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Children of mothers with epilepsy who used valproate or other antiseizure medications (ASMs) during pregnancy were more likely to develop epilepsy as well, a cohort study of more than 38,000 kids suggested, although causality was questionable.

Compared with children of mothers who had epilepsy but did not use ASMs during pregnancy, children of mothers who used valproate during pregnancy were more than twice as likely to develop epilepsy whether it had been used as monotherapy (adjusted HR 2.18, 95% CI 1.70-2.79) or in combination with other drugs (aHR 2.10, 95% CI 1.49-2.96), reported Julie Werenberg Dreier, PhD, of Aarhus University in Denmark, and colleagues.

Epilepsy risk also was elevated in children exposed in utero to topiramate monotherapy (aHR 2.32, 95% CI 1.30-4.16), clonazepam monotherapy (aHR 1.90, 95% CI 1.16-3.12), and polytherapy without valproate (aHR 1.39, 95% CI 1.04-1.84), they noted in .

Epilepsy risk associated with prenatal valproate exposure was not dose-dependent, but epilepsy risk was highest with in utero exposure to higher doses of topiramate (aHR 4.88 at ≥150 mg/day, 95% CI 2.47-9.62) and clonazepam (aHR 3.66 at ≥4 mg/day, 95% CI 1.48-9.05) in the limited number of children whose mothers took those drugs during pregnancy.

Labels for valproate sodium and related drugs for epilepsy that children exposed to these agents during gestation may suffer cognitive deficits or physical birth defects. In 2011, the FDA issued a stating that, if a decision is made to use valproate in a woman of childbearing age, effective birth control should be used.

"It is well-established that children that are exposed in utero to valproate are at increased risk of neurodevelopmental impairment -- e.g., delayed developmental milestones, impaired language and memory functions, impaired intellectual functioning, and neurodevelopmental disorders such as autism spectrum disorder and ADHD [attention deficit-hyperactivity disorder]," Dreier told MedPage Today in an email.

"Since prenatal exposure to valproate is believed to interfere with fetal brain development, and because aberrations in the development of the fetal brain can increase the risk of epilepsy," her group undertook what might be the first study to examine prenatal ASM exposure with kids' epilepsy risk.

Despite the increased risks that Dreier and colleagues reported, associations were attenuated in further analyses of discordant siblings and children whose mothers discontinued ASMs prior to pregnancy.

Of 258 mothers who used valproate in at least one pregnancy and no ASM in at least one other pregnancy, there was no difference in epilepsy risk between children with prenatal valproate exposure and their unexposed sibling (aHR 0.58, 95% CI 0.23-1.46). And of 418 sibling sets in which the mother used valproate in at least one pregnancy and no valproate in at least one other pregnancy, there was still no difference (aHR 0.95, 95% CI 0.50-1.82).

Furthermore, in analyses of children whose mothers discontinued ASM treatment before pregnancy, risk of epilepsy wasn't significant (aHR 1.69, 95% CI 0.91-3.16) in kids whose mothers used valproate during pregnancy compared with those whose mothers discontinued the drug before pregnancy. The same comparison for topiramate likewise showed no excess risk (aHR 1.19, 95% CI 0.26-5.44).

Altogether, the findings suggested not a direct causal link but confounding by indication for use, the researchers suggested.

"These findings suggest that prenatal ASM exposure may not increase epilepsy risk in children of mothers with epilepsy and indicate that differences were more likely associated with other underlying factors (e.g., possibly the heritability of the maternal epilepsy)," they wrote.

The study "brings us closer to understanding the full health implications of maternal ASM use," P. Emanuela Voinescu, MD, PhD, of Brigham and Women's Hospital in Boston, and Esther Bui, MD, of the University of Toronto, wrote in an in JAMA Network Open.

"While providing reassurance that, when needed, prenatal valproate and other ASMs are unlikely to independently confer an added burden of epilepsy to children, it does raise the concern of a heightened risk of major congenital malformations not only in the child exposed to valproate, but also among presumed unexposed siblings," they added.

For instance, in sensitivity analyses involving sibling sets of mothers who used valproate in one pregnancy and no valproate in another pregnancy, the exposed sibling had higher risk of autism spectrum disorder (ASD, aHR 6.41, 95% CI 2.00-20.58) and major malformations (adjusted risk ratio 1.66, 95% CI 1.03-2.67) compared with the unexposed sibling.

Sensitivity analyses also indicated that prenatal valproate exposure was associated with a clear dose-dependent risk pattern for ASD, with adjusted hazard ratios rising stepwise from 1.72 at low doses to 3.63 at high doses. The same was true for major malformations, with adjusted risk ratios rising from 1.30 to 5.23 across dose groups.

The study included 38,663 children born to mothers with epilepsy in Denmark, Finland, Iceland, Norway, and Sweden from 1996 through 2017. They were followed from birth to a mean age of 7.2 years.

While 57.4% of kids were not prenatally exposed to an ASM, 5.0% were exposed to valproate monotherapy and 2.1% to valproate in polytherapy.

Limitations of the study included the potential for misclassification of epilepsy status for mothers and children, lack of data on subtypes of maternal epilepsy, and the use of maternal prescription fills as a proxy for prenatal ASM exposure.

Additionally, "while it would have been of interest to also study the association in a population without epilepsy (e.g., children of mothers using valproate for bipolar disorder or migraine), this was not possible with our data, since the number of children who developed epilepsy in these groups was too low for any meaningful analysis," Dreier and colleagues noted.

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