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Association of Prenatal Exposure to Antiseizure Medication With Risk of Autism and Intellectual Disability
TAKE-HOME MESSAGE
- Using data from five Nordic countries, this population-based cohort study of 4.5 million mother–child pairs evaluated the risk of neurodevelopmental disorders in children exposed to antiseizure medications (ASMs) during pregnancy. Overall, 24,825 (0.6%) children were prenatally exposed to ASMs, of whom, 16,170 were born to mothers with epilepsy. The 8-year cumulative incidence of autism spectrum disorder (ASD) and intellectual disability (ID) was 4.3% and 3.1%, respectively, in children born to mothers with epilepsy exposed to topiramate, and 2.7% and 2.4%, respectively, in those exposed to valproate. This association was dose-dependent as higher ASM doses increased the risk of neurodevelopmental disorders in these children compared with children from the general population.
- This study demonstrates that prenatal exposure to ASMs is associated with an increased risk of neurodevelopmental disorders and provides some support to consider switching ASMs or decreasing ASM doses when safe to do so to decrease the overall risk of neurodevelopmental disorders.
abstract
This abstract is available on the publisher's site.
Access this abstract nowImportance
Women with epilepsy frequently need antiseizure medication (ASM) to prevent seizures in pregnancy. Risk of neurodevelopmental disorders after prenatal exposure to AMSs is uncertain.
Objective
To determine whether children exposed prenatally to ASMs in monotherapy and duotherapy have increased risk of neurodevelopmental disorders.
Design, Setting, and Participants
The Nordic register-based study of antiepileptic drugs in pregnancy (SCAN-AED) is a population-based cohort study using health register and social register data from Denmark, Finland, Iceland, Norway, and Sweden (1996-2017; analysis performed February 2022). From 4 702 774 alive-born children with available mother-child identities and maternal prescription data, this study included 4 494 926 participants. Children from a multiple pregnancy or with chromosomal disorders or uncertain pregnancy length were excluded (n = 207 848).
Exposures
Prenatal exposure to ASM determined from maternal prescription fills between last menstrual period and birth.
Main Outcomes and Measures
We estimated cumulative incidence at age 8 years in exposed and unexposed children. Cox regression adjusted for potential confounders yielded adjusted hazard ratios (aHRs) with 95% CIs for autism spectrum disorder (ASD), intellectual disability (ID), or any neurodevelopmental disorder (ASD and/or ID).
Results
A total of 4 494 926 children were included; 2 306 993 (51.3%) were male, and the median (IQR) age at end of follow-up was 8 (4.0-12.1) years. Among 21 634 unexposed children of mothers with epilepsy, 1.5% had a diagnosis of ASD and 0.8% (numerators were not available because of personal data regulations in Denmark) of ID by age 8 years. In same-aged children of mothers with epilepsy exposed to topiramate and valproate monotherapy, 4.3% and 2.7%, respectively, had ASD, and 3.1% and 2.4% had ID. The aHRs for ASD and ID after topiramate exposure were 2.8 (95% CI, 1.4-5.7) and 3.5 (95% CI, 1.4-8.6), respectively, and after valproate exposure were 2.4 (95% CI, 1.7-3.3) and 2.5 (95% CI, 1.7-3.7). The aHRs were elevated with higher ASM doses compared with children from the general population. The duotherapies levetiracetam with carbamazepine and lamotrigine with topiramate were associated with increased risks of neurodevelopmental disorders in children of women with epilepsy: levetiracetam with carbamazepine: 8-year cumulative incidence, 5.7%; aHR, 3.5; 95% CI, 1.5-8.2; lamotrigine with topiramate: 8-year cumulative incidence, 7.5%; aHR, 2.4; 95% CI, 1.1-4.9. No increased risk was associated with levetiracetam with lamotrigine (8-year cumulative incidence, 1.6%; aHR, 0.9; 95% CI, 0.3-2.5). No consistently increased risks were observed for neurodevelopmental disorders after prenatal exposure to monotherapy with lamotrigine, levetiracetam, carbamazepin, oxcarbazepine, gapapentin, pregabalin, clonazepam, or phenobarbital.
Additional Info
Association of Prenatal Exposure to Antiseizure Medication With Risk of Autism and Intellectual Disability
JAMA Neurol 2022 May 31;[EPub Ahead of Print], MH Bjørk, H Zoega, MK Leinonen, JM Cohen, JW Dreier, K Furu, NE Gilhus, M Gissler, Ó Hálfdánarson, J Igland, Y Sun, T Tomson, S Alvestad, J ChristensenFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The neurodevelopmental effects of fetal exposures to antiseizure medications (ASM) are largely unknown. This Nordic study provides additional information to guide care in women of childbearing potential. It found increased risks of neurodevelopmental disorders with prenatal monotherapy exposure to topiramate and valproate (autism spectrum disorder: topiramate, 4.3% and valproate, 2.7%; intellectual disability: topiramate, 3.1% and valproate, 2.4%). No consistent risks were found for lamotrigine, levetiracetam, carbamazepine, oxcarbazepine, gabapentin, pregabalin, clonazepam, or phenobarbital monotherapy. Increased risks were also noted for several ASM duotherapies, but not levetiracetam with lamotrigine. The study findings confirm the dose-dependent risks for valproate1 and raise concerns regarding the adverse effects due to topiramate.
The study strengths include the large population-based cohort, adjustment for many potentially confounding factors, and detailed analyses. Like any study, this one also has limitations, which include unmeasured confounders, no maternal IQ (which has an effect independent of education), no ASM levels given clearance changes during pregnancy, no folate exposure information, and two dichotomous categories that may miss pertinent clinical effects.
Prior studies demonstrated malformation risks for fetal topiramate exposure2 but not neurodevelopmental risks.3,4 Teratogens act in a dose-dependent manner, but a clear dose-dependent effect was noted only for valproate. High-dose topiramate had a higher mean risk than low-dose topiramate, but the confidence intervals overlapped. The lack of risk for several ASMs has been noted in some studies,5 but other prior studies have found risks.4,6 Notably, the sample sizes for women with epilepsy on topiramate, several other ASMs, and duotherapies are relatively small for this type of study.
As randomized clinical trials cannot be conducted in this population, confirmation of findings across multiple cohorts are needed. Delineation of the underlying teratogenic mechanisms are needed, given the diverse molecular structures and activities of ASMs. Further, outcomes vary across children with similar exposures, likely because teratogens act on a susceptible genotype, but we are woefully ignorant of the vulnerable genotypes.
References