Valproate in Pregnancy Linked to Neurodevelopmental Risk, suggests study

This was a population-based cohort study that used healthcare information obtained from the population of the United States who were insured by both the government and commercial insurance schemes between the years 2000 and 2021. Pregnant patients with epilepsy and their offspring were used in the study, making it possible to assess the outcomes longitudinally. Exposure was determined by the administration of a particular class of antiseizure medications in the second half of the pregnancy, which equates to the synaptogenesis phase of development, a crucial period in the development of the brain.

The medications used in the study included carbamazepine, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, valproate, and zonisamide. The outcome was the development of a neurodevelopmental disorder in the offspring. The secondary outcomes included attention deficit hyperactivity disorder, autism spectrum disorder, behavioral disorders, developmental coordination disorder, intellectual disability, learning difficulty, and speech or language disorders.

Key findings:

• An increased risk was associated with valproate and zonisamide, and this was seen in different neurodevelopmental outcomes, where the adjusted hazard ratios ranged from 1.26 to 4.50.

• No association with an increased risk for any neurodevelopmental outcome was observed for levetiracetam and phenytoin.

• An association with an increased risk for attention deficit hyperactivity disorder and behavioral disorders was observed for carbamazepine and oxcarbazepine, with hazard ratios between 1.23 and 1.40.

• A twofold to fourfold increase in risk for intellectual disability was observed for several AS drugs, although it was not precise because of low event numbers.

• No association with an increased risk for any neurodevelopmental outcome was observed for topiramate and lamotrigine, although signals for intellectual disability for both drugs and learning difficulty for topiramate, with a hazard ratio of 1.23, were observed.

• The size of the exposed group for each drug ranged from 219 (lacosamide) to 5,261 (levetiracetam), with an unexposed group consisting of 8,887 children.

Prenatal exposure to valproate is associated with increased neurodevelopmental risk in children, and several antiseizure medications, including zonisamide, are associated with additional signals. Some antiseizure medications, on the other hand, have more promising safety profiles, although these require further study.

Reference:

Straub, L., Hernandez-Diaz, S., Bateman, B. T., Zhu, Y., Mogun, H., Wisner, K. L., Gray, K. J., Lester, B., McDougle, C. J., Pennell, P. B., & Huybrechts, K. F. (2026). Prenatal antiseizure drug exposure and risk of neurodevelopmental disorders in children: population based cohort study. BMJ (Clinical research ed.), 392, e085725. https://doi.org/10.1136/bmj-2025-085725