered,it includes midface hypoplasia, epicanthal folds, short nose, broad this relative risk translates to a risk of approximately 3 to 6 cases pernasal bridge, thin upper lip, thick lower lip, micrognathia, and subtle 1000 pregnancies exposed in the critical period for lip and palatelimb defects (primarily hyperconvex ﬁngernails).54 In addition, there closure. Furthermore, an association has long been recognized betweenis some evidence that valproic acid monotherapy is associated with prenatal exposure to corticosteroids and intrauterine growth restric-reduced cognitive ability and additional educational needs in children tion in humans. The risk appears to be dose-related, suggesting thatprenatally exposed.55,56 this concern can be minimized with lower doses.69,70
CHAPTER 20 Teratogenesis and Environmental Exposure 353 craniosynostosis (adjusted OR, 2.5; CI, 1.5 to 4.0), and omphaloceleAntihypertensive Medications (adjusted OR, 2.8; CI, 1.3 to 5.7).78 A second large, multisite, case- control study did not conﬁrm these ﬁndings with respect to cranio-Angiotensin I Converting Enzyme synostosis, omphalocele, neural tube defects, or cardiac defects when(ACE) Inhibitors and Angiotensin II all SSRIs were evaluated as a group but did ﬁnd signiﬁcantly increasedReceptor Antagonists risks with speciﬁc drugs. With ﬁrst-trimester sertraline use, the oddsBased on case reports and case series, prenatal exposure to an ACE were increased for omphalocele (adjusted OR, 5.7; CI, 1.6 to 20.7) andinhibitor (benazepril, captopril, enalapril, enalaprilat, fosinopril, lisin- septal defects (adjusted OR, 2.0; CI, 1.2 to 4.0).79 With ﬁrst-trimesteropril, moexipril, quinapril, ramipril) or to an angiotensin II receptor paroxetine use, the odds were increased for right ventricular outﬂowantagonist (losartan, candesartan, valsartan, tasosartan, telmisartan) tract obstruction defects (adjusted OR, 3.3; CI, 1.3 to 8.8).during the second or third trimester of pregnancy is associated with In addition to these ﬁndings with respect to structural defects,an increased risk for fetal hypotension, renal failure, and oligohydram- several other adverse outcomes have been associated with late preg-nios leading to fetal growth restriction, joint contractures, pulmonary nancy exposure to SSRIs. These include a possible small increasedhypoplasia, and stillbirth or neonatal death. Calvarial hypoplasia has risk for persistent pulmonary hypertension of the newborn80 and aalso been reported as part of the fetopathy. In children who survive the well-established increased risk for a neonatal withdrawal or toxicityneonatal period, renal insufﬁciency often occurs. The magnitude of the syndrome consisting primarily of CNS, motor, respiratory, andrisk after second- or third-trimester exposure is not known.25,71 gastrointestinal signs that are generally mild and resolve by 2 weeks First-trimester exposure to ACE inhibitors or to angiotensin II of age.81receptor antagonists has not been well studied. One recent databaselinkage study suggested an increased risk for cardiovascular defects(risk ratio [RR], 3.72; CI, 1.89 to 7.30) and CNS defects (RR, 4.39; CI, Retinoids1.37 to 14.02) in infants born to mothers who had received a prescrip-tion for an ACE inhibitor in the ﬁrst trimester of pregnancy, compared Vitamin A (Retinol)with infants born to women with no exposure to antihypertensive The teratogenic potential of excessive doses of preformed vitamin A ismedications during pregnancy. However, these ﬁndings have not yet well described in animal models82,83; however, the threshold dose atbeen replicated, and it is possible that they were confounded by inabil- which naturally occurring vitamin A might be teratogenic in humansity to completely control for maternal diabetes.72 remains controversial. Two studies suggested that preformed vitamin A supplementation at amounts greater than 10,000 IU per day in the ﬁrst trimester of pregnancy is associated with a small increased risk ofPsychotherapeutic Medications selected defects that are consistent with those known to be induced by synthetic retinoids.84,85 However, other studies did not conﬁrm theseLithium ﬁndings or suggested that the elevated risk is concentrated at dosesEarly reports from a lithium exposure registry73 included information greater than 40,000 IU per day.86-88 The current recommended dailyon 143 infants exposed to lithium in utero; 13 of these were reported allowance (RDA) for pregnant women carrying a single fetus is 2560 IUto have malformations, 4 of which were Ebstein anomaly (downward of vitamin A. To avoid any of these potential concerns, many prenataldisplacement of the tricuspid valves within the right ventricle). This vitamin formulations have replaced retinol with β-carotene.ﬁnding represented an excess over expected numbers, because thebaseline incidence of Ebstein anomaly is approximately 1 in 20,000 Isotretinoin and Other Oral Synthetic Retinoidsbirths. A subsequent prospective cohort study involving follow-up of Consistent with animal data, an increased risk of pregnancy loss148 women with ﬁrst-trimester exposure to lithium noted one case of and a characteristic pattern of malformations and mental deﬁciencyEbstein anomaly, with no other cardiac malformations identiﬁed in the have been identiﬁed after prenatal exposure to isotretinoin. Thissample.74 In contrast, a case-control study published by Zalzstein and pattern includes CNS malformations, microtia/anotia, micrognathia,associates75 found no prenatal exposure to lithium among 59 patients cleft palate, cardiac and great vessel defects, thymic abnormalities, eyewith Ebstein anomaly. In summary, the available data suggest that, if anomalies, and, occasionally, limb reduction defects.20,89 The estimatedthere is a risk at all, the use of lithium in the ﬁrst trimester of pregnancy risks are at least as high as 22% for spontaneous abortion, 28% foris associated with a very small increased risk for Ebstein anomaly. structural defects, and 47% for mild to moderate mental deﬁciency, even if no structural abnormalities are present.20,90,91 Affected childrenSelective Serotonin Reuptake Inhibitors have been reported with exposures to usual therapeutic doses and withAlthough medications within the selective serotonin reuptake inhibi- treatment for durations shorter than 1 week in the ﬁrst trimester. Theretor (SSRI) class of antidepressants (ﬂuoxetine, paroxetine, sertraline, does not appear to be a risk of malformations when the drug is dis-citalopram, escitalopram, ﬂuvoxamine) have been studied extensively continued before conception, which is consistent with the half-life ofin pregnancy, most investigations have had insufﬁcient sample sizes to isotretinoin.92,93 Pregnancy prevention among women who are pre-rule out increased risks for speciﬁc malformations associated with scribed isotretinoin continues to be a challenge. A third-generationindividual medications. Several recent studies have suggested a small restricted distribution program, iPledge, was implemented in Marchincreased risk for cardiac defects (approximately twofold) speciﬁcally 2006; it mandates close monitoring of birth control practices andwith ﬁrst-trimester exposure to paroxetine.76,77 One recent large, mul- negative pregnancy testing before dispensing of prescriptions fortisite, case-control study did not ﬁnd an overall increase in cardiac isotretinoin.defects but found increased risks for other selected malformations in Risks for the retinoid embryopathy are also found with other oralassociation with ﬁrst-trimester use of all SSRIs combined. These spe- synthetic retinoids such as etretinate and its metabolite, acitretin,ciﬁc defects included anencephaly (adjusted OR, 2.4; CI 1.1 to 5.1), which are used for the treatment of psoriasis.94 The extremely long
354 CHAPTER 20 Teratogenesis and Environmental Exposurehalf-life of etretinate led to its removal from the U.S. market in 1998.The half-life of acitretin is considerably longer than that of isotretinoin(50 to 60 hours), and it can be converted to etretinate with maternalingestion of alcohol. Therefore, the drug must be discontinued beforepregnancy, and alcohol must be avoided during the entire periodof treatment and for at least 2 months after discontinuation oftherapy.95,96Ionizing RadiationPrenatal exposure to high-dose radiation is associated with an increasedrisk of microcephaly, mental deﬁciency, and growth deﬁciency basedon data derived from a small number of pregnant survivors of theatomic bombs in Nagasaki and Hiroshima.97 It is estimated that dosesof 50 rad (50 cGy) or greater to the uterus are required to producethese effects. The highest risk appears to be associated with exposuresbetween 8 and 15 weeks’ gestation, with a higher threshold dose atmore advanced gestational ages.98 The available data do not supportan increase in the risk of mental retardation associated with high-doseradiation exposure beyond 25 weeks or before 8 weeks of gestation.97Based on dose-response calculations, it is not thought that diagnosticprocedures involving radiation have the potential to pose a risk to thefetus unless the cumulative dose to the uterus is greater than 10 cGy;conservative guidelines suggest that doses should be kept below 5 cGyto the uterus during pregnancy if radiation exposure is required.99Environmental Agents FIGURE 20-1 Nine-month-old infant with fetal alcohol syndrome. (From Streissguth AP, Aase JM, Clarren SK, et al: FetalMethylmercury alcohol syndrome in adolescents and adults. JAMA 265:1961, 1991.Prenatal exposure to methylmercury has been recognized as a neuro- Copyright 1991, American Medical Association.)developmental teratogen since the experience of environmentalcontaminations in Japan (Minamata Bay) and Iraq in the mid-20thcentury.100,101 The reported effects, termed fetal methylmercury syn-drome or congenital Minamata disease, include cerebral palsy and a Social and Illicit Drugsvariety of neurologic and functional problems as well as mental deﬁ-ciency.102 Although the lower limit of exposure that may pose a risk in Alcoholprenatal development remains controversial, an independent U.S. A pattern of anomalies, known as the fetal alcohol syndrome (FAS), wasNational Research Council expert committee concluded that limiting ﬁrst described more than 35 years ago in a case series of infants bornmaternal intake to no more than 0.1 μg/kg/day was sufﬁcient to protect to alcoholic women.111 The characteristic features of this disorder arethe fetus.103 Currently, consumption of contaminated ﬁsh or marine prenatal and/or postnatal growth retardation, microcephaly or othermammals is the major source of methylmercury exposure in most CNS dysfunction including neurobehavioral deﬁcits and neurologicpopulations. The U.S. Environmental Protection Agency and FDA have impairment, and characteristic facial anomalies consisting of shortadvised pregnant women and women of childbearing age who may palpebral ﬁssures and a smooth philtrum, with a smooth, thin vermil-become pregnant to avoid eating shark, swordﬁsh, king mackerel, and ion border of the upper lip (Fig. 20-1).112,113 Although FAS is difﬁculttileﬁsh and to limit their average consumption of other cooked ﬁsh to to diagnose, particularly in the newborn period, estimates of its inci-12 ounces (340 g) per week in order to prevent fetal exposure to exces- dence in selected U.S. and Western European populations are approxi-sive amounts of methylmercury.104 Similarly, limiting tuna consump- mately 1 to 4 per 1000 live births.114tion to no more than three servings per week is recommended because Many more children are thought to have alcohol-related neurobe-of methylmercury concerns. havioral or neurologic impairment with or without some structural features. In addition, congenital heart defects, oral clefts, and abnor-Lead malities of the eyes, brain, and kidneys are more common than expectedIn utero exposure to very high levels of lead (maternal blood concen- among the children of women who drink moderately to heavily duringtrations >30 μg/dL) has been associated with an increase in spontane- pregnancy.115-118 These children, variably described as having partialous abortion, preterm birth, and mental deﬁciency.105,106 Prenatal FAS, alcohol-related neurodevelopmental abnormalities (ARND), orexposure to lower levels (>10 μg/dL) may be associated with subtle alcohol-related birth defects (ARBD), are now thought of as represent-neurobehavioral effects; however, these effects may not persist into ing a continuum known as fetal alcohol spectrum disorders (FASD).older childhood.107-109 Occupational and environmental exposures to Accurate estimates of the prevalence of FASD are lacking; however, onelead that precede pregnancy may result in fetal exposure due to mobi- population-based study in the Seattle, Washington, area suggestedlization of lead stored in maternal bone. These effects may be modiﬁed that the rates may be as high as 1 per 100 children.114 Increased risksby maternal intake of calcium.110 for spontaneous abortion, stillbirth, and sudden infant death syn-
CHAPTER 20 Teratogenesis and Environmental Exposure 355drome have also been linked to prenatal alcohol exposure, particularly 700exposure from alcohol consumed in a heavy episodic or bingepattern.119-122 Both animal and human data support a dose-response relation in Umbilical blood flow 600terms of risk for FAS/FASD. However, because of variabilities in diag- (mL/min)nosis and difﬁculties in obtaining and validating exposure informationreported by pregnant women, estimates vary widely regarding the 500magnitude of the risk. For example, estimates for the full-blown syn-drome range from about 4% to 44% of children born to women whodrink heavily during pregnancy.123,124 The women at highest risk appear 400to be those who have already had an affected child and who continueto consume alcohol in subsequent pregnancies. Lower levels of mater- 300nal alcohol consumption have been associated with less severe neu- Umbilical vascular resistancerobehavioral outcomes and persistent growth effects.125-127 However,the exact threshold doses and patterns of consumption for these effects 0.175are not well understood. For example, full-blown FAS is typically seen (mm Hg/mL)among the children of women who report consuming an average of 0.150six or more standard drinks (beer, wine, or spirits) per day duringpregnancy. However, some studies have suggested that women who 0.125consume more than two standard drinks per day during pregnancyare at increased risk. These risks may be mediated or ameliorated by 0.100the pattern of drinking (i.e., binge drinking versus more frequent andlesser quantities), maternal age, nutrition, and genetic susceptibil- 0.075ity.118,128-130 Furthermore, the duration of exposure is likely to be impor- Saline 10 20 30tant, in that CNS development continues throughout gestation.131 Dose of nicotine At present, the data are insufﬁcient to assign a risk to certain (μg/kg/min)common patterns of prenatal alcohol exposure, such as alcohol con-sumption limited to occasional binge episodes before recognition of FIGURE 20-2 Umbilical blood ﬂow and umbilical vascularpregnancy. However, the data do support the notion that reduction or resistance response to maternally administereddiscontinuation of alcohol consumption at any point in pregnancy nicotine. Maternal administration produced a decrease in umbilicalmay be beneﬁcial. A lower threshold of exposure, below which no blood ﬂow from a baseline of 554 ± 37 to 449 ± 52 mL/min, whicheffects will be seen, has not been deﬁned. Therefore, for those women was signiﬁcant only at the 30 μg/kg/min dose (P < .05). Umbilicalwho are planning pregnancy or who have the potential to become vascular resistance increased from a baseline of 0.110 ± 0.013 topregnant, the U.S. Surgeon General has recommended that the safest 0.161 ± 0.020 mm Hg/mL, which was signiﬁcant only at the 30 μg/kg/course is to avoid alcohol entirely during pregnancy.132 min dose (P < .05). For the 20 μg/kg/min dose, n = 6. For saline solution and all other doses, n = 8. (From Clark KE, Irion GL: Fetal hemodynamic response to maternal intravenous nicotineTobacco administration. Am J Obstet Gynecol 167:1624, 1992.)Maternal cigarette smoking is associated with a variety of harmfuleffects on the embryo and fetus, including increased risks for speciﬁccongenital malformations, spontaneous abortion, placental complica-tions, preterm delivery, reduced birth weight, and sudden infant death The deleterious effects of cigarette smoking on other pregnancysyndrome. The structural malformations that have been signiﬁcantly outcomes are well documented. Intrauterine growth restriction is theassociated with ﬁrst-trimester smoking include oral clefts and gastro- most consistently reported adverse outcome. On average, babies bornschisis. A recent meta-analysis of 24 studies estimated the risk for oral to women who smoke during pregnancy are 200 g lighter than thoseclefts to be low: the relative risk for cleft lip with or without cleft palate born to comparable women who do not smoke, with a clear dose-was 1.34 (CI, 1.25 to 1.44), and for cleft palate alone it was 1.22 (CI, response gradient.141 This may be a result, in part, of the reduction in1.10 to 1.35).133 Some studies have suggested gene-environment inter- uterine blood ﬂow associated with rising levels of plasma nicotine inactions in susceptibility for oral clefts when mothers smoke during women who smoke (Fig. 20-2).142 Lesser reductions in birth weightearly pregnancy. Infants who have a null deletion of the detoxifying have also been noted when exposure is limited to environmentalgene GSTT1, or infant genotype at the Taq1 site for transforming or passive smoke.143 A strong gene-environment and gene-gene–growth factor-α and whose mothers smoke are at higher risk for environment interaction has been demonstrated between the cyto-certain oral clefts than infants with either risk factor alone.134,135 The chrome P450 isozyme CYP1A1 and GSTT1 maternal metabolic geneselevated risks for gastroschisis after maternal smoking are also esti- and infant birth weight in mothers who smoke.144mated to be low.136 However, as with oral clefts, there is some evidence Perinatal mortality is also increased with maternal smoking, in partfor gene-environment interaction between maternal smoking and because of the increased risks of placental complications and pretermpolymorphisms of fetal genes involved in vascular response.137 Other delivery. In one large study, the combined risk for fetal or infant deathdefects reported to occur with increased frequency after pregnancy for primiparous women who smoked less than one pack per day wasexposure to tobacco smoke include craniosynostosis and club estimated to be 25% higher than that for nonsmoking women, and thefoot.138-140 Most studies with dose information available have suggested risk was 56% higher for those who smoked one pack per day or more.145a dose-response relation for each of these defects, with the heaviest However, if smoking is discontinued in the ﬁrst half of gestation, evi-smokers being at highest risk. dence indicates that the effects on birth weight can be eliminated.146-148
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