The author reports no financial relationships relevant to this article.
Fifty years ago, the thalidomide experience—a high incidence of major birth defects following prenatal use of the drug—made clear the devastating potential of drug exposure during pregnancy. Since that disaster, healthcare providers and patients have adopted a conservative approach to medication use during pregnancy, especially during the first trimester and lactation. That is a wise strategy, although very few medications are associated with abnormal fetal development.
In this article, I’ll guide you through some of the issues that must be considered when assessing a drug’s teratogenicity, help you find information on a host of medications, and familiarize you with some of the challenges involved in counseling the patient. I also present a table listing the adverse effects known to be associated with selected drugs during the first, second, and third trimesters and lactation (TABLE). We are fortunate that a large body of information about medication use during pregnancy and lactation is readily available on the Web and in books and medical journals. This information is far from definitive, however, because much of the evidence concerning prescribed drugs is anecdotal or presented with insufficient warning about their use during pregnancy and lactation.
A discussion of these issues with the patient will help set the risks and benefits of a particular drug into proper perspective, alleviate fears, and improve compliance. Nonprescription medications should also be discussed, and the patient should be advised that we have very little data concerning their use during pregnancy.
Assignment of risk is an uncertain science
Major structural defects are apparent at birth in about 3% of all pregnancies and in about 4.5% of all children by the age of 5 years.1 A cause or proposed mechanism for the defects can be determined in fewer than 50% of these cases. Nor can we count on expert consensus about the safety of many medications during pregnancy because it rarely occurs and, in some cases, may be impossible to achieve.
Animal studies are the means of assessing the teratogenicity of most drugs. Animals commonly used to study fetal effects include rodents (fertility, birth defects, birth weight, behavior), rabbits (birth defects), baboons (uterine blood flow), and sheep (uterine blood flow, cardiovascular effects, fetal hypoxia, and acidosis). Dosages are often much higher (in relation to body weight or surface area) to “test the systems” for any possible reproductive harm. Although these studies may be helpful, they do not reliably predict the human response.
Even when humans are the subject of study, conclusions must be viewed with caution. To determine the risk of teratogenesis, it is necessary to know the stage of development during which the exposure occurred, as well as the identity and dose of the medication and the genetic susceptibility of the mother and fetus.
Three critical stages. In utero exposure to a drug occurs in one of three periods of fetal development:
- ovum – from fertilization to implantation
- embryo – from the second through the eighth week of gestation
- fetus – from the eighth completed week until delivery.
An “all-or-none” effect (i.e., spontaneous abortion or not) is believed to arise from exposure during the first period, but the embryo stage is the most critical time because it involves organogenesis. Detrimental effects may occur even beyond this period as cells continue to divide in the hematologic, reproductive, and central nervous systems.
Many fine points of exposure are difficult to clarify
Retrospective and uncontrolled studies, as well as individual case reports or small series, may overestimate the risk to the fetus of exposure to a specific drug or combination of medications. Case reports do not establish causation.
It can also be difficult to differentiate between the risks of a specific drug and the hazards of maternal illness to explain an unfavorable outcome. For example, is a particular case of stillbirth the result of fetal exposure to enoxaparin or maternal thrombophilia, or both? Can fetal growth restriction be attributed to use of azathioprine during pregnancy or to the mother’s underlying illness? And so on.