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TOPLINE:

Maternal use of antiseizure medications (ASMs) during pregnancy does not increase epilepsy risk in offspring beyond the risk associated with maternal epilepsy itself, a new study shows.

METHODOLOGY:

• This prospective, population-based register cohort study included 38,663 singleton babies (51.4% male) born to mothers with epilepsy in Denmark, Finland, Iceland, Norway, and Sweden between January 1, 1996, and December 31, 2017.
• Investigators tracked redeemed prescriptions for an ASM (eg, valproate, lamotrigine, levetiracetam, carbamazepine, oxcarbazepine, and clonazepam) from 30 days prior to pregnancy until birth.
• The main outcome was epilepsy in offspring, while secondary analyses included dose-response analyses, analyses of mothers who discontinued ASM prior to pregnancy (reference), and sibling analyses.
• Children were followed from birth, with a mean follow-up of 7 years.

TAKEAWAY:

• Compared to no ASM exposure during pregnancy, there was significantly higher risk for epilepsy among offspring with prenatal exposure to valproate monotherapy (adjusted hazard ratio [aHR], 2.18; 95% CI, 1.70-2.79) or polytherapy (aHR, 2.10; 95% CI, 1.49-2.96), topiramate monotherapy (aHR, 2.34; 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).
• However, the association between offspring epilepsy risk and prenatal valproate use was not dose-dependent, and there was no difference in risk between offspring with or without prenatal exposure to topiramate.
• Analysis of a subset of 258 mothers who used valproate in at least one pregnancy and no ASM in at least one other pregnancy revealed no significant difference in epilepsy risk between siblings.
• No associations were found for prenatal exposure to lamotrigine, levetiracetam, carbamazepine, or oxcarbazepine.

IN PRACTICE:

Although children of mothers who used valproate or topiramate during pregnancy were more likely to develop epilepsy than children whose mothers used no ASM in pregnancy, sensitivity analyses suggested that the associations were most likely explained by differences in other factors, the authors wrote. "These analyses suggest that the increased risk of epilepsy found in children with prenatal valproate exposure was likely confounded by underlying factors associated with both maternal valproate use and the child's risk of epilepsy (eg, the type of maternal epilepsy)."

SOURCE:

Julie Werenberg Dreier, PhD, senior researcher, Aarhus University, Aarhus, Denmark, was the lead and corresponding author on the study. The study was published online on February 26 in JAMA Network Open.

LIMITATIONS:

The researchers relied on register-based identification of epilepsy in children and their mothers, and some misclassification of their epilepsy status was possible. Moreover, classification of the subtype of maternal epilepsy (a key confounder in this study) was "challenging" due to the low validity of ICD-10 codes for epilepsy subclassification. Using maternal prescription fills as a proxy for prenatal ASM exposure might have also led to some misclassification.

DISCLOSURES:

This study was supported by grants from the NordForsk Nordic program on health, the Independent Research Fund Denmark, IMI Conception, the Danish Epilepsy Association, the Central Denmark Region, and the Novo Nordisk Foundation. Dreier reported no relevant financial relationships. The other authors' disclosures are listed on the original paper.