Association of Prenatal Exposure to Antiseizure Medication With Risk of Autism and Intellectual Disability

Abstract

IMPORTANCEWomen 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 PARTICIPANTSThe 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 MEASURESWe 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. CONCLUSIONS AND RELEVANCEIn this cohort study, prenatal exposure to topiramate, valproate, and several duotherapies were associated with increased risks of neurodevel...

Risk of Autism Spectrum Disorder according to the dose and trimester of Exposure to Antiseizure Medications: A Systematic Review and Meta-analysis

“…However, the con dence intervals of the second and third trimester exposures varies widely, probably due to the smaller sample size used (67 children), and so was not powered enough to detect a meaningful association. The ndings of Christensen was supported by Bjørk et al [15] who found that exposure to valproate during the second and third trimesters without exposure during the rst trimester was still associated with an increased risk of ASD with a HR of 1.94 (1.04-3.60). Bjørk et al [18], and Wood et al [13] studied the usefulness of folic acid supplements in the rst trimester in preventing ASD, so the supposed increase in the risk of ASD in rsttrimester exposure to ASM is extrapolated from the fact that women who did not take folic acid early in pregnancy had increased risks of producing autistic children.…”

“…After screening the title/abstracts and full-text information, 196 and 27 studies were excluded, respectively. Finally, 10 studies that met the inclusion criteria were included [9][10][11][12][13][14][15][18][19][20] .The study selection ow chart is shown in Fig. 1.…”

“…The other studies that looked at a combination of ASM were Rasalam et al, [14], the Nordic countries cohort by Bjørk et al [15] and the Norwegian mother and Baby cohorts by Veiby et al, [20] and Bjørk et al, [18]. In all these studies, in utero exposure to ASM, in general, showed an increased risk of ASD.…”

“…The Nordic countries cohort study by Bjork et al [15], assessed the relationship between dosage of ASM used and the risk of ASD and noticed positive associations. In their study they found HR of 1.7 (95% CI, 1.0-2.8) for those exposed to topiramate doses less than 100mg per day, and HR of 2.9 (95% CI, 1.3-6.7) for doses greater than 100mg per day.…”

“…[10,13,14]. [15] This systematic review and meta-analysis thus sought to examine and synthesize evidence from all relevant studies that have characterized and evaluated the association between fetal exposures to ASM in women with epilepsy, with particular attention to the relative risk of ASD among children exposed to the different ASM in utero, and which trimester of pregnancy and/or dosage of exposure carries the most increased risk.…”