Women who used valproate for seizure control during pregnancy had an increased risk of attention deficit-hyperactivity disorder (ADHD) in their children, a population-based study in Denmark found.
Prenatal exposure to valproate was tied to a 48% increased risk of ADHD after adjusting for maternal psychiatric disease, maternal epilepsy, and other potential confounders, according to Jakob Christensen, MD, PhD, of Aarhus University Hospital, and colleagues.
ADHD was diagnosed in 8.4% of children exposed to valproate during pregnancy, compared with 3.2% of children who were not exposed, they reported in JAMA Network Open.
The research adds to a rising number of studies linking prenatal valproate with adverse neurodevelopmental outcomes. In the U.S., valproate labels warn that children exposed to the drug during gestation may have cognitive deficits and physical birth defects.
“The study raises concern that treatment with valproate in pregnancy may be associated with increased risk of ADHD in the offspring — this is a new finding,” Christensen told MedPage Today. “However, because the results are based on observations, other factors may explain the association. The risk of ADHD in offspring of women with epilepsy using anti-epileptic drugs should therefore be further studied.”
The finding contrasts with the results from a recent meta-analysis that did not find a statistically significant increased risk of ADHD from in utero valproate exposure. The discrepancy might be due to methodology: the meta-analysis used different analytical approaches and examined studies with smaller sample sizes, higher attrition rates, shorter follow-ups, and cohort differences, noted Kimford Meador, MD, of the Stanford University School of Medicine in California, in an accompanying editorial.
“Nevertheless, the findings by Christensen et al. are consistent with multiple studies demonstrating adverse neurodevelopmental effects associated with fetal valproate exposure,” he wrote.
Counseling about valproate’s risk 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,” Meador added. “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.”
The study included 913,302 children born in Denmark from 1997 through 2011. The researchers used national registries to identify children who were diagnosed with ADHD or who redeemed a prescription for ADHD medication, following them from birth until the day of ADHD diagnosis or the end of 2015. Children were an average of 10.1 years at the end of the study and 51.3% were male.
The researchers identified 580 children who had been exposed to valproate during pregnancy; of them, 49 (8.4%) had ADHD. Of the 912,722 children who were not exposed to valproate, 29,396 (3.2%) had ADHD. The mean age at ADHD diagnosis was 8.8 years.
Overall, 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 unexposed children. The absolute 15-year risk of ADHD was 4.6% (95% CI 4.5%-4.6%) in children not exposed to valproate and 11.0% (95% CI 8.2%-14.2%) in exposed children.
When the analysis was restricted to children of women with epilepsy, the increased risk for valproate-exposed children (n=516) dropped to 39%. When restricted to children of women without epilepsy, the increased risk was higher, but not statistically significant due to small sample size.
No associations were found between other anti-epileptic drugs and ADHD.
Christensen and colleagues noted several study limitations. ADHD risk may be tied to the mother’s health: because pregnancy is a contraindication for valproate, women who take it during pregnancy may have different disorder presentation and severity from other women. Seizures during pregnancy, which could not be identified in this study, may have affected outcomes. Clinical practices may be more restrictive in diagnosing ADHD in Denmark than countries like the U.S. and only more severe cases may be in Danish registries. In addition, other fetal medication exposures — prescription, recreational, and abused drugs, including alcohol — were not controlled for in this study, Meador noted.
Christensen disclosed relevant relationships with UCB Nordic and Eisai AB, as well as support from the Danish Epilepsy Association, the Central Denmark Region, and the Novo Nordisk Foundation. Co-authors disclosed support from the Danish Epilepsy Association, the Central Denmark Region, the Novo Nordisk Foundation, the Aarhus University Research Foundation, the Lundbeck Foundation, the NIH, and the European Commission.
Meador disclosed relevant relationships with and support from Sunovion Pharmaceuticals, UCB Pharma, Eisai, GW Pharmaceuticals, NeuroPace, Novartis, Supernus, Upsher-Smith Laboratories, Vivus Pharmaceuticals, and the Epilepsy Study Consortium.