Chapter 20Teratogenesis and Environmental Exposure                                                         Christina Chamb...
348       CHAPTER 20             Teratogenesis and Environmental Exposureis necessary to aid clinicians in advising patien...
CHAPTER 20           Teratogenesis and Environmental Exposure                349by genetic susceptibility and other modify...
350      CHAPTER 20              Teratogenesis and Environmental Exposureexample, health maintenance organization claims d...
CHAPTER 20             Teratogenesis and Environmental Exposure             351(OTIS) provides individualized information ...
352      CHAPTER 20              Teratogenesis and Environmental Exposureadverse outcome was found to be significantly grea...
CHAPTER 20           Teratogenesis and Environmental Exposure                353                                          ...
354       CHAPTER 20             Teratogenesis and Environmental Exposurehalf-life of etretinate led to its removal from t...
CHAPTER 20                                    Teratogenesis and Environmental Exposure   355drome have also been linked to...
356                         CHAPTER 20          Teratogenesis and Environmental Exposure                                  ...
CHAPTER 20            Teratogenesis and Environmental Exposure                     35729. Glaxo Smith Kline: Paroxetine St...
358      CHAPTER 20                Teratogenesis and Environmental Exposure 82. Geelen JA, Langman J, Lowdon JD: The influe...
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  1. 1. 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
  2. 2. 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
  3. 3. 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
  4. 4. 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
  5. 5. 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.
  6. 6. 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
  7. 7. 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
  8. 8. 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-
  9. 9. 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
  10. 10. 356 CHAPTER 20 Teratogenesis and Environmental Exposure 2. Forrest JM, Turnbull FM, Sholler GF, et al: Gregg’s congenital rubella 35 patients 60 years later. Med J Aust 177:664, 2002. 33.33 3. McBride WG: Thalidomide and congenital abnormalities. Lancet 2:1358, 1961. 30 4. Lenz W: Diskussionbemerkung zu dem Vortrag von RA Pfeiffer and K Kosenow: Zur Frage der exogenen Entstehung schwere Extremitatens- 25 missbil-dungen. Tagung Rheinischwestful Kinderarztevere Dusseldorf 25.0 19:11, 1961. Premature birth (%) 5. Krantz JC: New drugs and the Kefauver-Harris amendment. J New Drugs 20 6:77, 1966. 6. Kutcher JS, Engle A, Firth J, et al: Bendectin and birth defects II: Ecological analyses. Birth Defects Res A Clin Molec Teratol 67:88, 2003. 15 7. Koren G, Pastuszak A, Ito S: Drugs in pregnancy. N Engl J Med 338:1128, 13.6 1998. 8. Lo WY, Friedman JM: Teratogenicity of recently introduced medications 10 11.36 in human pregnancy. Obstet Gynecol 100:465, 2002. 11.18 9. Andrade SE, Gurwitz JH, Davis RL, et al: Prescription drug use in preg- nancy. Am J Obstet Gynecol 191:398, 2004. 5 7.06 10. Werler MM, Mitchell AA, Hernandez-Diaz S, et al: Use of over-the-counter 6.39 medications during pregnancy. Am J Obstet Gynecol 193:771, 2005. 11. Wilson JG, Fraser FC (eds): Handbook of Teratology. Vol. 1: General 1–5 6–10 11–15 16–20 21–30 31 Principles and Etiology. New York, Plenum Press, 1977, pp 49-62. Number cigarettes per day 12. Fratta ID, Sigg EB, Maiorana K: Teratogenic effects of thalidomide in rabbits, rats, hamsters, and mice. Toxicol Appl Pharmacol 7:268, 1965.FIGURE 20-3 Dose-response relationship of cigarette smoking 13. Shaw GM, Wasserman CR, Lammer EJ, et al: Orofacial clefts, parentaland prematurity. (From Simpson WJ: A preliminary report on cigarette smoking, and transforming growth factor-alpha gene variants.cigarette smoking and the incidence of prematurity. Am J Obstet Am J Hum Genet 58:551, 1996.Gynecol 73:808, 1957.) 14. Shaw GM, Wasserman CR, Murray JC, et al: Infant TGF-alpha genotype, orofacial clefts, and maternal periconceptional multivitamin use. Cleft Palate-Craniofac J 35:366, 1997.Furthermore, based on dose-response data, any reduction in the 15. Buehler BA, Delimont D, van Waes M, et al: Prenatal prediction of risk ofnumber of cigarettes smoked may reduce risk for low birth weight, the fetal hydantoin syndrome. N Engl J Med 322:1567, 1990.preterm birth, and placental complications (Fig. 20-3).149-153 16. Rosa FW: Spina bifida in infants of women treated with carbamazepine during pregnancy. N Engl J Med 321:674, 1991.Cocaine 17. Matalon S, Schechtman S, Goldzweig G, et al: The teratogenic effect ofVarious structural defects have been reported in newborns prenatally carbamazepine: A meta-analysis of 1255 exposures. Reprod Toxicol 16:9, 2002.exposed to cocaine and are thought to be the result of intrauterine 18. Schaeffer C, Hanneman D, Meister R, et al: Vitamin K antagonists andvascular accidents; they include cavitary CNS lesions, genitourinary pregnancy outcome: A multi-centre prospective study. Thromb Haemostanomalies, terminal transverse limb reduction defects, and intestinal 95:949, 2006.atresia/infarction.154-157 In addition to these structural defects, an 19. Omtzigt JG, Los FJ, Grobbee DE, et al: The risk of spina bifida aperta afterincreased risk for placental abruption and premature rupture of mem- first-trimester exposure to valproate in a prenatal cohort. Neurologybranes was documented in a systematic review.158 However, assessment 42:119, 1992.of the absolute risk for these outcomes after cocaine exposure is com- 20. Lammer EJ, Chen DT, Hoar RM, et al: Retinoic acid embryopathy. N Englplicated by the fact that affected pregnancies often involve use of other J Med 313:837, 1985.drugs, tobacco, and alcohol as well as cocaine; the purity and dose of 21. Shapiro L, Pastuszak A, Curto G, et al: Safety of first-trimester exposurethe drug is often not known, and multiple potential other confounding to topical tretinoin: Prospective cohort study. Lancet 250:1143, 1997. 22. Loureiro KD, Kao KK, Jones KL, et al: Minor malformations characteristicfactors could be involved. of the retinoic acid embryopathy and other birth outcomes in children of The most consistently reported effects of prenatal cocaine exposure women exposed to topical tretinoin during early pregnancy. Am J Medare a small but statistically significant increase in intrauterine growth Genet A 136:117, 2005.restriction159,160 and abnormalities in neonatal state regulation and 23. Floyd RL, O’Connor MJ, Sokol RJ, et al: Recognition and prevention ofmotor performance.161 However, based on a synthesis of 36 published fetal alcohol syndrome. Obstet Gynecol 106:1059, 2005.studies of children 6 years of age or younger, Frank and colleagues162 24. Hernandez-Diaz S, Werler MM, Walker AM, et al: Neural tube defects inconcluded that no consistent negative association existed between relation to use of folic acid antagonists during pregnancy. Am J Epidemiolprenatal cocaine exposure and postnatal physical growth, develop- 153:961, 2001.mental test scores, receptive language, or standardized parent and 25. Barr M: Teratogen update: angiotensin-converting enzyme inhibitors.teacher reports of child behavior. An association between prenatal Teratology 50:399, 1994. 26. Honein MA, Paulozzi LJ, Cragan JD, et al: Evaluation of selected charac-cocaine exposure and decreased emotional expressiveness has been teristics of pregnancy drug registries. Teratology 60:356, 1999.suggested.163 27. Wyszynski DF, Nambisan M, Surve T, et al: Antiepileptic Drug Pregnancy Registry: Increased rate of major malformations in offspring exposed to valproate during pregnancy. Neurology 64:961, 2005.References 28. Jones KL, Lacro RV, Johnson KA, et al: Pattern of malformations in the 1. Moore KL, Persaud TVN: The Developing Human: Clinically Oriented children of women treated with carbamazepine during pregnancy. N Engl Embryology, 7th ed. Philadelphia: Saunders, 2002. J Med 320:1661, 1989.
  11. 11. CHAPTER 20 Teratogenesis and Environmental Exposure 35729. Glaxo Smith Kline: Paroxetine Studies: EPIP083. Available at http://ctr. 57. Ornoy A, Cohen E: Outcome of children born to epileptic mothers treated gsk.co.uk/summary/paroxetine/studylist.asp (accessed January 14, 2008). with carbamazepine during pregnancy. Arch Dis Child 75:517, 1996.30. Pastuszak AL, Schuler L, Speck-Martins CE, et al: Use of misoprostol 58. Nulman I, Scolnik D, Chitayat D, et al: Findings in children exposed in during pregnancy and Mobius’ syndrome in infants. N Engl J Med utero to phenytoin and carbamazepine monotherapy: Independent effects 339:1553, 1998. of epilepsy and medications. Am J Med Genet 68:18-24, 1997.31. Mitchell AA: Systematic identification of drugs that cause birth defects: A 59. Wide K, Henning E, Tomson T, Winbladh B: Psychomotor development new opportunity. N Engl J Med 349:2556, 2003. in preschool children exposed to antiepileptic drugs in utero. Acta Paediatr32. Polifka J, Friedman JM: Developmental toxicity of Ribavirin/IFalpha com- 91:409, 2002. bination therapy: Is the label more dangerous than the drugs? Birth 60. Vaux KK, Kahole NCO, Jones KL: Cyclophosphamide, methotrexate and Defects Res A Clin Molec Teratol 67:8, 2003. cytarabine embryopathy: Is apoptosis the common pathway? Birth Defects33. Scialli A, Buelke-Sam JL, Chambers CD, et al: Communicating risk during Res A Clin Mol Teratol 67:403, 2003. pregnancy: A workshop on the use of data from animal developmental 61. Milunsky A, Graef JW, Gaynor MF Jr: Methotrexate-induced congenital toxicity studies in pregnancy labels for drugs. Birth Defects Res A Clin malformations. J Pediatr 72:790, 1968. Molec Teratol 70:7, 2004. 62. Del Campo M, Kosaki K, Bennett FC, et al: Developmental delay in fetal34. Weiner CP, Buhimschi C: Drugs for Pregnant and Lactating Women, 2nd aminopterin/methotrexate syndrome. Teratology 60:10, 1999. ed. New York: Churchill Livingstone, 2007. 63. Feldkamp M, Carey JC: Clinical teratology counseling and consultation35. Schaeffer C, Peters PWJ, Miller RK (eds): Drugs During Pregnancy and case report: Low dose methotrexate exposure in the early weeks of preg- Lactation: Treatment Options and Risk Assessment. New York: Academic nancy. Teratology 47:553, 1993. Press, 2007. 64. Lewden B, Vial T, Elefant E, et al: Low dose methotrexate in the first tri-36. Holzgreve W, Carey JC, Hall BD: Warfarin-induced fetal abnormalities. mester of pregnancy: Results of a French collaborative study. J Rheumatol Lancet 2:914, 1976. 31:2360, 2004.37. Hall JG, Pauli RM, Wilson KM: Maternal and fetal sequelae of anticoagu- 65. Rodriguez-Pinilla E, Martinez-Frias ML: Corticosteroids during preg- lation during pregnancy. Am J Med 68:122, 1980. nancy and oral clefts: A case-control study. Teratology 58:2, 1988.38. van Driel D, Wesseling J, Sauer PJ, et al: Teratogen update: Fetal effects 66. Czeizel AE, Rockenbauer M: Population-based case-controls study of tera- after in utero exposure to coumarins overview of cases, follow-up findings, togenic potential of corticosteroids.Teratology 56:335, 1997. and pathogenesis. Teratology 66:127, 2002. 67. Carmichael SL, Shaw GM: Maternal corticosteroid use and risk of selected39. Cotrufo M, DeFeo M, DeSanto LS, et al: Risk of warfarin during congenital anomalies. Am J Med Genet 86:242, 1999. pregnancy with mechanical valve prostheses. Obstet Gynecol 99:35, 68. Pradat P, Robert-Gnasia E, Di Tanna GL, et al: First trimester exposure to 2002. corticosteroids and oral clefts. Birth Defects Res A Clin Mol Teratol 67:968,40. van Driel D, Wesseling J, Sauer PJ, et al: In utero exposure to coumarins 2003. and cognition at 8-14 years. Pediatrics 107:123, 2001. 69. Reinisch JM, Simon NG, Karow WG, et al: Prenatal exposure to predni-41. Gilmore J, Pennell PB, Stern BJ: Medication use during pregnancy for sone in humans and animals retards intrauterine growth. Science 202:436, neurologic conditions. Neurol Clin 16:189, 1998. 1978.42. Canger R, Battino D, Canevini MP, et al: Malformations in offspring of 70. Rayburn WF. Glucocorticord therapy for rheumatic diseases: Maternal, women with epilepsy: A prospective study. Epilepsia 40:1231, 1999. fetal, and breast-feeding considerations. Am J Reprod Immunol 28:138,43. Holmes LB, Harvey EA, Coull BA, et al: The teratogenicity of anticonvul- 1992. sant drugs. N Engl J Med 344:1132, 2001. 71. Alwan S, Polifka JE, Friedman JM: Angiotensin II receptor antagonists44. Yerby MS: Epilepsy and pregnancy: New issues for an old disorder. Neurol treatment during pregnancy. Birth Defects Res A Clin Mol Teratol 73:123, Clin 11:777, 1993. 2005.45. Kaneko S, Otani K, Fukushima Y, et al: Teratogenicity of antiepileptic 72. Cooper WO, Hernandez-Diaz S, Arbogast PG et al: Angiotensin convert- drugs: An analysis of possible risk factors. Epilepsia 29:459, 1988. ing enzyme inhibitors and the risk of major congenital malformations. N46. Koch S, Losche G, Jager-Roman E, et al: Major and minor birth malforma- Engl J Med 354:2443, 2006. tions and antiepileptic drugs. Neurology 42:83, 1992. 73. Weinstein MR, Goldfield M: Cardiovascular malformations with lithium47. Hanson JW, Smith DW: The fetal hydantoin syndrome. J Pediatr 87:285, use during pregnancy. Am J Psychiatry 132:529-531, 1975. 1975. 74. Jacobson SJ, Jones K, Johnson K, et al: Prospective multicentre study of48. Hanson JW, Myrianthopoulos NC, Harvey MA, et al: Risks to offspring of pregnancy outcome after lithium exposure during first trimester. Lancet women treated with hydantoin anticonvulsants with emphasis on the fetal 339:869, 1992. hydantoin syndrome. J Pediatr 89:662, 1976. 75. Zalzstein E, Koren G, Einarson T, Freedom RM: A case-control study on49. Kelly TE, Rein M, Edwards P: Teratogenicity of anticonvulsant drugs I: the association between first trimester exposure to lithium and Ebstein’s Review of the literature. Am J Med Genet 19:413, 1984. anomaly. Am J Cardiol 65:817-818, 1990.50. Hanson JW: Teratogen update: Fetal hydantoin effects. Teratology 33:349, 76. Kallen BAJ, Olausson PO: Maternal use of selective serotonin re-uptake 1986. inhibitors in early pregnancy and infant congenital malformations. Birth51. Adams J, Voorhees CV, Middaugh LD: Developmental neurotoxicity of Defects Res A Clin Mol Teratol 79:301, 2007. anticonvulsants: Human and animal evidence on phenytoin. Neurotoxicol 77. Berard A, Ramos E, Rey E, et al: First trimester exposure to paroxetine and Teratol 12:203, 1990. risk of cardiac malformations in infants: The importance of dosage. Birth52. Scolnik D, Nulman I, Rovet J, et al: Neurodevelopment of children exposed Defects Res B Reprod Toxicol 80:18, 2007. in utero to phenytoin and carbamazepine monotherapy. JAMA 271:767, 78. Alwan S, Reefhuis J, Rasmussen SA, et al: Use of selective serotonin- 1994. reuptake inhibitors in pregnancy and the risk of birth defects. N Engl53. Robert E, Guibaud P: Maternal valproic acid and congenital neural tube J Med 354:2684, 2007. defects. Lancet 2:937, 1982. 79. Louik C, Lin AE, Werler MM, et al: First-trimester use of selective sero-54. DiLiberti JH, Farndon PA, Dennis NR, et al: The fetal valproate syndrome. tonin-reuptake inhibitors and the risk of birth defects. N Engl J Med Am J Med Genet 19:473, 1984. 356:2675, 2007.55. Adab N, Jacoby A, Smith D, et al: Additional educational needs in children 80. Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al: Selective sero- born to mother with epilepsy. J Neurol Neurosurg Psychiatry 70:15, tonin-reuptake inhibitors and risk fo persistent pulmonary hypertension 2001. of the newborn. N Engl J Med 354:579, 2006.56. Adab N, Kini V, Vinten J, et al: The longer-term outcome of children born 81. Moses-Kolko EL, Bogen D, Perel J, et al: Neonatal signs after late in utero to mothers with epilepsy. J Neurol Neurosurg Psychiatry 75:1575, 2004. exposure to serotonin reuptake inhibitors JAMA 293:2372, 2005.
  12. 12. 358 CHAPTER 20 Teratogenesis and Environmental Exposure 82. Geelen JA, Langman J, Lowdon JD: The influence of excess vitamin A on 110. Hertz-Picciotto I, Schramm M, Watt-Morse M, et al: Patterns and neural tube closure in the mouse embryo. Anat Embryol (Berl) 159:223, determinants of blood lead during pregnancy. Am J Epidemiol 152:829, 1980. 2000. 83. Rosa FW, Wilk AL, Kelsey FP: Teratogen update: Vitamin A congeners. 111. Jones KL, Smith DW, Ulleland CN, et al: Pattern of malformation in off- Teratology 33:355, 1986. spring of chronic alcoholic mothers. Lancet 1:1267, 1973. 84. Rothman KJ, Moore LL, Singer MR, et al: Teratogenicity of high vitamin 112. Streissguth AP, Aase JM, Clarren SK, et al: Fetal alcohol syndrome in ado- A intake. N Engl J Med 333:1369, 1995. lescents and adults. JAMA 265:1961, 1991. 85. Botto LD, Loffredo C, Scanlon KS, et al: Vitamin A and cardiac outflow 113. Hoyme HE, May PA, Kalberg WO, et al: A practical clinical approach to tract defects. Epidemiology 12:491, 2000. diagnosis of fetal alcohol spectrum disorders: Clarification of the 1996 86. Werler MM, Lammer EJ, Rosenberg L, et al: Maternal vitamin A supple- institute of medicine criteria. Pediatrics 115:39, 2005. mentation in relation to selected birth defects. Teratology 42:497, 1990. 114. Sampson PD, Streissguth AP, Bookstein FL, et al: Incidence of fetal alcohol 87. Mills JL, Simpson JL, Cunningham GC, et al: Vitamin A and birth defects. syndrome and prevalence of alcohol-related neurodevelopmental disor- Am J Obstet Gynecol 177:31, 1997. der. Teratology 56:317, 1997. 88. Martinez-Frias ML, Salvador J: Epidemiological aspects of prenatal 115. Moore CA, Khoury MJ, Liu Y: Does light-to-moderate alcohol consump- exposure to high doses of vitamin A in Spain. Eur J Epidemiol 6:118, tion during pregnancy increase the risk for renal anomalies among off- 1990. spring? Pediatrics 99:E11, 1997. 89. Rizzo R, Lammer EJ, Parano E, et al: Limb reduction defects in humans 116. Shaw GM, Lammer EJ: Maternal periconceptional alcohol consumption associated with prenatal isotretinoin exposure. Teratology 44:599, 1991. and risk for orofacial clefts. J Pediatr 134:298, 1999. 90. Dai WS, LaBraico JM, Stern RS: Epidemiology of isotretinoin exposure 117. Williams LJ, Correa A, Rasmussen S: Maternal lifestyle factors and risk for during pregnancy. J Am Acad Dermatol 26:599, 1992. ventricular septal defects. Birth Defects Res A Clin Mol Teratol 70:59, 91. Adams J, Lammer EJ: Neurobehavioral teratology of isotretinoin. Reprod 2004. Toxicol 7:175, 1993. 118. Martínez-Frías ML, Bermejo E, Rodríguez-Pinilla E, et al: Risk for con- 92. Dai WS, Hsu M-A, Itri LM: Safety of pregnancy after discontinuation of genital anomalies associated with different sporadic and daily doses of isotretinoin. Arch Dermatol 125:362, 1989. alcohol consumption during pregnancy: A case-control study. Birth 93. Kallen B: Restriction of the use of drugs with teratogenic properties: Defects Res A Clin Mol Teratol 70:194, 2004. Swedish experiences with isotretinoin. Teratology 60:53, 1999. 119. Kesmodel U, Wisborg K, Olsen SF, et al: Moderate alcohol intake in preg- 94. Geiger J-M, Baudin M, Saurat J-H: Teratogenic risk with etretinate and nancy and the risk of spontaneous abortion. Alcohol Alcohol 37:87, acitretin treatment. Dermatology 189:109, 1994. 2002. 95. Maradit H, Geiger J-M: Potential risk of birth defects after acitretin dis- 120. Kesmodel U, Wisborg K, Olsen SF, et al: Moderate alcohol intake during continuation. Dermatology 198:3, 1999. pregnancy and the risk of stillbirth and death in the first year of life. Am 96. Grønhøj Larsen F, Steinkjer B, Jakobsen P, et al: Acitretin is converted to J Epidemiol 155:305, 2002. etretinate only during concomitant alcohol intake. Br J Dermatol 143:116, 121. Iyasu S, Randall LL, Welty TK, et al: Risk factors for sudden infant death 2000. syndrome among northern plains Indians. JAMA 288:2717, 2002. 97. Otake M, Schull WJ: In utero exposure to A-bomb radiation and mental 122. Carpenter RG, Irgens LM, Blair PS, et al: Sudden unexplained infant retardation: A reassessment. Br J Radiol 57:409, 1984. death in 20 regions in Europe: Case control study. Lancet 363:185, 98. Yamazaki JN, Schull WJ: Perinatal loss and neurological abnormalities 2004. among children of the atomic bomb: Nagasaki and Hiroshima revisited, 123. Abel EL: An update on the incidence of FAS: FAS is not an equal oppor- 1949 to 1989. JAMA 265:605-609, 1990. tunity birth defect. Neurotoxicol Teratol 17:437, 1995. 99. Brent RJ: The effect of embryonic and fetal exposure to x-ray, microwaves, 124. Jones KL, Smith DW: The fetal alcohol syndrome. Teratology 12:1, and ultrasound: Counseling the pregnant and nonpregnant patient about 1975. these risks. Semin Oncol 16:347, 1989. 125. Streissguth AP, Barr HM, Sampson PD: Moderate prenatal alcohol expo-100. Matsumoto H, Koya G, Takeuchi T: Fetal Minimata disease: A neuro- sure: Effects on child IQ and learning problems at age 7 1/2 years. Alcohol pathological study of two cases of intrauterine intoxication by a methyl- Clin Exp Res 14:662, 1990. mercury compound. J Neuropath Exp Neurol 24:563, 1965. 126. Day NL, Leech SL, Richardson GA, et al: Prenatal alcohol exposure pre-101. Bakir F, Damluji SF, Amin-Zaki L, et al: Methylmercury poisoning in Iraq: dicts continued deficits in offspring size at 14 years of age. Alcohol Clin An interuniversity report. Science 181:230, 1973. Exp Res 26:1584, 2002.102. Kondo K: Congenital Minamata disease: Warnings from Japan’s experi- 127. Jacobson SW: Specificity of neurobehavioral outcomes associated with ence. J Child Neurol 15:458, 2000. prenatal alcohol exposure. Alcohol Clin Exp Res 22:313-320, 1998.103. Mahaffey KR: Recent advances in recognition of low-level methylmercury 128. Jacobson SW, Jacobson JL, Sokol RJ, et al: Maternal age, alcohol abuse poisoning. Curr Opin Neurol 13:699, 2000. history, and quality of parenting as moderators of the effects of prenatal104. U.S. Environmental Protection Agency and U.S. Food and Drug Admin- alcohol exposure on 7.5-year intellectual function. Alcohol Clin Exp Res istration: What You Need to Know about Mercury in Fish and Shellfish. 28:1732, 2004. Available at http://www.epa.gov/waterscience/fishadvice/advice.html 129. Khaole NC, Ramchandani VA, Viljoen DL, et al: A pilot study of alcohol (accessed January 14, 2008). exposure and pharmacokinetics in women with or without children with105. Rom WN: Effects of lead on the female and reproduction: A review. Mt fetal alcohol syndrome. Alcohol Alcohol 39:503, 2004. Sinai J Med 43:542-53, 1976. 130. Warren KR, Li T-K: Genetic polymorphisms: Impact on the risk of fetal106. Hertz-Picciotto I: The evidence that lead increases the risk for spontane- alcohol spectrum disorders. Birth Defects Res A Clin Mol Teratol 73:195, ous abortion. Am J Ind Med 38:300, 2000. 2005.107. Bellinger D, Leviton A, Waternaux C, et al: Longitudinal analyses of pre- 131. Goodlett CR, West JR: Fetal alcohol effects: Rat model of alcohol exposure natal and postnatal lead exposure and early cognitive development. N Engl during the brain growth spurt. In Zagon IS, Slotkin TA (eds). Maternal J Med 316:1037, 1987. Substance Abuse and the Developing Nervous System. San Diego, Aca-108. Dietrich KN, Krafft KM, Bornschein RL, et al: Low-level fetal lead expo- demic Press, 1992, pp 45-75. sure effect on neurobehavioral development in early infancy. Pediatrics 132. U.S. Department of Health and Human Services, Office of the Surgeon 80:721, 1987. General: News Release: U.S. Surgeon General Releases Advisory on109. Tong SL, Baghurst P, McMichael A, et al: Lifetime exposure to environ- Alcohol Use in Pregnancy, February 21, 2005. Available at http://www. mental lead and children’s intelligence at 11-13 years: The Port Pirie surgeongeneral.gov/pressreleases/sg02222005.html (accessed January 14, cohort study. BMJ 312:1569, 1996. 2008).

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