Department of Pediatrics, Aalborg University Hospital, Aalborg, Denmark
Unit of Epidemiology and Biostatistics, Aalborg University Hospital, Aalborg, Denmark.
J Neurol Neurosurg Psychiatry. 2018 Dec;89(12):1324-1331. doi: 10.1136/jnnp-2018-318386. Epub 2018 Aug 3.
In utero exposure to antiepileptic drugs has previously been associated with adverse outcome among offspring, but evidence on longer term milestone development remains limited. We investigated the association between in utero exposure to antiepileptic drugs and learning disabilities in the first year of compulsory education among offspring and assessed which antiepileptic drugs carried the highest risk.
This population-based case-cohort study used Danish nationwide register data from 2005 to 2008. Cases were offspring exposed to antiepileptic drugs in utero, and controls were unexposed offspring of mothers previously redeeming antiepileptic drug prescriptions. Offspring were followed from birth until the first year of compulsory education from 2011 to 2015. Learning disabilities were defined as mental retardation, specific developmental disorders, autism spectrum disorders, emotional/behavioural disorders or having special educational needs. Logistic regression was used to compute ORs with 95% CIs adjusted for potential confounding.
Of 117 475 incident singleton births, 636 cases and 434 controls were included (median age: 6.1 years, males: 55.7%). Learning disabilities were identified among 7.1% cases compared with 3.7% for controls. During any trimester, the adjusted OR of the association between in utero exposure to antiepileptic drugs and learning disabilities was 2.20 (95% CI 1.16 to 4.17). Among cases not exposed to polytherapy (n=556), in utero exposure to lamotrigine compared with another antiepileptic drug was associated with the lowest adjusted risk (OR 0.42, 95% CI 0.19 to 0.92), and valproate carried a higher risk (OR 4.67, 95% CI 1.73 to 12.59).
In utero exposure to antiepileptic drugs was significantly associated with learning disabilities among offspring. Lamotrigine should preferentially be considered over, for example, valproate if clinically feasible.
先前有研究表明，胎儿期接触抗癫痫药物与后代的不良结局相关，但关于长期里程碑发育的证据仍然有限。本研究旨在调查胎儿期接触抗癫痫药物与子女义务教育第一年学习障碍之间的关联，并评估哪些抗癫痫药物风险最高。
本基于人群的病例对照研究使用了丹麦全国范围内 2005 年至 2008 年的登记数据。病例为胎儿期暴露于抗癫痫药物的子女，对照组为母亲之前曾领取抗癫痫药物处方但未暴露于抗癫痫药物的子女。子女从出生到 2011 年至 2015 年的义务教育第一年进行随访。学习障碍定义为智力迟钝、特定发育障碍、自闭症谱系障碍、情绪/行为障碍或有特殊教育需求。使用逻辑回归计算了调整潜在混杂因素后的 OR 和 95%CI。
在 117475 例单胎活产中，纳入 636 例病例和 434 例对照（中位年龄：6.1 岁，男性：55.7%）。病例组中学习障碍的发生率为 7.1%，对照组为 3.7%。在任何一个孕期，胎儿期接触抗癫痫药物与学习障碍之间的关联的调整 OR 为 2.20（95%CI 1.16 至 4.17）。在未接受多药治疗的病例中（n=556），与其他抗癫痫药物相比，拉莫三嗪暴露与最低的调整风险相关（OR 0.42，95%CI 0.19 至 0.92），而丙戊酸风险较高（OR 4.67，95%CI 1.73 至 12.59）。
胎儿期接触抗癫痫药物与子女学习障碍显著相关。如果临床可行，应优先考虑拉莫三嗪，而非丙戊酸等药物。
