A teratogen is any agent that acts during embryonic or fetal development to produce a permanent alteration of form or function. The word is derived from the Greek teratos, meaning monster. Approximately 3 percent of infants have a major structural malformation that is detectable at birth. By age 5, another 3 percent have been diagnosed with a malformation, and another 8 to 10 percent are discovered to have one or more functional or developmental abnormalities by age 18. For most birth defects, approximately 65 percent, the etiology is unknown. Importantly, chemically induced birth defects, which include those caused by medications, are believed to account for less than 1 percent of all birth defects.
With few notable exceptions, most commonly prescribed drugs and medications can be used with relative safety during pregnancy. The list of known or suspected teratogens is small (Table 8-1). For those drugs believed to be teratogenic, counseling should emphasize relative risk. Exposure to a confirmed teratogen usually increases a woman’s chance of having a child with a birth defect by only 1 or 2 percent. The concept of risk versus benefit should also be introduced. Some diseases, if untreated, pose a more serious threat to both mother and fetus than any theoretical risks from medication exposure.
TABLE 8-1. Selected Drugs or Substances Suspected or Proven to Be Human Teratogens
CRITERIA FOR TERATOGENICITY
In order to establish a cause-and-effect relationship between a birth defect and prenatal exposure to a certain drug, chemical, or environmental agent, specific criteria are required (Table 8-2). It is important for exposure to occur during a critical developmental period. Figure 8-1 illustrates the critical structural development period for each organ system. The preimplantation period is the 2 weeks from fertilization to implantation and has traditionally been called the “all or none” period. This is because development is usually normal if only a small number of cells are damaged, and damage to a large number of cells results in pregnancy loss. The embryonic period, from the second through the eighth week, encompasses organogenesis and is the most crucial with regard to structural malformations. Throughout the fetal period, which extends from 9 weeks until term, maturation important for functional development continues while the fetus remains vulnerable. For example, the brain remains susceptible to alcohol throughout pregnancy.
TABLE 8-2. Criteria for Proof of Human Teratogenicity
FIGURE 8-1 Timing of organogenesis during the embryonic period. (Reproduced, with permission, Sadler TW. Langman’s Medical Embryology. 6th ed. Baltimore, MD: Williams & Wilkins; 1990, p. 130.)
FOOD AND DRUG ADMINISTRATION CLASSIFICATION
To provide therapeutic guidance, the Food and Drug Administration developed pregnancy risk categories, a system for rating drug safety in pregnancy (Table 8-3). Unfortunately, the category assigned may be based on case reports or limited animal data, and updates are sometimes slow. The FDA has proposed new rules for labeling drugs for use by pregnant women, which would include a fetal risk summary, clinical considerations, and guidelines for inadvertent exposure. Meanwhile, current and accurate information can be obtained from a drug information service or through an on-line reproductive toxicity service.
TABLE 8-3. Food and Drug Administration Categories for Drugs and Medications
The medications or substances strongly suspected or proven to be human teratogens are listed in Table 8-1. New or infrequently used drugs for which there is inadequate safety information should be given in pregnancy only if benefits outweigh any theoretical risks.
Ethyl alcohol is one of the most potent teratogens and is the leading cause of preventable birth defects in the United States. Fetal alcohol syndrome occurs in 0.6 to 3 per 1000 births and is characterized by dysmorphic facial features, growth restriction, and central nervous system abnormalities (Table 8-4). Numerous birth defects have been associated with alcohol exposure (Table 8-4). Fetal alcohol spectrum disorder, which includes the full range of prenatal alcohol damage that may not meet the criteria for fetal alcohol syndrome, is estimated to occur in up to 1 in 100 children born in the United States. The minimum amount of alcohol required to produce adverse fetal consequences is unknown.
TABLE 8-4. Fetal Alcohol Syndrome and Alcohol-Related Birth Defects
Anticonvulsant use is directly related to adverse fetal outcome, with risk increasing directly with the number of drugs. The most frequently reported malformations are orofacial clefts, cardiac malformations, neural-tube defects, and developmental delay. Table 8-5 lists teratogenic effects of common anticonvulsant medications. Because the need for drug therapy, high serum levels, and multiple medications also reflect severity of maternal disease, it is possible that at least part of the increased risk is related to epilepsy itself.
TABLE 8-5. Teratogenic Effects of Common Anticonvulsant Medications
Angiotensin-Converting Enzyme (ACE) Inhibitors and Angiotensin-Receptor Blockers
ACE inhibitors may cause prolonged fetal hypotension and hypoperfusion, initiating a sequence of events leading to renal ischemia, tubular dysgenesis, and anuria. The resulting oligohydramnios prevents normal lung development and causes limb contractures. Reduced perfusion can also cause growth restriction, relative limb shortening, and hypocalvarium—hypoplasia of the membranous skull bones. Because these changes occur during the fetal period they are termed ACE inhibitor fetopathy. It is not a syndrome, but instead is a classical example of a sequence in which one initial insult leads to a cascade of other problems. Angiotensin-receptor blockers exert their effects through a similar mechanism, and concerns about toxicity have been generalized to include this entire category of medications. Based on a report that first-trimester exposure to ACE inhibitors may increase the risk for fetal cardiovascular and central nervous system malformations, these medications are avoided throughout pregnancy.
Nonsteroidal anti-inflammatory drugs are not considered teratogenic but may have adverse fetal effects when used in the third trimester. Indomethacin, particularly when used for longer than 72 hours, has been associated with constriction of the fetal ductus arteriosus with subsequent pulmonary hypertension. It may also decrease fetal urine output and thereby reduce amnionic fluid volume. Leflunomide, which is used to treat rheumatoid arthritis, is considered contraindicated in pregnancy. It has been associated with hydrocephalus, eye anomalies, skeletal abnormalities, and embryonic death in animal studies. Because it may take 2 years after discontinuation for the active metabolite to be nondetectable in plasma, the manufacturer has developed a cholestyramine treatment/washout plan in the event of unintended pregnancy.
The majority of antibiotics are considered safe for use in pregnancy, with the following considerations. Aminoglycosides have potential to result in nephrotoxicity in both adults and preterm newborns. They do not pose any significant teratogenic risk. Gentamicin is commonly used to treat serious infections in pregnant women and infants, as its benefits typically outweigh potential risks. Chloramphenicol readily crosses the placenta and results in significant fetal levels. It is not considered teratogenic, but when given to the preterm neonate, the gray baby syndrome has been reported, manifested by cyanosis and vascular collapse. Sulfonamides displace bilirubin from protein binding sites, raising theoretical concerns about hyperbilirubinemia in the preterm neonate if used near delivery. They do not appear to pose any significant teratogenic risk. Tetracyclines may cause yellow–brown discoloration of deciduous teeth or be deposited in fetal long bones.
By their mechanisms of action, many anticancer drugs intuitively would be teratogenic or carcinogenic. Fortunately, this is not the case for most, with a few notable exceptions. Cyclophosphamide is an alkylating agent that has been associated with missing and hypoplastic digits (fingers and toes), cleft palate, single coronary artery, imperforate anus, and fetal growth restriction with microcephaly. Methotrexate and aminopterin are folic acid antagonists associated with a rare pattern of anomalies. Principal features of fetal methotrexate/aminopterin syndrome are growth restriction, failure of calvarial ossification, craniosynostosis, hypoplastic supraorbital ridges, small posteriorly rotated ears, micrognathia, and severe limb abnormalities. Tamoxifen, a nonsteroidal selective estrogen-receptor modulator, is both fetotoxic and carcinogenic in animal species, causing impaired growth and changes similar to those following maternal diethylstilbestrol (DES) exposure. It is recommended that exposed offspring be followed for up to 20 years to assess risk of carcinogenicity.
Amantadine is used in the prevention and treatment of influenza infections. It is teratogenic in animals at high doses and has been associated with cardiac defects in human pregnancy. Ribavirin, which is used to treat respiratory syncitial virus in infants and young children, is highly teratogenic in animal species, causing skull, palate, eye, skeletal, and gastrointestinal abnormalities. It is considered contraindicated in pregnancy (category X). Efavirenz is a nonnucleoside reverse transcriptase inhibitor used to treat HIV infection. It has been associated with anencephaly, cleft palate, and micropthalmia in primates; however, no increase in birth defects has been reported in human pregnancy. As data are limited, options for treating pregnant women with efavirenz are best individualized.
Hydrocortisone, prednisone, and other corticosteroids are commonly used to treat serious medical conditions such as asthma and autoimmune disease. They are associated with a threefold increased incidence of facial clefts, an absolute risk of 3 per 1000. Based on these findings, corticosteroids are category D, however, they are not considered to represent a major teratogenic risk.
Exposure to exogenous sex hormones between 7 and 12 weeks can result in full masculinization of a female fetus. The tissue continues to exhibit some response until 20 weeks when partial masculinization or genital ambiguity can develop. This does not apply to oral contraceptives, which have not been associated with any congenital anomalies. Testosterone and anabolic steroids may result in varying degrees of virilization of female fetuses, including labioscrotal fusion after first-trimester exposure and phallic enlargement later. Danazol may result in dose-related virilation in as many as 40 percent of female fetuses exposed in early pregnancy. Diethylstilbestrol (DES), which was used from 1940 until 1971, is both a teratogen and a carcinogen. Although the absolute risk is low (1 per 1000), DES daughters are at substantially increased risk for clear-cell adenocarcinoma of the cervix and/or vagina.
Radioactive iodine-131, which is used to treat thyroid malignancies and hyper-thyroidism, crosses the placenta and is concentrated by the fetal thyroid. It is contraindicated in pregnancy because it may ablate the fetal thyroid and increase the risk for childhood thyroid cancer.
The developing nervous system is particularly susceptible to the effects of mercury, and prenatal exposure may result in a range of defects, from developmental delay and mild neurological abnormalities to microcephaly and severe brain damage. Several varieties of older fish absorb and retain mercury from the water or ingest it when they eat smaller fish and aquatic organisms. For this reason, the Food and Drug Administration recommends that pregnant women should not eat shark, swordfish, king mackerel, or tilefish. On a weekly basis, pregnant women are advised to eat no more than 6 ounces of albacore tuna or 12 ounces of fish or shellfish low in mercury.
Lithium, which is used to treat manic-depressive illness, has been associated with an increased risk for the rare Ebstein anomaly, a cardiac abnormality characterized by apical displacement of the tricuspid valve. The overall risk is low; however, fetal echocardiography is recommended for exposed pregnancies. Lithium may also cause transient neonatal toxicity, including hypothyroidism, diabetes insipidus, cardiomegaly, electrocardiogram abnormalities, and hypotonia.
Selective Serotonin Reuptake Inhibitors (SSRIs)
These are the most commonly used antidepressants in pregnancy. In one study, SSRI medications were associated with a slightly increased risk for omphalocele, craniosynostosis, and anencephaly. This risk, approximately 2 per 1000 infants, was primarily with paroxetine exposure, and paroxetine has also been associated with increased risk for congenital cardiac anomalies in other studies. As a class, SSRIs are not considered major teratogens. However, it is recommended that paroxetine be avoided in women who are pregnant or planning pregnancy and fetal echocardiography be considered for women with early pregnancy paroxetine exposure.
Two types of neonatal effects have been described following maternal SSRI use in pregnancy. A neonatal behavioral syndrome has been observed in up to 25 percent following third-trimester exposure. Considered to be mild and self-limited, it consists of jitteriness, hypertonia, feeding or digestive disturbances, irritability, or respiratory abnormalities. Rarely—in approximately 0.3 percent of infants—manifestations are more severe and similar to those of adults with SSRI toxicity or withdrawal. Exposed infants may also demonstrate persistent pulmonary hypertension. This is characterized by high pulmonary vascular resistance, right-to-left shunting, and hypoxia, and has been reported in 6 to 12 per 1000 neonates.
Retinoids, especially vitamin A, are essential for normal growth and tissue differentiation. High doses of vitamin A have been associated with congenital anomalies, and for this reason, it is recommended that pregnant women avoid doses above 5000 IU daily. Isotretinoin, or 13-cis-retinoic acid, which is used to treat cystic acne, is one of the most potent teratogens. First-trimester exposure is associated with high rates of fetal loss and malformations involving the cranium, face, heart, central nervous system, and thymus. Abnormalities have been described only with first-trimester use and are not increased in women who discontinue therapy before conception. Acitretin, used to treat psoriasis, is associated with severe anomalies similar to those with isotretinoin. Acitretin is metabolized to etretinate, which has a half-life of 120 days and has been detected in serum almost 3 years after cessation of therapy. Tretinoin, or all-trans-retinoic acid, is usually used as a topical gel to treat acne vulgaris. The skin metabolizes most of the drug without apparent absorption, and no increase in congenital anomalies has been reported. However, tretinoin is also given orally to treat acute promyelocytic leukemia, at thousands of times higher than the topical dose, and it is considered highly teratogenic in this setting. Another retinoid, bexarotene, which used to treat refractory T-cell lymphoma, is similarly considered highly teratogenic.
Thalidomide is an anxiolytic and sedative drug that was available in much of the world between 1956 and 1960, before its teratogenicity became evident. It produced no defects in mice and rats and had been assumed safe in humans. Thalidomide results in malformations in approximately 20 percent of exposed fetuses. Phocomelia is the prototypical anomaly, but a wide variety of limb-reduction defects have been reported. Anomalies of the ears, cardiovascular system, and bowel musculature were also common. Thalidomide was approved for use in the United States in 1999 for treatment of erythema nodosum leprosum, and it has also been effective in cutaneous lupus erythematosus, chronic graft-verus-host disease, prurigo nodularis, and certain malignancies. It is recommended that women of reproductive age who need thalidomide use two highly effective forms of birth control.
Warfarin and dicoumarol have a low molecular weight, readily cross the placenta, and can cause significant teratogenic and fetal effects. It is estimated that one in six exposed pregnancies results in an abnormal liveborn infant, and one in six results in abortion or stillbirth. When exposure occurs between the sixth and ninth week, the fetus is at risk for warfarin embryopathy, characterized by nasal hypoplasia and stippled vertebral and femoral epiphyses—virtually identical to chondrodysplasia punctata. During the second and third trimesters, defects associated with fetal warfarin exposure are likely due to hemorrhage and scarring, which may lead to the central nervous system findings of agenesis of the corpus callosum, Dandy-Walker malformation, microphthalmia, optic atrophy, and developmental delays.
It is difficult to estimate the risk or safety of various herbal remedies because they are not regulated by the FDA. Often, the identity and quantity of all ingredients are unknown. Few human or animal studies of their teratogenic potential have been reported, and knowledge of complications is essentially limited to acute toxicity. In general, because it is not possible to assess the safety of herbal remedies on the developing fetus, pregnant women should be counseled to avoid these substances. A number of herbal preparations with possible adverse physiological or pharmacological effects are listed in Table 8-6.
TABLE 8-6. Possible Adverse Effects of Some Herbal Medicines
Recreational Drugs and Tobacco
It is estimated that at least 10 percent of fetuses are exposed to one or more illicit drugs. The effects of any one drug may be confounded by concomitant use of alcohol, tobacco, or other drugs; by poor maternal heath, nutrition, or infectious disease; or by contaminants in the drug—such as lead, cyanide, herbicides, pesticides, arsenic, or even Coumadin. Some effects of illicit substances of abuse are shown in Table 8-7.
TABLE 8-7. Effects of Illicit Substances of Abuse in Pregnancy
Cigarette smoke contains a complex mixture of nicotine, cotinine, cyanide, thiocyanate, carbon monoxide, cadmium, lead, and various hydrocarbons. In addition to being fetotoxic, many of these substances have vasoactive effects or reduce oxygen levels. Smoking has been associated with an increase in several birth defects, including hydrocephaly, microcephaly, omphalocele, gastroschisis, cleft lip and palate, and hand abnormalities. Importantly, smoking also has a direct dose-response effect on fetal growth. Infants of mothers who smoke are on average 200 g lighter than those of nonsmokers. The risk of low birthweight is doubled, and that of a small-for-gestational age infant is increased 2.5-fold. In addition, smoking is associated with an increased incidence of subfertility, spontaneous abortion, placenta previa and abruption, and preterm delivery.
For further reading in Williams Obstetrics, 23rd ed.,
see Chapter 14, “Teratology and Medications That Affect the Fetus.”