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...

Key Points Question What is the risk of attention-deficit/hyperactivity disorder in children prenatally exposed to valproate and other antiepileptic drugs? Findings In a population-based cohort study of 913 302 children in Denmark, prenatal exposure to valproate was significantly associated with a 48% increased risk of attention-deficit/hyperactivity disorder compared with children with no valproate exposure. No association was identified for other antiepileptic drugs. Meaning The findings of this study corroborate that counseling is appropriate for the use of valproate in pregnancy and in women of childbearing potential.

IMPORTANCE Valproate sodium is used for the treatment of epilepsy and other neuropsychiatric disorders in women of childbearing potential. However, there are concerns about impaired cognitive development in children who have been exposed to valproate during pregnancy. OBJECTIVE To estimate the association between long-term school performance and prenatal exposure to valproate and a number of other antiepileptic drugs (AEDs). DESIGN, SETTING, AND PARTICIPANTS In a prospective, population-based cohort study conducted from August 1, 2015, to May 31, 2017, data used in the study were provided by Statistics Denmark on April 15, 2016. All children born alive in Denmark between 1997 and 2006 (n = 656 496) were identified. From this cohort, children who did not participate in the national tests, with presumed coding errors in gestational age and children missing information on their mother's educational level or household income were excluded (n = 177 469) leaving 479 027 children for the analyses. Children were identified and linked across national registers that had information on exposure, covariates, and outcome. The primary outcome was performance in national tests, an academic test taken by students in Danish primary and lower secondary state schools. We assessed performance in Danish and mathematics at different grades among valproate-exposed children and compared their performance with that of unexposed children and children exposed to another AED (lamotrigine). Test scores were standardized to z scores and adjusted for risk factors. MAIN OUTCOME AND MEASURES Difference in standardized z scores in Danish and mathematics tests among valproate-exposed children compared with unexposed and lamotrigine-exposed children. RESULTS Of the 656 496 children identified, 479 027 children who participated in the national tests were evaluated, including children exposed to the following AEDs in monotherapy: valproate, 253; phenobarbital, 86; oxcarbazepine, 236; lamotrigine, 396; clonazepam, 188; and carbamazepine, 294. The mean (SD) age of the 244 095 children completing the sixth grade Danish test was 12.9 (0.39) years; 122 774 (50.3%; 95% CI, 50.1% to 50.5%) were boys and 121 321 (49.7%; 95% CI, 49.5% to 49.9%) were girls. Valproate-exposed children scored worse on the sixth-grade Danish tests (adjusted difference, −0.27 SD; 95% CI, −0.42 to −0.12) and sixth-grade mathematics tests (adjusted difference, −0.33 SD; (95% CI, −0.47 to −0.19) compared with unexposed children and children exposed to lamotrigine (adjusted difference, −0.33 SD; 95% CI, −0.60 to −0.06). Also, children exposed to clonazepam scored worse in the sixth-grade Danish tests (adjusted difference, −0.07 SD; 95% CI, −0.12 to −0.02). Carbamazepine, lamotrigine, phenobarbital, and oxcarbazepine were not linked to poor school performance compared with unexposed children. CONCLUSIONS AND RELEVANCE Maternal use of valproate was associated with a significant decrease in school performance in offspring compared with children unexposed to AEDs and children exposed to l...