Prenatal Valproate Exposure Raises ADHD Risk

January 17, 2019

Children exposed to the antiepileptic drug valproate in utero had a 48% increased risk of developing attention-deficit/hyperactivity disorder (ADHD), compared with children with no exposure to the drug, according to a new observational study published online in JAMA Network Open.

“The risk of ADHD was related to valproate exposure mainly in the first trimester, but the number of cases exposed only in later trimesters was low,” wrote study lead author Jakob Christensen, MD, PhD, DrMedSci, Aarhus University Hospital, Denmark, and colleagues. “Our findings therefore do not exclude the possibility that valproate exposure across all stages of pregnancy may be associated with an increased risk of ADHD in the offspring.”

Previous research has linked the drug, which in addition to epilepsy is used to treat a slate of neurological and psychiatric disorders, with increased risk of congenital malformations and adverse neurodevelopment in offspring exposed during gestation.

Placental Gene Expression Altered With Valproate Exposure

Researchers used registry data to look at prenatal exposure to valproate and other antiepileptic medications and subsequent ADHD among 913,302 children born in Denmark between 1997 and 2011. The study defined exposure as pregnancies where mothers filled at least one prescription for an antiepileptic drug. It was not known if and how much of the medication was actually taken.

Among the 913,000 children, 580 were exposed to valproate during pregnancy—8.4% of whom went on to be diagnosed with ADHD. Meanwhile, the rate of ADHD in 912,722 children not exposed to valproate was 3.2%, according to the study.

In addition to a 48% increased risk of developing ADHD with prenatal exposure to valproate, researchers identified an 11% absolute 15-year risk of ADHD in offspring exposed to valproate, compared with a 4.6% absolute 15-year risk of ADHD in children with no such exposure.

DES Tied to ADHD Generations Later

Researchers found no associations between other antiepileptic drugs and ADHD.

In an accompanying editorial, Kimford J. Meador, MD, Stanford University School of Medicine, Palo Alto, California, noted the study findings are consistent with other studies demonstrating neurodevelopmental issues associated with fetal exposure to valproate, such as reduced IQ and autism spectrum disorder, and recommended the need for patient education about the risks for women of reproductive age considering the medication.

“The counseling 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,” Dr. Meador advised. “There are a limited number of women for whom valproate may be the best choice, but this should not be prescribed without appropriate informed consent.”

—Jolynn Tumolo


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

Meador KJ. Fetal valproate exposure and attention-deficit/hyperactivity disorder. JAMA Network Open. 2019;2(1):e186603.

Study examines association between prenatal exposure to antiepileptic drugs and ADHD in children [press release]. Chicago, Illinois: JAMA Network; January 4, 2019.