Importance 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. Conclusions and Relevance In this cohort study, prenatal exposure to topiramate, valproate, and several duotherapies were associated with increased risks of neurodevelopmental disorders.

中文翻译：

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产前接触抗癫痫药物与自闭症和智力障碍风险的关联。

重要性 患有癫痫症的女性经常需要抗癫痫药 (ASM) 来预防妊娠期癫痫发作。产前接触 AMS 后神经发育障碍的风险尚不确定。目的 确定在单药治疗和双药治疗中暴露于产前 ASM 的儿童是否会增加神经发育障碍的风险。设计、设置和参与者北欧妊娠期抗癫痫药物登记研究 (SCAN-AED) 是一项基于人群的队列研究，使用来自丹麦、芬兰、冰岛、挪威和瑞典的健康登记和社会登记数据（1996 年至今） 2017 年；分析于 2022 年 2 月进行）。来自 4 702 774 名具有可用母子身份和母亲处方数据的活产婴儿，本研究包括 4 494 926 名参与者。来自多胎妊娠或患有染色体疾病或不确定妊娠长度的儿童被排除在外 (n = 207 848)。暴露 产前暴露于 ASM 的情况根据母亲在末次月经期和出生之间的处方药确定。主要成果和措施 我们估计了暴露和未暴露儿童在 8 岁时的累积发病率。针对潜在混杂因素进行调整后的 Cox 回归得出自闭症谱系障碍 (ASD)、智力障碍 (ID) 或任何神经发育障碍（ASD 和/或 ID）的调整后风险比 (aHR) 和 95% 置信区间。结果共纳入儿童4 494 926人；2 306 993 (51.3%) 为男性，随访结束时的中位 (IQR) 年龄为 8 (4.0-12.1) 岁。在患有癫痫母亲的 21 634 名未暴露儿童中，1.5% 诊断为 ASD，0. 8 岁时 ID 的 8%（由于丹麦的个人数据法规，分子不可用）。在暴露于托吡酯和丙戊酸盐单一疗法的癫痫母亲的同龄儿童中，分别有 4.3% 和 2.7% 患有 ASD，3.1% 和 2.4% 患有 ID。托吡酯暴露后 ASD 和 ID 的 aHR 分别为 2.8（95% CI，1.4-5.7）和 3.5（95% CI，1.4-8.6），丙戊酸盐暴露后为 2.4（95% CI，1.7-3.3）和2.5（95% CI，1.7-3.7）。与一般人群的儿童相比，aHRs 随着 ASM 剂量的增加而升高。左乙拉西坦与卡马西平和拉莫三嗪与托吡酯的双重疗法与癫痫妇女儿童神经发育障碍的风险增加有关：左乙拉西坦与卡马西平：8 年累积发生率，5.7%；aHR，3.5；95% 置信区间，1.5-8.2；拉莫三嗪联合托吡酯：8 年累积发生率，7.5%；aHR，2.4；95% 置信区间，1.1-4.9。左乙拉西坦联合拉莫三嗪没有增加风险（8 年累积发生率，1.6%；aHR，0.9；95% CI，0.3-2.5）。在产前接受拉莫三嗪、左乙拉西坦、卡马西平、奥卡西平、加帕喷丁、普瑞巴林、氯硝西泮或苯巴比妥单药治疗后，未观察到神经发育障碍的风险持续增加。结论和相关性 在这项队列研究中，产前接触托吡酯、丙戊酸和几种联合疗法与神经发育障碍风险增加有关。在产前接受拉莫三嗪、左乙拉西坦、卡马西平、奥卡西平、加帕喷丁、普瑞巴林、氯硝西泮或苯巴比妥单药治疗后，未观察到神经发育障碍的风险持续增加。结论和相关性 在这项队列研究中，产前接触托吡酯、丙戊酸和几种联合疗法与神经发育障碍风险增加有关。在产前接受拉莫三嗪、左乙拉西坦、卡马西平、奥卡西平、加帕喷丁、普瑞巴林、氯硝西泮或苯巴比妥单药治疗后，未观察到神经发育障碍的风险持续增加。结论和相关性 在这项队列研究中，产前接触托吡酯、丙戊酸和几种联合疗法与神经发育障碍风险增加有关。