Prenatal Exposure to Antiseizure Medications, Duotherapies Increased Risk of Neurodevelopmental Disorders

Jakob Christensen, MD, PhD

Using a cohort of 4.5 million mother-child pairs, data from new research show robust and dose-dependent associations between prenatal exposure to antiseizure medications (ASMs) topiramate (Topamax; Janssen) and valproate to neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). Additionally, ASM duotherapies, except lamotrigine with levetiracetam, were similarly associated with neurodevelopmental disorders.¹

Results showed that among unexposed children of mothers with epilepsy, the 8-year cumulative incidence of ASD and ID was 1.5% and 0.8%, respectively, while in children of mothers with epilepsy exposed to topiramate, it was 4.3% and 3.1%. Similarly, the 8-year cumulative incidence of ASD and ID for valproate-exposed children was 2.7% and 2.4%, respectively.

Senior investigator Jakob Christensen, MD, PhD, specialist in Clinical Pharmacology and Neurology, University of Bergen, and colleagues wrote that "with regulatory warnings cautioning against valproate use in women of childbearing potential, safety data are urgently needed for alternative treatment options." They added, "however, our results do not suggest that topiramate is a safe alternative to valproate. Women of reproductive age who are prescribed topiramate should be informed of the potential risks, and these should be weighed against the benefits and available treatment options."

Called the SCAN-AED study, this work included health registry and social registry data on 4,494,926 alive-born children from Denmark, Finland, Iceland, Norway, and Sweden from 1996-2017. To avoid misclassification of the pregnancy period, the analysis excluded births with a recorded gestational length of 154 days or less, or 314 days or more; implausible combinations of birth weight and pregnancy length; or missing information on these variables. Prenatal exposure was defined as the mother filling at least 1 ASM prescription from her last menstrual period until birth.

Over the 8-year observed period, the adjusted hazard ratios (aHRs) of ASD were 2.8 (95% CI, 1.4-5.7) and 2.4 (95% CI, 1.7-3.3), respectively for the topiramate and valproate groups, respectively. In terms of ID, the aHRs were 3.5 (95% CI, 1.4-8.6) for those exposed to topiramate and 2.5 (95% CI, 1.7-3.7) for those exposed to valproate. Overall, the aHR of any neurodevelopmental disorder was 2.1 (95% 1.1-4.0) for topiramate-exposed children and 2.4 (95% CI, 1.9-3.1) for children exposed to valproate. Notably, the risk for neurodevelopmental disorders did not increase with exposure to any other monotherapies.

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In comparison with children from the general population, those exposed to at least 100 mg of topiramate had aHR of 2.9 (95% CI, 1.3-6.7) for the risk of any neurodevelopmental disorder, whereas those exposed to doses less than 100 mg had aHR of 1.7 (95% CI, 1.0-2.8). For valproate, the aHR was 2.3 (95% CI, 1.9-2.8) with doses less than 750 mg per day and 5.6 (95% CI, 4.7-6.8) with doses of 750 mg or more per day. For other ASMs, there were minimal to no dose-related associations observed.

The results also demonstrated that prenatal exposure to several ASM duotherapies may increase the risk of neurodevelopmental disorders. All told, children exposed to duotherapy with lamotrigine (Lamictal; GlaxoSmithKline) with valproate (aHR, 1.65; 95% CI, 0.95-2.85), lamotrigine with topiramate (aHR, 2.35; 95% CI, 1.13-4.87), levetiracetam (Keppra; UCB Pharma) with carbamazepine (0.91; 0.34-2.48), or lamotrigine with oxcarbazepine (aHR, 3.46; 95% CI, 1.46-8.18) had and an elevated risk that was similar to valproate. Notably, the combination of levetiracetam and lamotrigine was not associated with adverse neurodevelopment, which the study investigators suggested should be further investigated.

When comparing monotherapy-exposed children with children whose mothers filled a prescription for the same ASM in the 2 years preceding pregnancy, but not from 90 days before the last menstrual period to birth, the aHR was 2.0 (95% CI, 1.3-3.0) for any neurodevelopmental disorder after prenatal exposure to valproate and 2.3 (95% CI, 1.1-4.8) for topiramate, but no increased risks were observed for other ASMs. The overall estimates on valproate and topiramate did not change after adjusting for maternal neurodevelopmental disorders, body mass index, and smoking.

Previous studies have shown that valproate can elevate the risk of major congenital malformations and neurodevelopmental disorders in children exposed in utero.² As a result, in 2014, the European Medicines Agency (EMA) recommended that VPA should not be prescribed to adolescent girls, women of childbearing age, or pregnant women. Recently published data from two cross-section studies carried out in 2013 and 2016—before and after the EMA reinforced its warnings regarding the use of valproate among women of childbearing age—showed significant changes in practice, with fewer women exposed to the antiseizure medication during pregnancy and before pregnancy.³

REFERENCE
1. Bjork MH, Zoega H, Leinonen MK, et al. Association of prenatal exposure to antiseizure medication with risk of autism and intellectual disability. JAMA Neurol. 2022;79(7):672-681. doi:10.1001.jamaneurol.2022.1269
2. Weston J, Bromley R, Jackson CF, et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database Syst Rev. 2016;11(11):CD010224.
3. Degremont A, Kerbat S, Balusson F, et al. Prescribing trends for valproate among pregnant women: a cross-sectional study in 2013 and 2016 using the French Health Insurance Database. Neurology. Published online April 4, 2022. doi:10.1212/WNL.000000000000200260