The use of valproate in pregnant women is associated with attention-deficit/hyperactivity disorder (ADHD) in children, according to research results published in JAMA Network Open.

Valproate use during pregnancy is associated with congenital malformations and adverse neurodevelopment. Researchers sought to determine whether prenatal exposure to valproate and other antiepileptic drugs (AEDs) increases the risk for ADHD in offspring.

The population-based cohort study enrolled 913,302 children age 9 to 12 in Denmark. Researchers determined prenatal exposure to valproate and other AEDs through the Danish National Prescription registry. The children were either diagnosed with ADHD in the Danish Psychiatric Central Research Register or had redeemed a prescription for ADHD medication. The cohort was followed from birth until the day of ADHD diagnosis, death, emigration, or December 31, 2015, whichever came first. Researchers used Cox regression models to estimate the hazard ratio of ADHD and adjusted for potential confounders.

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In the study, 580 children had been exposed to valproate and 49 of them had ADHD (8.4%). Of the children with no valproate exposure, only 3.2% had ADHD. Prenatal exposure to valproate was associated with a 48% increased risk for ADHD compared with that in unexposed children. There was no identified association for other antiepileptic drugs.

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The study has several limitations, including the reliance on register data and not controlling for medications other than AEDs.  In addition, because pregnancy is a contraindication for valproate treatment, it is likely that women who continue to be prescribed valproate during pregnancy differ in terms of disorder presentation and severity.

 “These findings have important implications for the counseling of women of childbearing potential who are undergoing treatment with valproate, and they support warnings issued by authorities,” the researchers write. They add that large-scale observational studies of the adverse effects of AEDs are warranted.


Christensen J, Pedersen LH, Sun Y, Dreier JW, Brikell I, Dalsgaard S. Association of prenatal exposure to valproate and other antiepileptic drugs with risk for attention-deficit/hyperactivity disorder in offspring. JAMA Netw Open. 2019;2(1):e186606.