Prenatal exposure to valproate, but not other anti-epileptic drugs, is associated with a small but significantly increased risk of ADHD in children.

The findings, from a cohort of more than 900,000 children born in Denmark, have implications for the use of valproate during pregnancy and counselling of women during their childbearing years, researchers say.

Their study found 49 of 580 children (8.4%) exposed to valproate in utero were subsequently diagnosed with ADHD. Of the children who were not exposed to the anti-epileptic drug, only 3.2% had a diagnosis of ADHD during the study period.

The mean age at ADHD diagnosis in the study was 8.8 years.

“Overall, the children who were prenatally exposed to valproate had a 48% increased risk of ADHD (adjusted HR 1.48; 95%CI, 1.09-2.00) compared with the unexposed children,” the study said.

“The absolute 15-year risk of ADHD was 4.6% (95%CI, 4.5%-4.6%) in children unexposed to valproate and 11.0% (95%CI, 8.2%-14.2%) in children who were exposed to valproate in pregnancy.”

The risk was mainly related to valproate use in the first trimester of pregnancy and significant even after adjusting for maternal psychiatric disease, maternal epilepsy, and other potential confounders.

The authors said valproate use in pregnancy was already associated with other adverse neurodevelopmental outcomes including poor cognitive function and autism however evidence for an association with ADHD has not always been inconsistent.

An Invited Commentary also published in JAMA Network Open said the increased risks of major congenital malformations and neurodevelopmental problems – including ADHD from prenatal valproate exposure – should be communicated to all women of childbearing age who are prescribed valproate for epilepsy or other conditions.

“The counselling about valproate’s risks to women of childbearing potential should occur not only well before pregnancy but also at any time a prescription for valproate is written for a woman of childbearing potential since approximately half of pregnancies are unplanned,” it advised.