Gross malformations are produced by exposure to teratogens during the embryonic period (roughly the first trimester). This is the time when the basic shape of internal organs and other structures is being established. Because the fetus is especially vulnerable during the embryonic period, pregnant patients must take special care to avoid teratogen exposure during this time.
Teratogen exposure during the fetal period (i.e., the second and third trimesters) usually disrupts function rather than gross anatomy. Of the developmental processes that occur in the fetal period, growth and development of the brain are especially important. Disruption of brain development can result in learning deficits and behavioral abnormalities.
Identification of Teratogens
For the following reasons, human teratogens are extremely difficult to identify:
• The incidence of congenital anomalies is generally low.
• Animal tests may not be applicable to humans.
• Prolonged drug exposure may be required.
• Teratogenic effects may be delayed.
• Behavioral effects are difficult to document.
As a result, only a few drugs are considered proven teratogens. Drugs whose teratogenicity has been documented (or at least is highly suspected) are listed in Table 7.1. It is important to note, however, that lack of proof of teratogenicity does not mean that a drug is safe—it only means that the available data are insufficient to make a definitive judgment. Conversely, proof of teratogenicity does not mean that every exposure will result in a birth defect. In fact, with most teratogens, the risk for malformation after exposure is only about 10%.
TABLE 7.1
Drugs That Should Be Avoided During Pregnancy Because of Proven or Strongly Suspected Teratogenicity*
| Drug | Teratogenic Effect |
| ANTICANCER/IMMUNOSUPPRESSANT DRUGS | |
| Cyclophosphamide | CNS malformation, secondary cancer |
| Methotrexate | CNS and limb malformations |
| Thalidomide | Shortened limbs, internal organ defects |
| ANTISEIZURE DRUGS | |
| Carbamazepine | Neural tube defects, craniofacial defects, malformations of the heart, hypospadias |
| Phenytoin | Growth delay, CNS defects |
| Topiramate | Growth delay, cleft lip with cleft palate |
| Valproic acid | Neural tube defects, craniofacial defects, malformations of the heart and extremities, and hypospadias |
| SEX HORMONES | |
| Androgens (e.g., danazol) | Masculinization of the female fetus |
| Diethylstilbestrol | Vaginal carcinoma in female offspring |
| Estrogens | Congenital defects of female reproductive organs |
| ANTIMICROBIAL DRUGS | |
| Tetracycline | Tooth and bone anomalies |
| Trimethoprim-sulfamethoxazole | Neural tube defects, cardiovascular malformations, cleft palate, clubfoot, and urinary tract abnormalities |
| OTHER DRUGS | |
| Alcohol | Fetal alcohol syndrome, stillbirth, spontaneous abortion, low birth weight, intellectual disabilities |
| 5-Alpha-reductase inhibitors (e.g., dutasteride, finasteride) | Malformations of external genitalia in males |
| Angiotensin-converting enzyme inhibitors | Renal failure, renal tubular dysgenesis, skull hypoplasia (from exposure during the second and third trimesters) |
| Antithyroid drugs (propylthiouracil, methimazole) | Goiter and hypothyroidism |
| HMG CoA reductase inhibitors (atorvastatin, simvastatin) | Facial malformations and CNS anomalies, including holoprosencephaly (single-lobed brain) and neural tube defects |
| Isotretinoin and other vitamin A derivatives (etretinate, megadoses of vitamin A) | Multiple defects (CNS, craniofacial, cardiovascular, others) |
| Lithium | Epstein anomaly (cardiac defects) |
| NSAIDs | Premature closure of the ductus arteriosus |
| Oral hypoglycemic drugs (e.g., tolbutamide) | Neonatal hypoglycemia |
| Warfarin | Skeletal and CNS defects |
To prove that a drug is a teratogen, three criteria must be met:
• The drug must cause a characteristic set of malformations.
• The drug must act only during a specific window of vulnerability (e.g., weeks 4 through 7 of gestation).
• The incidence of malformations should increase with increasing dosage and duration of exposure.
Obviously, we cannot do experiments on humans to determine whether a drug meets these criteria. The best we can do is systematically collect and analyze data on drugs taken during pregnancy in the hope that useful information on teratogenicity will be revealed.
Studies in animals may be of limited value, in part because teratogenicity may be species specific. That is, drugs that are teratogens in laboratory animals may be safe in humans. Conversely, and more important, drugs that fail to cause anomalies in animals may later prove teratogenic in humans. The most notorious example is thalidomide. In studies with pregnant animals, thalidomide was harmless; however, when thalidomide was taken by pregnant patients, about 30% had babies with severe malformations. The take-home message is this: lack of teratogenicity in animals is not proof of safety in humans. Accordingly, we cannot assume that a new drug is safe for use in human pregnancy just because it has met FDA requirements, which are based on tests done in pregnant animals.
Some teratogens act quickly, whereas others require prolonged exposure. Thalidomide represents a fast-acting teratogen: a single dose can cause malformation. In contrast, alcohol (ethanol) must be taken repeatedly in high doses if gross malformation is to result. (Lower doses of alcohol may produce subtle anomalies.) Because a single exposure to a rapid-acting teratogen can produce obvious malformation, rapid-acting teratogens are easier to identify than slow-acting teratogens.
Teratogens that produce delayed effects are among the hardest to identify. The best example is diethylstilbestrol, an estrogenic substance that causes vaginal cancer in female offspring 18 years or so after they were born.
Teratogens that affect behavior may be nearly impossible to identify. Behavioral changes are often delayed and therefore may not become apparent until the child goes to school. By this time, it may be difficult to establish a correlation between drug use during pregnancy and the behavioral deficit. Furthermore, if the deficit is subtle, it may not even be recognized.
Although we have been discussing the effect of teratogens, it is important to note that drug-related effects are not limited to the distortions of gross anatomy caused by teratogens. Drugs may also include neurobehavioral and metabolic anomalies. For example, benzodiazepines taken late in pregnancy may cause hypoglycemia and respiratory complications along with a hypotonic state that is commonly called floppy infant syndrome. The aminoglycoside streptomycin provides another example. Although the teratogen risk of aminoglycosides is low, children born to women taking streptomycin have been born with congenital deafness. Some drugs taken by pregnant women may be dangerous (e.g., the anticoagulant warfarin has been associated with fetal hemorrhage) or life threatening (e.g., misoprostol, a drug taken to protect the stomach of people taking nonsteroidal antiinflammatory drugs [NSAIDs]) can cause a spontaneous abortion.
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