National Centre for Register-Based Research, School of Business and Social Science, Aarhus University, Aarhus, Denmark.
Department of Clinical Medicine, University of Bergen, Bergen, Norway.
JAMA Neurol. 2023 Jun 1;80(6):568-577. doi: 10.1001/jamaneurol.2023.0674.
Prenatal antiseizure medication (ASM) exposure has been associated with adverse early neurodevelopment, but associations with a wider range of psychiatric end points have not been studied.
To examine the association between prenatal exposure to ASM with a spectrum of psychiatric disorders in childhood and adolescence in children of mothers with epilepsy.
DESIGN, SETTING, AND PARTICIPANTS: This prospective, population-based register study assessed 4 546 605 singleton children born alive in Denmark, Finland, Iceland, Norway, and Sweden from January 1, 1996, to December 31, 2017. Of the 4 546 605 children, 54 953 with chromosomal disorders or uncertain birth characteristics were excluded, and 38 661 children of mothers with epilepsy were identified. Data analysis was performed from August 2021 to January 2023.
Prenatal exposure to ASM was defined as maternal prescription fills from 30 days before the first day of the last menstrual period until birth.
The main outcome measure was diagnosis of psychiatric disorders (a combined end point and 13 individual disorders). Estimated adjusted hazard ratios (aHRs) using Cox proportional hazards regression and cumulative incidences with 95% CIs are reported.
Among the 38 661 children of mothers with epilepsy (16 458 [42.6%] exposed to ASM; 19 582 [51.3%] male; mean [SD] age at the end of study, 7.5 [4.6] years), prenatal valproate exposure was associated with an increased risk of the combined psychiatric end point (aHR, 1.80 [95% CI, 1.60-2.03]; cumulative risk at 18 years in ASM-exposed children, 42.1% [95% CI, 38.2%-45.8%]; cumulative risk at 18 years in unexposed children, 31.3% [95% CI, 28.9%-33.6%]), which was driven mainly by disorders within the neurodevelopmental spectrum. Prenatal exposure to lamotrigine, carbamazepine, and oxcarbazepine was not associated with an increased risk of psychiatric disorders, whereas associations were found for prenatal exposure to topiramate with attention-deficit/hyperactivity disorder (aHR, 2.38; 95% CI, 1.40-4.06) and exposure to levetiracetam with anxiety (aHR, 2.17; 95% CI, 1.26-3.72) and attention-deficit/hyperactivity disorder (aHR, 1.78; 95% CI, 1.03-3.07).
Findings from this explorative study strengthen the evidence for the warning against the use of valproate in pregnancy and raise concern of risks of specific psychiatric disorders associated with topiramate and levetiracetam. This study provides reassuring evidence that lamotrigine, carbamazepine, and oxcarbazepine are not associated with long-term behavioral or developmental disorders but cannot rule out risks with higher doses.
产前抗癫痫药物（ASM）暴露与早期神经发育不良有关，但与更广泛的精神科终点的关联尚未研究。
研究母亲癫痫患儿产前暴露于 ASM 与儿童和青少年时期一系列精神疾病之间的关联。
设计、地点和参与者：本前瞻性、基于人群的登记研究评估了 1996 年 1 月 1 日至 2017 年 12 月 31 日期间在丹麦、芬兰、冰岛、挪威和瑞典出生的 4546605 名活产单胎儿童。在 4546605 名儿童中，排除了 54953 名患有染色体疾病或出生特征不确定的儿童，以及 38661 名母亲患有癫痫的儿童。数据分析于 2021 年 8 月至 2023 年 1 月进行。
产前暴露于 ASM 定义为从末次月经第一天前 30 天到分娩期间母亲的处方。
主要结局指标是诊断为精神疾病（综合终点和 13 种单独疾病）。使用 Cox 比例风险回归和 95%CI 报告估计的调整后的危险比 (aHR)。
在 38661 名母亲患有癫痫的儿童中（16458 名[42.6%]暴露于 ASM；19582 名[51.3%]男性；研究结束时的平均[SD]年龄为 7.5[4.6]岁），产前丙戊酸暴露与联合精神科终点的风险增加相关（aHR，1.80[95%CI，1.60-2.03]；暴露于 ASM 的儿童在 18 岁时的累积风险为 42.1%[95%CI，38.2%-45.8%]；未暴露于 ASM 的儿童在 18 岁时的累积风险为 31.3%[95%CI，28.9%-33.6%]），这主要是由神经发育谱系内的疾病驱动的。产前暴露于拉莫三嗪、卡马西平和奥卡西平与精神疾病风险增加无关，而产前暴露于托吡酯与注意力缺陷/多动障碍（aHR，2.38；95%CI，1.40-4.06）和左乙拉西坦与焦虑（aHR，2.17；95%CI，1.26-3.72）和注意力缺陷/多动障碍（aHR，1.78；95%CI，1.03-3.07）有关。
这项探索性研究的结果加强了在怀孕期间使用丙戊酸的警告证据，并引起了对与托吡酯和左乙拉西坦相关的特定精神疾病风险的关注。本研究提供了令人安心的证据，表明拉莫三嗪、卡马西平和奥卡西平与长期行为或发育障碍无关，但不能排除高剂量的风险。
