Risk of fetal exposure to folic acid antagonists

Several folic acid antagonists are considered by the Food and Drug Administration (FDA) to be toxic or potentially toxic to fetuses, including some folic acid antagonists that were once considered safe, such as trimethoprim. Information on fetal exposure to folic acid antagonists is sparse.

In this study, we conducted a thorough search of English literature on human uses of various folic acid antagonists, and made an indirect estimation of potential exposure to folic acid antagonists during pregnancy by analyzing the data from the outpatient prescription drug database of the Canadian province of Saskatchewan.

The numbers of women of reproductive age (16 to 44 years) with at least 1 prescription of dihydrofolate reductase inhibitors was 14195 in 1977, 20455 in 1991, and 16054 in 1999. Corresponding figures for other folic acid antagonists were 2136, 1954, and 2720, respectively. According to these figures, the rates of prescription given to women of reproductive age in any particular calendar year were 8.45% (95% confidence interval [CI], 8.33% - 8.57%) for dihydrofolate reductase inhibitors and 1.14% (95% CI, 0.67% - 1.61%) for other folic acid antagonists.

Prescription of folic acid antagonists to women of reproductive age is quite frequent, and there has been no apparent decline in prescriptions in recent years. Increase in unplanned pregnancies in industrial countries, lack of adequate scientific evidence on the adverse effects of folic acid antagonists, potential ignorance in clinical practice, and conflicting needs to treat maternal diseases and to protect fetuses, can all lead to frequent prescription of potentially toxic folic acid antagonists to pregnant women, thus posing serious threat to the fetuses. In this paper, strategies that may be used to reduce the risk of fetal exposure to folic acid antagonists are proposed.