Teratogenesis and Environmental Exposure

Historical Perspective

Before the 1940s, most clinicians thought that the placenta provided a protective barrier for the developing embryo and fetus and that agents to which the mother was exposed could not interfere with normal prenatal development. The revolutionary concept that a maternal exposure could endanger the developing embryo or fetus was first raised in the clinical literature by an Australian ophthalmologist, Norman Gregg, who observed an unusual number of children diagnosed with congenital cataracts in his clinical practice shortly after a rubella epidemic. Gregg’s work led to investigations that identified additional features of a variable but characteristic pattern of developmental abnormalities associated with fetal rubella infection, including congenital heart defects, hearing deficits, poor growth, and thrombocytopenia, which came to be known as the congenital rubella syndrome . ^,

In the early 1960s, an Australian obstetrician, William McBride, and a German geneticist, Widukind Lenz, independently recognized that first-trimester maternal use of thalidomide, a sedative-hypnotic drug, was associated with the appearance of a characteristic pattern of limb reduction anomalies and other defects. Although the drug had undergone premarket testing in rodents, it had not shown the characteristic limb defects in the species tested. In the United States, this and subsequent recognition that therapeutic agents could induce malformations was a major stimulus for the implementation of the 1962 Kefauver-Harris Amendment to the Food, Drug, and Cosmetic Act of 1938, which expanded the role of the US Food and Drug Administration (FDA) as a regulatory agency charged with ensuring the efficacy and safety of products.

Although the thalidomide experience raised public awareness of the potential risks of prenatal exposures, the thalidomide episode was accompanied by misunderstandings about how to differentiate exposures that cause birth defects from coincidental exposures occurring in women whose pregnancy outcome is abnormal for other, unrelated reasons. A classic example is a once-popular antiemetic medication, Bendectin (doxylamine succinate and pyridoxine hydrochloride with or without dicyclomine hydrochloride), used by as many as 30% of American women for the treatment of nausea and vomiting of pregnancy. In 1983, this agent was voluntarily withdrawn from the market after an onslaught of litigation claiming teratogenicity despite voluminous scientific evidence to the contrary.

Within the past 40 years, research in the field of teratology has advanced, and many previously unrecognized exposures that are teratogenic in humans have been identified, including treatment with several anticonvulsants, antineoplastic agents, tetracycline, warfarin, isotretinoin, inhibitors of the renin-angiotensin system, ethanol abuse, and exposure to toxic amounts of methyl mercury. Work continues to better define the range of adverse outcomes associated with these and other exposures, the magnitude of risk for a given dose at a specific gestational age, and the subgroups of mothers and infants who may be at particularly increased risk because of their genotypes. However, major knowledge gaps exist for most agents, few of which have been adequately evaluated in human pregnancy. It has also been learned that, although animal and other model system studies are critical for understanding the biological mechanisms that produce teratogenic effects and for identifying potential teratogenic hazards to human pregnancy before they occur, ultimately only human studies can establish and quantitate human teratogenic risks. ^,

Drug exposure during pregnancy is extremely common. In a 2011 analysis of two US population-based studies, a steadily increased frequency of medication use during pregnancy was observed over the previous 30 years. Between 89% and 94% of women reported using at least one over-the-counter or prescription medication during pregnancy, and 70% to 82% reported taking at least one medication during the first trimester. Moreover, the average number of medications taken during pregnancy increased from 2.5 to 4.2 per woman over the preceding 30 years. Usage varies by country, but high frequencies of over-the-counter or prescription medication use during pregnancy were also reported by 9459 women who participated in an 18-nation internet-based survey performed in 2011–12.

In many cases these medications are necessary for the health of the mother or fetus, but in other cases the exposures could have been avoided. A theoretical and practical framework is necessary to aid clinicians in advising patients who may have experienced several exposures by the time their pregnancy is recognized and to support clinical decision making in the common situations in which treatment during pregnancy is recommended.

Principles of Teratology

James G. Wilson outlined the basic principles of teratology in the early 1970s. These six principles, given here in Wilson’s own words, were based on his experience with experimental animal studies more than 50 years ago, but these principles can be applied equally well to human pregnancy today.

• “1. Susceptibility to teratogenesis depends on the genotype of the conceptus and the manner in which this interacts with environmental factors.”

Exposures do not occur in a vacuum; women and their fetuses bring different genetic makeups to the exposure scenario. Different genetic characteristics may alter the way a drug or chemical is metabolized or may alter the susceptibility of a developmental process to disturbance by an exposure. For example, women with infants who have cleft lip with or without cleft palate or isolated cleft palate are approximately twice as likely to report heavy first-trimester tobacco use compared to mothers of normal newborns. However, women who have a certain transforming growth factor-α polymorphism and who smoke heavily have a 3 to 11 times higher risk of having a child with an oral cleft in some studies, suggesting an interaction of the genetic characteristics of the mother with the tobacco smoke exposure. This risk appears to be lessened by maternal multivitamin use. ^, Similarly, a low level of epoxide hydrolase enzyme activity influenced by epoxide hydrolase polymorphisms has been implicated as a risk factor for fetal hydantoin syndrome in children whose mothers have taken phenytoin for the treatment of a seizure disorder during pregnancy.

• “2. Susceptibility to teratogenic agents varies with the developmental stage at the time of exposure.”

The principle of gestational timing, or critical developmental windows of exposure, requires that the exposure occur during the stage in development when the targeted developmental process is most susceptible, and different outcomes may be induced depending on the gestational timing of exposure. For example, the critical window for an agent that interferes with closure of the neural tube in the human embryo is approximately 21 to 28 days after conception. Maternal therapy with valproic acid, an anticonvulsant associated with about a 10-fold increased risk of neural tube defects in the fetus, ^, does not produce this defect if the treatment begins later in pregnancy. However, maternal valproic acid treatment during the second and third trimesters of pregnancy may impair the child’s subsequent cognitive function ^, because brain development continues throughout gestation.

• “3. Teratogenic agents act in specific ways (mechanisms) on developing cells and tissues to initiate abnormal embryogenesis (pathogenesis).”

There is no teratogenic exposure that increases the risk of all adverse outcomes; rather, teratogenic exposures act on specific developmental processes to produce a characteristic pattern of effects. This principle underlies the methods by which many human teratogenic exposures have been recognized: the pattern of abnormalities produced in the child helps to identify the maternal exposure during pregnancy as teratogenic. ^, For example, the characteristic pattern of abnormalities comprising the fetal alcohol syndrome (FAS) includes minor craniofacial features (i.e., short palpebral fissures, smooth philtrum, and thin vermilion border of the upper lip) accompanied by microcephaly, growth deficiency, and cognitive and behavioral deficits. ^, The prenatal effects of ethanol, although pervasive, nevertheless represent a constellation of features that is very unlikely to occur without exposure to alcohol in substantial amounts during early pregnancy.

Wilson used the term mechanisms to refer to very early molecular or developmental events in the pathogenetic pathway that lead to a teratogenic effect. He gave as examples alterations of processes such as cell division, nucleic acid function, energy metabolism, and biosynthesis, and subsequent research has revealed many others, such as alterations of genomic structure, epigenetic control, cytoskeletal structure, organelle integrity, and intracellular or intercellular signaling. These mechanisms may result in excessive or reduced cell death, failed cellular interactions, reduced production of critical molecules, impeded morphogenetic movement, mechanical disruption of tissues, or final common pathways of teratogenesis.

Because teratogenic effects are mediated through shared mechanisms and developmental pathways, different teratogenic exposures may produce similar outcomes. For example, maternal treatment during the second half of pregnancy with either an angiotensin I–converting enzyme (ACE) inhibitor (e.g., enalapril or lisinopril) or an angiotensin II receptor antagonist (ARB; e.g., losartan or valsartan) may produce fetal hypotension with consequent hypoperfusion and oligohydramnios, resulting in a strikingly similar fetopathy that includes renal tubular dysplasia, oligohydramnios, and hypocalvarium. ^,

• “4. The final manifestations of abnormal development are death, malformation, growth retardation, and functional disorder.”

Depending on the nature of the exposure and timing during gestation, adverse outcomes may encompass effects ranging from spontaneous abortion or stillbirth to major and minor structural defects, prenatal or postnatal growth deficiency, and intellectual disability or other functional deficits. These abnormalities often occur in combination. For example, moderate to heavy maternal ethanol intake, particularly if consumed in a binge pattern, increases the risks for spontaneous abortion, stillbirth, a characteristic pattern of minor craniofacial abnormalities, major structural defects such as atrial and ventricular septal defects or oral clefts, prenatal and postnatal growth deficiency, deficits in global IQ, and specific behavioral and learning abnormalities. ^, Experimental animal and human studies support the notion that the entire spectrum of outcomes associated with ethanol teratogenesis rarely occurs in any single affected pregnancy; rather, the results may vary by dose and pattern of drinking, gestational timing of exposure, genetic susceptibility, and other modifying factors such as maternal nutrition or concomitant exposures.

• “5. The access of adverse environmental influences to developing tissues depends on the nature of the influences (agents).”

The teratogenic risk of an exposure depends on the pharmacokinetics and pharmacodynamics of the agent’s transfer to the embryo or fetus. For example, isotretinoin (13- cis -retinoic acid) and tretinoin (all- trans -retinoic acid) are chemically identical stereoisomers. Oral isotretinoin, which undergoes rapid systemic absorption, when taken by the mother for only a few days in early pregnancy, produces an approximately 20% risk of brain, conotruncal heart, ear, and thymus malformations and an even higher risk of intellectual disability in liveborn children. ^, In contrast, topical tretinoin, which is poorly absorbed through the skin, is not associated with an increased risk of the same pattern of adverse effects, ^, despite the fact that tretinoin has a greater teratogenic potency when both drugs are administered systemically to experimental animals.

• “6. Manifestations of deviant development increase in degree as dosage increases from the no-effect level to the totally lethal level.”

The principle of dose response suggests that for all exposures there is a threshold dose below which no effect is detected, higher doses produce stronger effects compared with lower doses, and a sufficiently high dose may be lethal. Experimental teratology studies are often done with a range of doses that directly demonstrates this principle, but most human exposures, especially intentional exposures to medications, occur in a much narrower range of doses, so that the effect of dosage may not be obvious. A greater risk of major malformations has been observed in the children of women treated early in pregnancy with higher doses of the anticonvulsants valproic acid, carbamazepine, and lamotrigine than in the children of women who were treated with lower doses of these same drugs. ^,

Sources of Data on Safety and Risks of Exposures in Pregnancy

For most medications, information on pregnancy effects is only available from experimental animal studies that were done as part of the drug’s regulatory approval process. These studies are useful in indicating the exposure level at which adverse effects are seen, the nature of those effects, and associated effects on the mother in the species tested. Use of these studies for counseling pregnant women requires an understanding of similarities and differences in the pharmacokinetics and pharmacodynamics of the drug and in the molecular mechanisms of embryonic development in the experimental model and in humans, information that often is not available. Although precautions or reassurance may appear in the product labeling on the basis of experimental animal data, the only way that we can be certain that an exposure is teratogenic in humans is to recognize that it causes structural or functional abnormalities in the children of women who were treated during pregnancy.

Risk Assessments and Resources

Before 2015, product labels for prescription medications approved by the FDA used an A, B, C, D, X designation to summarize pregnancy drug safety data. Due to the substantial potential for misinterpretation of these pregnancy letter categories, the system was revised. Any drug that was first marketed in the United States after June 30, 2001, and any older drug for which the FDA-approved label was revised after that date is now required to include a structured narrative summary of risks related to use in pregnancy. Each medication’s narrative summary is authored by the drug’s manufacturer and vetted by the FDA prior to approval. These labels are therefore authoritative, but they may be written in a manner that many pregnant women find unnecessarily alarming. Physicians who wish to gain a fuller understanding of the teratogenic risks of an exposure should also consult independent information sources for up-to-date, expert assessments of teratogenic risks or safety associated with prescription drug treatments during pregnancy. FDA pregnancy labels are only available on exposures that involve prescription medications, and other resources must be consulted to obtain information that is needed to counsel patients who are concerned about over-the-counter medications or nonmedication exposures.

Information available to clinicians includes several print resources ^, and online databases ^, that provide summary statements prepared by experts in the field of teratology and are updated on a regular basis. In addition, MotherToBaby provides individualized information to clinicians and the public by telephone, live chat, text, and the Internet. Similar information is available in other countries through services affiliated with the European Network of Teratology Information Services. Clinicians or patients who are interested in pregnancy registries that are open for enrollment can locate a current list provided by the FDA’s Office of Women’s Health.

Selected Human Teratogenic Exposures

For information about specific exposures, clinical teratology resources such as those mentioned in the previous section should be consulted. A few selected examples of pregnancy exposures that may raise concern about possible teratogenic risks are discussed in this section. Exposures that are not discussed here cannot be assumed to be safe. Other examples of teratogenic effects related to congenital infections and substance abuse in pregnancy are discussed in Chapter 51, Chapter 68 , respectively. Potential teratogenic effects of maternal illnesses and their treatment are considered in Chapters 56 (malignancy), 57 (renal disease), 59 (diabetes mellitus), 61 (thyroid disease), 63 (gastrointestinal disease), 65 (rheumatic disease), 66 (neurologic disorders), and 67 (depression and psychosis).