Drugs in Pregnancy

Counseling Women about Teratogenic Risks

In one study, women exposed to nonteratogenic drugs who sought counseling estimated, on average, that they had a 25 percent risk of major malformations, which is in the range of the teratogenic risk associated with thalidomide. After counseling, this estimate was substantially reduced, thereby preventing numerous terminations of otherwise wanted pregnancies. The same women correctly estimated the risk of major malformations in the general population (5 percent), indicating that the high risk they assigned to their own pregnancies was not due to a misunderstanding of the concept of base-line risk.

What are the sources of this misperception? Numerous lay publications misinform women by assigning risks to drugs not known to be teratogenic in humans. Women often report that their physicians have encouraged them to terminate otherwise wanted pregnancies just to be on the safe side, suggesting that many physicians are unfamiliar with the current literature on the safety of drugs taken during pregnancy.

Physicians counseling women who are pregnant or are planning a pregnancy should make sure that they understand clearly the nature and magnitude of a risk associated with a drug. Women’s attitudes toward voluntary abortion differ. In addition, the same information about the nature and magnitude of a teratogenic risk may prompt different decisions by different women, according to the clinical situation and specific circumstances. For example, women with epilepsy that has been treated effectively with phenytoin since their childhood may be glad to hear that although the drug is teratogenic, the overall risk of malformations is not high. In contrast, women who have been treated with phenytoin for a single grand mal seizure and who have normal children born before phenytoin was prescribed may find it unacceptable to continue an unplanned pregnancy after learning about the higher-than-normal risk of adverse effects.

During counseling, it is important to ensure that a woman understands the concept of base-line teratogenic risk and the fetal or perinatal risks, if any, associated with her medical condition. For example, a woman with manic depression treated with lithium in the first trimester will need to understand not only the slightly increased risk of fetal cardiac anomalies associated with the drug (less than 1 percent) but also the increased genetic risk of manic depression in her child. The counselor should be sure to communicate the same information to the woman’s physician so that she does not receive conflicting advice.

To receive up-to-date, evidence-based information on the safety and risk of drugs during pregnancy, physicians can consult a teratogen-information service.

The FDA Classification of Teratogenicity

To guide physicians in the interpretation of the teratogenic risk associated with prescription drugs, the FDA has established a system that classifies drugs on the basis of data from humans and animals, ranging from class A drugs, which are designated as safe for use during pregnancy, to class X drugs, which are contraindicated during pregnancy because of proven teratogenicity. This system has resulted in ambiguous statements that may be difficult to interpret and use for counseling and that can cause anxiety among women. In addition, the classification is often not changed when new data become available. For example, until recently, combined oral contraceptives were classified as class X drugs. Yet meta-analyses revealed that these combinations of estrogen and progestin were not associated with an increased risk of major malformations, in general, or genitourinary malformations, in particular. Each year, thousands of women become pregnant while taking these contraceptive hormones because of noncompliance or less-than-perfect efficacy, and their fetuses are exposed to the drugs during embryogenesis. In a similar fashion, tricyclic antidepressant drugs are classified as D (“positive evidence of human fetal risk”), even though no such evidence exists and the available data suggest that these drugs are safe. The Teratology Society has proposed that the FDA abandon the current classification system in favor of more meaningful, evidence-based, narrative statements. At an FDA hearing held on September 15, 1997, this proposal received public support. Other countries (e.g., Sweden, Australia, the Netherlands, Switzerland, and Denmark) have different classification systems, although all are based on a hierarchy of estimated fetal risk.

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