Current Trends in Preventing Fetal Exposure to Teratogens

The advent of effective injectable hormonal contraceptives has made it possible to minimize the risk of an unplanned pregnancy during therapy with a known teratogen. This approach was first implemented in South America, where sexually active women with cutaneous leprosy were injected with medroxyprogesterone before receiving a prescription for thalidomide. Yet numerous new cases of thalidomide-associated embryopathy have been reported in the children of women who continued to take the drug after the period of contraceptive efficacy (three months) or who received the drug from their male partners.

Because any new drug may be teratogenic, it is important to develop more effective methods to prevent fetal exposure. One such method may be the use of implantable hormonal compounds (e.g., levonorgestrel implants), which can provide long-term, reversible contraception for up to five years. Levonorgestrel implants have documented efficacy in young women in whom oral methods of contraception are likely to fail. Implants should be considered by sexually active women who are taking a teratogen medicinally (e.g., phenytoin or warfarin) or as part of a pattern of substance abuse (e.g., alcohol or cocaine). Furthermore, women taking teratogenic drugs who are not sexually active should be informed of the availability of effective postcoital contraceptives.

The Process of Establishing Risk or Safety of Drugs in Pregnancy

Every year, many new drugs are approved and marketed. By this stage, several thousand people have usually participated in studies of the drugs, but the majority have been men. Since there are scarcely any data on fetal effects at the time of marketing, data from studies in animals provide the initial guidelines.

The Value of Studies in Animals

Typically, studies of reproductive toxicology in animals compare the outcome of pregnancy in groups of animals receiving a range of doses of the drug in question during the period of organogenesis with the outcome in untreated (control) animals. The occurrence of thalidomide-associated embryopathy led to the erroneous belief that human teratogenicity could not be predicted on the basis of studies in animals. However, every drug that has since been found to be teratogenic in humans has caused similar teratogenic effects in animals, except misoprostol, which causes a morphologic pattern known as the Moebius sequence in humans. In at least one case, that of isotretinoin, the studies in animals probably prevented a disaster similar to that of thalidomide.

However, there are drugs that have teratogenic effects in animals when administered in high doses that are not teratogenic in humans given clinically relevant doses. For example, high doses of glucocorticoids or benzodiazepines can cause oral clefts in animals, but clinically relevant doses in humans have no such effects. Similarly, salicylates cause cardiac malformations in animals but not in humans. Such discrepancies have led to unwarranted anxiety on the part of women, their families, and physicians and may have contributed to unnecessary terminations of pregnancies. Although studies in animals may identify teratogenic effects, it can be difficult to extrapolate these effects to humans.