Before marketing a new drug, the manufacturer almost never tests the product in pregnant women to determine its effects on the fetus. Consequently, most drugs are not labeled for use during pregnancy. Typically, descriptions of drugs that appear in the Physicians’ Desk Reference and similar sources contain statements such as, “Use in pregnancy is not recommended unless the potential benefits justify the potential risks to the fetus.” Since the risk has been adequately established for only a few drugs, physicians caring for pregnant women have very little information to help them decide whether the potential benefits to the mother outweigh the risks to the fetus. These typical disclaimers, although understandable from the medicolegal standpoint, put large numbers of women and their physicians in difficult situations for several reasons. One is that at least half the pregnancies in North America are unplanned, and every year, hundreds of thousands of women therefore expose their fetuses to drugs before they know they are pregnant. Such women often interpret the statement that use during pregnancy is not recommended as meaning that the drug is not safe during pregnancy.
There is evidence that this perception of fetal risk causes many women to consider or even seek termination of otherwise wanted pregnancies. Another reason is that with the recent increase in the age at which women have children, conditions that necessitate long-term drug therapy are diagnosed in larger numbers of women before pregnancy. Furthermore, for pregnant women with certain conditions once believed to be incompatible with pregnancy, such as systemic lupus erythematosus and heart diseases, the outcome of pregnancy has improved dramatically in the past few decades.
In this article, we review current knowledge of the fetal and neonatal effects of prescription and over-the-counter drugs given to pregnant women, with an emphasis on the approaches used to determine safety and risk. In addition, we review approaches to communicating such information to pregnant women and their families.
Teratogenesis is defined as the dysgenesis of fetal organs as evidenced either structurally or functionally (e.g., brain functions). The typical manifestations of teratogenesis are restricted growth or death of the fetus, carcinogenesis, and malformations, defined as defects in organ structure or function. These abnormalities vary in severity (e.g., hypospadias that is mild and may be missed, or is severe, necessitating several corrective operations). Major malformations may be life-threatening and require major surgery or may have serious cosmetic or functional effects.
A Historical Perspective
Several milestones highlight the problems of drug therapy facing pregnant women, their families, and health professionals.
For decades it was believed that the placenta served as a barrier that protected the fetus from the adverse effects of drugs. The thalidomide disaster drastically changed this perception by demonstrating that fetal exposure to the drug during critical periods of development resulted in severe limb defects and other organ dysgenesis (e.g., kidney and heart defects). Despite the high rates of malformations (20 to 30 percent) and their characteristic pattern, the teratogenicity of thalidomide was not suspected for years. The suffering it caused has prompted the belief that every drug has the potential to be a new thalidomide.
Most known human teratogens are associated with much lower rates of malformations, and the syndromes they cause are not always so pathognomonic, making causation more difficult to confirm. Yet 35 years after the recognition of thalidomide-associated embryopathy, fewer than 30 drugs have been proved to be teratogenic in humans when used in clinically effective doses, and even fewer are currently in clinical use (Table 1 - Drugs with Proven Teratogenic Effects in Humans). Many other commonly used drugs, including salicylates, glucocorticoids, and spermicides, were once thought to be teratogenic but have been shown to be safe in subsequent studies that were larger and better controlled than the initial studies (Table 2 - Common Drugs Initially Thought to Be Teratogenic but Subsequently Proved Safe).
One example of the gap between the perception of teratogenic risk and evidence-based proof of safety is the case of Bendectin. During the late 1950s and the 1960s, this drug, a combination of an antihistamine (doxylamine) and pyridoxine, was the most widely used medication in the United States for nausea and vomiting associated with pregnancy. During the 1970s, many lawsuits claiming that Bendectin was teratogenic were filed against the manufacturer in American courts. Therefore, the drug was withdrawn from the market by its manufacturer in 1982, which left millions of pregnant women without a drug approved by the Food and Drug Administration (FDA) for the treatment of nausea and vomiting. The rate of hospitalization for severe nausea and vomiting during pregnancy increased by a factor of 2 in both the United States and Canada after Bendectin was withdrawn from the market.
The drug was withdrawn despite a substantial body of evidence that the rate of major malformations among the children of women who had received Bendectin during pregnancy did not differ from the rate in the general population. Withdrawal of the drug from the American market did not decrease the rate of any specific category of malformation, as would be expected for a truly teratogenic drug estimated to have been used by up to 40 percent of pregnant women at one time.
In Canada, the drug continues to be marketed under the trade name Diclectin. A review committee has advised the Canadian Minister of Health that the drug is safe. A recent study revealed that severe nausea and vomiting of pregnancy often lead women to terminate or consider the termination of otherwise wanted pregnancies. Other formulations of doxylamine in combination with pyridoxine are available in other countries (e.g., South Africa, Spain, and Thailand).
The experience with thalidomide led drug regulators, drug manufacturers, and the medical community to believe that appropriate labeling of teratogenic drugs, with warnings not to take them around the time of conception, would be effective in preventing fetal exposure to the drugs. The naivete’ of this belief became evident after isotretinoin was introduced in North America in the early 1980s for the treatment of acne. For years before its clinical introduction, this drug had been known to cause malformations in animals. Despite explicit warning labels, scores of children with retinoid embryopathy were born in the years after the drug was introduced. Such warnings are not sufficient, because women taking isotretinoin may not plan their pregnancies, or their birth-control methods may fail. In addition, some women and men are functionally illiterate, and they may not read or understand the content of a drug label.
The initial experience with isotretinoin led to the development of a more comprehensive program to prevent teratogenesis. The Retinoid Pregnancy Prevention Program includes explicit and detailed printed warnings as well as a line drawing of a malformed child, and as part of the program, women are asked to sign a consent form indicating that they agree to use two effective methods of contraception before therapy is started. Since the program was implemented in 1989, a substantial number of fetuses have been exposed to the drug. As many as 30 percent of the women with exposed fetuses did not use any mode of contraception, even though they were cognizant of the high fetal risk. Many of these women explained that they did not believe they were fertile, since they had not conceived during periods of months or years when they had not used contraceptive methods.