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

项目摘要 在瑞典和联合王国的一项多国流行病学研究中，我们的目标是研究孕产妇 癫痫和在怀孕期间使用抗癫痫药物（AEDs）与自闭症风险增加有关 谱系障碍（ASD）。此外，我们将研究与AED使用相关的孕产妇健康结果， 提供关于妊娠期间继续使用药物的风险-获益比的数据。癫痫是一种 最常见的严重神经系统疾病影响妇女在怀孕期间，并与10倍的 分娩期间死亡的风险增加。抗癫痫药物是控制癫痫发作所必需的，但AED的作用 怀孕期间的使用仍然没有得到充分研究。尽管有很好的证据表明， 妊娠至先天性畸形，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， 妊娠和ASD，但两项研究都有不到10例ASD病例暴露于AED。而且很多 AED和神经发育结果的研究存在方法学问题。两篇文献综述 暴露于AED的儿童的神经发育结果发现， 关于AED暴露不良影响的明确结论。主要问题包括：混淆， 选择偏差和小样本量，统计功效有限。我们建议进行一项流行病学研究， 在瑞典出生的近300万儿童的综合样本中， 英国. 所有暴露、混杂因素和结局数据均来自瑞典的临床和人群数据库， 英国.在目标1中，我们将估计母亲癫痫和儿童ASD的关联。在目标2中，我们评估 AED使用的安全性和妊娠期间特定AED对儿童ASD的影响。在目标3中，我们将估计 与妊娠期间使用AED相关的妊娠和分娩结局的风险或风险降低，例如 癫痫自残或死亡在所有的分析中，因果推理技术将被用来 确定调查结果的有效性。方法包括倾向评分匹配，同胞和阴性对照， 和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.