REVIEW OF: Smolinski NE et al, JAMA Netw Open 2024;7(5):e2412680

STUDY TYPE: Retrospective cohort study

Valproate remains one of the most teratogenic drugs in psychiatry and neurology, yet its use among women of childbearing age continues. This large US cohort study examined over 165,000 treatment episodes from 2005 to 2020 to see whether pregnancy rates or contraceptive use changed after repeated FDA warnings.

Despite the safety alerts, pregnancy rates during valproate treatment failed to decline and instead trended slightly upward, from about 1.7 per 100 person-years in 2005 to 1.9 per 100 person-years in 2019. Most patients were treated for mood disorders (43%) or migraines (20%); epilepsy accounted for only 15%. Women treated for mood or migraine were twice as likely to become pregnant while taking valproate compared with those treated for epilepsy. Only 22% of treatment episodes overlapped with any prescription contraception, most often oral forms.

CARLAT TAKE

Valproate remains overprescribed in women of childbearing potential despite safer alternatives. If you’re treating bipolar disorder or migraine, reconsider whether valproate is truly necessary. Exposure in the first trimester carries a 9%–10% risk of major congenital malformations, including neural tube defects, and increases the risk of neurodevelopmental disorders (Hernandez-Diaz S et al, Neurology 2025;105(3):e213786; Hernandez-Diaz S et al, N Engl J Med 2024;390(12):1069–1079). Many pregnancies are unplanned, and neural tube development occurs within the first six weeks, often before pregnancy is recognized. Discuss reproductive and contraception plans early and consider safer alternatives whenever possible.