Maternal epilepsy, antiepileptic drug use during pregnancy, and risk of autism

项目摘要 在瑞典和英国的一项多国流行病学研究中，我们的目标是研究孕妇 癫痫和孕期使用抗癫痫药物会增加患自闭症的风险 谱系障碍(ASD)。此外，我们将检查与使用AED相关的产妇健康结果 提供有关怀孕期间继续用药的风险-收益比的数据。癫痫是最重要的 最常见的严重神经系统疾病在怀孕期间影响女性，并与10倍于 分娩过程中死亡风险增加。抗癫痫药物是控制癫痫发作的必要药物，但AED的作用 怀孕期间的使用仍未得到充分研究。尽管有很好的证据表明在 妊娠到先天畸形，关于不良反应的高质量证据较少 神经发育结果。两项研究发现，在服用AED的过程中， 妊娠和自闭症，但两项研究都有不到10例自闭症患者接触AEDs。此外，许多人 对抗癫痫药物和神经发育结果的研究存在方法学问题。前人研究的两点回顾 暴露于AEDs的儿童的神经发育结果发现严重的问题，阻止了 关于AED暴露的不良影响的明确结论。主要问题包括：混淆， 选择偏向，样本容量小，统计能力有限。我们建议进行一项流行病学研究 在近300万名出生在瑞典和英国的儿童的联合样本中，解决了上述每个问题 英国。 所有暴露、混杂和结果数据均来自瑞典的临床和人口数据库 英国。在目标1中，我们将评估母体癫痫和儿童自闭症的关系。在目标2中，我们评估 与儿童自闭症相关的AED使用和孕期特定AEDs的安全性。在目标3中，我们将估计 与怀孕期间使用AED有关的妊娠和分娩结果的风险或降低风险，如 如癫痫发作、自残或死亡。在所有分析中，将使用因果推理技术来 确定调查结果的有效性。方法包括倾向得分匹配、兄弟姐妹和阴性对照， 以及对未观察到的混杂因素的模拟。

Project Abstract In a multi-national epidemiological study in Sweden and the United Kingdom, we aim to study if maternal epilepsy and use of anti-epileptic drugs (AEDs) during pregnancy is associated with increased risk of autism spectrum disorders (ASD). In addition, we will examine maternal health outcomes associated with AED use to provide data regarding the risk-benefit ratio of continuing medication use during pregnancy. Epilepsy is the most common serious neurological disorder affecting women during pregnancy, and is linked with a 10-fold increased risk of death during delivery. Antiepileptic drugs are necessary for seizure control, but effects of AED use during pregnancy remain understudied. Although there is good evidence linking use of AEDs during pregnancy to congenital malformations, there is less high-quality evidence concerning adverse neurodevelopmental outcomes. Two studies have found an association between AED exposure during pregnancy and ASD, but both studies had fewer than 10 ASD cases exposed to AEDs. Moreover, many studies of AEDs and neurodevelopmental outcomes have methodological issues. Two review of past studies of neurodevelopmental outcomes in children exposed to AEDs found substantial problems that prevented definitive conclusions regarding adverse effects of AED exposure. The chief problems included: confounding, selection bias, and small sample sizes with limited statistical power. We propose an epidemiological study that addresses each of these issues, in a combined sample of nearly 3 million children born in Sweden and the United Kingdom. All exposure, confounder, and outcome data are derived from clinical and population databases in Sweden and the UK. In Aim 1 we will estimate associations of maternal epilepsy and child ASD. In Aim 2, we evaluate the safety of AED use and of specific AEDs during pregnancy with regard to child ASD. In Aim 3, we will estimate the risk or risk reduction of pregnancy and delivery outcomes associated with AED use during pregnancy, such as seizure, self-harm, or death. Throughout all analyses, causal inference techniques will be employed to determine the validity of findings. Methods include propensity score matching, sibling and negative controls, and simulation of unobserved confounders.