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Prenatal Exposure to Valproate Linked to Heighten ADHD Risk


Is prenatal exposure to valproate and other antiepileptic drugs (AEDs) associated with an increased risk of adverse neurodevelopmental outcomes, including attention-deficit/hyperactivity disorder (ADHD)? A new analysis of these drugs suggests it is—specifically offspring exposed to valproate.

Children prenatally exposed to valproate had a 48 percent increased risk of ADHD, according to a large population-based study in Denmark published online on January 4 in JAMA Network Open. ADHD was diagnosed in 8.4 percent of children exposed to valproate during pregnancy, compared with 3.2 percent of children who were not exposed to the drug.

The study adds to the growing body of evidence that has linked valproate use during pregnancy with adverse neurodevelopmental outcomes. These outcomes include poor cognitive function and autism, as well as an increased risk of congenital malformations. The U.S. Department of Health and Human Services and the European Medicines Agency have issued warnings about the use of valproate during pregnancy.

Jakob Christensen, MD, PhD, of Aarhus University Hospital in Aarhus, Denmark, and his colleagues said t the new 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."

For their analysis, the researchers reviewed data on 913,302 children born in Denmark from 1997 through 2011. Using national registries, they obtained Information on prenatal exposure to AEDs, including valproate, and children diagnosed with ADHD or who redeemed a prescription for ADHD medication. The cohort was followed from birth until the day of ADHD diagnosis or the end of 2015.

At the end of the study, children were an average of 10.1 years old; 51.3 percent were male.

The researchers observed that 49 of 580 children with ADHD had been exposed to valproate during pregnancy. Of the 912,722 children not exposed to valproate, 29,396 had ADHD. The average age at ADHD diagnosis was 8.8 years old.

Children prenatally exposed to valproate had a 48 percent increased risk of ADHD (adjusted HR [aHR] 1.48, 95% CI 1.09-2.00) compared with unexposed children.

The absolute 15-year risk of ADHD was 4.6 percent (95% CI, 4.5%-4.6%) in children not exposed to valproate and 11.0 percent (95% CI, 8.2%-14.2%) in children who were exposed to valproate in pregnancy.

In children born to women with epilepsy (n=7620), prenatal exposure to valproate (n=516) was associated with a 39 percent higher risk of ADHD (aHR, 1.39; 95% CI, 1.00-1.93), compared with the X% (?_ risk of children born to mothers with epilepsy who were not prenatally exposed to valproate (n=7104).

No significant associations were found between other AEDs and ADHD.

Due to the observational nature of the study, however, the study authors acknowledged the findings only show association and not causation.

The findings warrant further investigation in other populations to validate or invalidate the association.

Study limitations ranged from ADHD risk possibly being tied to maternal health to the lack of control for fetal medication exposures, such as prescription, recreational, and abuse of drugs, like alcohol.


Christensen J, Pedersen LH, Sun Y, et al. Association of prenatal exposure to valproate and other antiepileptic drugs with risk for attention-deficit/hyperactivity disorder in offspring. JAMA Netw Open 2019; Epub 2019 Jan 4.