Valproate in Pregnancy: Recent Research and Regulatory Responses

Valproate and formulations thereof are approved for the management of seizure disorders, bipolar disorder, and migraine. Valproate is also used for many off-label indications. Unfortunately, data from observational studies indicate that valproate is perhaps the most teratogenic drug in the neuropsychiatric pharmacopeia. It is significantly more teratogenic than many other antiepileptic drugs (AEDs). In observational studies, gestational exposure to valproate is also associated with higher risks of cognitive, language, and psychomotor delay during early childhood and possibly with an increased risk of autism, as well. Although untreated epilepsy is itself associated with many adverse gestational and neonatal outcomes, confounding by indication is an unlikely explanation for the adverse outcomes observed with valproate. This is because of the range of the adverse outcomes, the magnitude of the risks, the dose-dependent nature of the risks, the consistency of findings across studies, the specificity of outcomes for valproate exposure, and the greater risks with valproate relative to other AEDs. Despite the existence of a large body of literature that documents these risks, valproate continues to be prescribed to a substantial proportion of women of childbearing potential. As a result, many regulatory bodies across the world have discouraged and even banned the use of valproate during pregnancy and in women of childbearing potential unless no satisfactory alternatives exist or unless a pregnancy prevention program is implemented.