Risk Management of Valproate and Other Teratogenic Anticonvulsants in the Era of Proliferating Use.

Valproic acid, carbamazepine and topiramate have well-known teratogenic risk and all 3 rank among the top 10 teratogenic medications with the highest prenatal exposure risk. Importantly, pregnancies exposed to valproic acid are not dominated by patients with epilepsy but rather with less serious conditions such as migraine. In the United States, only a weight loss combination product containing topiramate has a mandatory pregnancy prevention program, a so-called Risk Evaluation and Mitigation Strategy (REMS), while prevention of fetal exposure to all three single ingredient products relies on information in the product labeling and a medication guide provided at dispensing. REMS have been avoided for antinconvulsants because of concerns about reduced medication access for patients with serious conditions such as epilepsy, hence weighting maternal harm due to uncontrolled disease against adverse pregnancy or infant outcomes. However, the broad and growing spectrum of indications for all three medications, paired with increasingly strict abortion laws that may not allow pregnancy termination if accidental fetal exposure occurs, may require re-assessment of the benefit-risk of REMS. Here we argue that formal quantitative approaches are needed that allow assessments of maternal and infant risk, considering maternal disease, adverse pregnancy outcomes and teratogenic effects on infants, and the overall public health impact of REMS for anticonvulsants. For valproic acid, given its broad use, high risk of fetal exposure, and profound impact on child health, we predict the public health impact of a REMS will be favorable.