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Maternal use of valproate increases ADHD risk in offspring

Offspring of women who used valproate during pregnancy were at greater risk for ADHD, according to findings recently published in JAMA Network Open.

“Antiepileptic drug exposure during pregnancy is associated with an increased risk for congenital malformations and delayed cognitive development in the offspring,” Jakob Christensen, MD, PhD, of the department of neurology at Aarhus University Hospital in Denmark and colleagues wrote.

“However, to our knowledge, only five small studies and a meta-analysis of these studies including a total of 816 persons with attention-deficit hyperactivity disorder have examined a possible association between prenatal exposure to valproate and ADHD in the offspring,” they added.

Researchers reviewed registry data from 913,302 live singleton births in Denmark and followed them from birth until ADHD diagnosis, death, emigration or Dec. 31, 2015. The children were aged a median of 10.1 years at study’s end.

Christensen and colleagues found 580 children were exposed to valproate during pregnancy and of those, 8.4% had ADHD. Of the children not exposed, only 3.2% had ADHD. In addition, children whose mothers used valproate had a 48% increased risk for ADHD (adjusted HR = 1.48; 95% CI, 1.09-2) vs. children whose mothers did not use it. Further, the absolute 15-year risk for ADHD was 11% (95% CI, 8.2-14.2) in children exposed and 4.6% (95% CI, 4.5-4.6) in children unexposed.

Researchers noted the link between prenatal exposure to valproate and an increased risk for ADHD was exceptionally strong and was maintained after adjusting for the mother’s age, diabetes, epilepsy, smoking, and psychiatric disorder status. The link persisted but was less robust when examining valproate dose and polytherapy.

“These 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,” Christensen and colleagues wrote.

Kimford J. Meador, MD, of the department of neurology and neurological sciences at Stanford University School of Medicine, reiterated the authors’ warning in a related editorial. He also outlined steps for future research.

 

Offspring of women who used valproate during pregnancy were at greater risk for ADHD, according to findings recently published in JAMA Network Open.

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“Given the potential lifelong consequences of fetal medication exposures, new approaches should be used to determine these risks more expediently,” Meador wrote.

“Considerations should include 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,” he added. – by Janel Miller

Disclosures: Christensen reports receiving honoraria from serving on the scientific advisory boards of and giving lectures for UCB Nordic and Eisai AB; and receiving travel funding from UCB Nordic. Meador reports receiving research support from the National Institutes of Health and Sunovion Pharmaceuticals, and travel support from UCB Pharma. The Epilepsy Study Consortium pays Meador’s university for his research consultant time related to Eisai, GWPharmaceuticals, NeuroPace, Novartis, Supernus, Upsher-Smith Laboratories, UCB Pharma, and Vivus Pharmaceuticals. None of the other authors report any relevant financial disclosures.