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What is the risk of attention-deficit/hyperactivity disorder in children prenatally exposed to valproate (Depakote) and other antiepileptic drugs?

In a population-based study of 913,302 children in Denmark, prenatal exposure to valproate was significantly associated with a 48% increased risk of attention-deficit/hyperactivity disorder compared with children with no valproate exposure. No association was identified for other antiepileptic drugs.

The findings of this study corroborate that counseling is appropriate for the use of valproate in pregnancy and in women of childbearing potential.

Valproate is an antiepileptic drug (AED) used in the treatment of epilepsy and many other neurological and psychiatric disorders. Its use in pregnancy is associated with increased risks of congenital malformations and adverse neurodevelopment in the offspring and may be associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD).
Maternal use of valproate, but not other AEDs, during pregnancy was associated with an increased risk of ADHD in the offspring. These findings have important implications for the counseling of women of childbearing potential using valproate.
“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; 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. When examining doses of valproate, prenatal exposure to estimated higher doses tended to be associated with higher risks of ADHD than exposure to estimated lower doses of valproate, although the difference between high and low doses was not significant.”
Conclusions:

 

Maternal use of valproate during pregnancy was associated with a small but significantly increased risk of ADHD in the offspring, even after adjusting for maternal psychiatric disease, maternal epilepsy, and other potential confounding covariates. 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.  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. Replication of our findings in large-scale observational studies of adverse drug effects is warranted as such effects have not been evaluated adequately in controlled trials (ie, during pregnancy).

SOURCE: “This is an open access article distributed under the terms of the CC-BY License. © 2019 Christensen J et al. JAMA Network Open.

Author: Jakob Christensen, MD, PhD, DrMedSci, Department of Neurology, Aarhus University Hospital, Norrebrogade 44, DK-8000 Aarhus C, Denmark

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