In addition to teratogenic effects resulting in recognizable structural or functional alterations in organ systems, more subtle functional, cognitive, or neurobehavioral changes can occur as a result of drug exposure during pregnancy. These are obviously much more difficult to detect; costly and complex long-term follow-up studies are required to establish a cause-and-effect relationship. Barbiturates, an ingredient in commonly used headache medications in the United States and Canada, are suspected of causing long-term neurobehavioral effects.

Drugs used for headache can have myriad other effects on pregnancy, including lengthening labor (magnesium and verapamil) (16), affecting fetal birth weight (beta-adrenergic blockers) (24), or causing other physiologic effects. Some of these effects may be specific to the stage of pregnancy in which the drug is taken. Drugs that interfere with prostaglandin formation, such as aspirin, can cause premature closure of the ductus arteriosus if taken late in pregnancy, while they are generally without adverse effects if taken early in pregnancy (23). Other drugs emerging for use in migraine may have serious adverse effects during pregnancy. For example, preliminary information suggests that lisinopril is an effective migraine preventive agent (35). However, angiotensin-converting enzyme inhibitor use during pregnancy, especially in the second and third trimesters, can cause low blood pressure, severe kidney failure, potassium excess, or even death in the newborn. Studies in mice and rats at doses many times the recommended human dose have shown that use of lisinopril causes a decrease in successful pregnancies, a decrease in the weight of infants, and an increase in infant deaths (18).

As of January 2004, information from the prospective sumatriptan pregnancy registry showed no statistically significant difference between the rate of birth defects in pregnancies where first-trimester exposure to sumatriptan occurred and the background rate of birth defects in the general population (1). Complementary sources of information about triptan risk in pregnancy include the Swedish Medical Birth Registry (21), the Danish Birth Registry (31), a Canadian teratogen information service study (37), and a year-long postsurveillance safety study during which unintended pregnancies occurring during sumatriptan use were prospectively followed (32). These sources of information have likewise produced no signal of teratogenicity from triptan use. No single method of assessing drug risk in pregnancy provides complete or perfect information, but the consistency of information from multiple sources of data is reassuring information for the woman whose fetus has been inadvertently exposed to sumatriptan during pregnancy (26).

The limitations of current information must be appreciated, however. A large increase in risk for a single birth defect from sumatriptan exposure can be confidently
excluded based on present information, but a small increase in risk for common birth defects or a modest increase in risk for rare birth defects cannot be ruled out, based on the number of pregnancy outcomes for which we have information. This is because if a drug is associated with a high level of birth defects (e.g., thalidomide), relatively few exposures are needed to detect this risk; if the medication is associated with a slight increase in the overall occurrence of birth defects, approximately 300 exposed pregnancies need to be followed to detect a doubling of risk; and if the medication is associated with a rare increase of a specific defect (e.g., 1 in 1000), approximately 10,000 exposed pregnancies need to be followed to detect a doubling of risk (26).

In the authors’ view, the current classification of triptans as Pregnancy Category C in the widely used United States Food and Drug Administration (FDA) Pregnancy Classification remains appropriate. For drugs in Category C, “safety in human pregnancy has not been determined” and “…potential benefits should justify potential risks” if used in pregnancy. Thus, in deciding whether to recommend the use of sumatriptan in pregnancy, the risks of the drug must be weighed against the beneficial effects of treatment. The FDA’s five categories of pregnancy risk (A, B, C, D, and X) are intended to assess the therapeutic risks of drugs, and emphasize weighing treatment benefits against drawbacks (Table 133-1) (29). The system has been widely criticized. For example, tricyclic antidepressants are still classified as class D, even though the evidence suggests they are safe (23). An alternative method of assessing drug risks in pregnancy is the TERIS system (Teratogen Information System), a computerized database of information “designed to assist physicians or other healthcare professionals in assessing the risks of possible teratogenic exposures in pregnant women.” TERIS ratings classify a drug risk as “none,” “minimal,” “small,” “moderate,” “high,” or “undetermined.” Within the TERIS system, decisions about risk are made “on the basis of the reproducibility, consistency, and biological plausibility of available clinical, epidemiological, and experimental data.” Information on over 1000 drugs is available in this system, although access to the information requires a subscription (19). The TERIS rating for an individual drug is based on a consensus of expert opinion and the literature (14). There is limited agreement between TERIS and FDA ratings of risks (Table 133-2) (13).