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Prenatal valproate exposure raises ADHD risk

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The data from the current study differ from a recent meta-analysis of five studies that did not find a statistically significant increase in ADHD risk in children associated with prenatal valproate exposure, Kimford J. Meador, MD, wrote in an accompanying editorial (JAMA Network Open. 2019;2[1]:e186603. doi: 10.1001/jamanetworkopen.2018.6603).

Dr. Jakob Christensen of Aarhus University Hospital in Denmark

Dr. Jakob Christensen

“The discrepancy between the present study and the prior meta-analysis might be due to the meta-analysis using different analytical approaches and examining studies with smaller sample sizes, higher attrition rates, shorter follow-ups, and cohort differences,” Dr. Meador said. “Nevertheless, the findings by Christensen et al. are consistent with multiple studies demonstrating adverse neurodevelopmental effects associated with fetal valproate exposure.”

Given the potential risks associated with valproate exposure not only for behavior problems such as ADHD but also for congenital malformations and other cognitive and behavioral issues in children, women of childbearing age who are using valproate or considering a prescription should be counseled for informed consent, Dr. Meador said.

Dr. Meador advocated additional research on the impact of antiepileptic drugs during pregnancy and risk assessment strategies, including “a national reporting system for congenital malformations, routine preclinical testing of all new antiseizure medications for neurodevelopmental effects, monitoring of antiseizure medication prescription practices for women of childbearing age to determine whether emerging knowledge is being appropriately applied, and improved funding of basic and clinical research to fully delineate risks and underlying mechanisms of anatomical and behavioral teratogenesis from antiseizure medications.”

Dr. Meador is affiliated with the department of neurology and neurological sciences at Stanford (Calif.) University. He disclosed research support from the National Institutes of Health and Sunovion, and travel support from UCB. The Epilepsy Study Consortium pays Stanford University for his research consultant time related to Eisai, GW Pharmaceuticals, NeuroPace, Novartis, Supernus, Upsher-Smith Laboratories, UCB, and Vivus.



Children exposed to valproate in utero were 48% more likely to be diagnosed with ADHD when compared with unexposed children in a population-based cohort study of more than 900,000 children in Denmark.

Dr. Kimford J. Meador of Stanford (Calif.) University

Dr. Kimford J. Meador

Antiepileptic drug exposure is associated with an increased risk of various congenital malformations, but its role in the development of ADHD in children has not been well documented, first author Jakob Christensen, MD, PhD, DrMedSci, of Aarhus (Denmark) University Hospital, and his colleagues wrote in their paper, published online Jan. 4 in JAMA Network Open.

The researchers identified 913,302 singleton births in Denmark from 1997 through 2011, with children followed through 2015.

Overall, children who were prenatally exposed to valproate had a 48% increased risk of ADHD. Antiepileptic drug exposure was defined as 30 days before the estimated day of conception to the day of birth, and included valproate, clobazam, and other antiepileptic drugs. The average age of the children at the study’s end was 10 years, and approximately half were male.

A total of 580 children were exposed to valproate in utero; of these, 8.4% were later diagnosed with ADHD, compared with 3.2% of 912,722 children who were not exposed to valproate. In addition, the absolute 15-year risk of ADHD was 11% in valproate-exposed children vs. 4.6% in unexposed children. No significant associations appeared between ADHD and other antiepileptic drugs.

The study findings were limited by several factors, including the contraindication of valproate for use in pregnancy, which may mean that the women taking valproate had more severe disease, the researchers noted.

“Due to the observational nature of this study, we cannot rule out that the observed risk increase for ADHD is at least in part explained by the mother’s health condition that triggered the prescription of valproate during pregnancy,” they said. Other limitations included a lack of data on the exact amounts of valproate taken during pregnancy and the potential impact of nonepilepsy medications, they noted.

However, the results were strengthened by the large size and population-based cohort, and support warnings by professional medical organizations against valproate use in pregnancy, the researchers said. “As randomized clinical trials of valproate use during pregnancy are neither feasible nor ethical, our study provides clinical information on the risk of ADHD associated with valproate use during pregnancy,” they concluded.

The study was supported by grants to various authors from the Danish Epilepsy Association Central Denmark Region, the Aarhus University Research Foundation, the Lundbeck Foundation, the National Institutes of Health, the Novo Nordisk Foundation, and the European Commission.

SOURCE: Christensen J et al. JAMA Network Open. 2019;2(1):e186606. doi: 10.1001/jamanetworkopen.2018.6606.

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