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

孕产妇癫痫、怀孕期间抗癫痫药物的使用以及自闭症的风险

• 批准号: 9816282
• 负责人: Brian Kane Lee
• 金额: $ 50.67万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9816282
• 关键词: Address; Adult; Adverse effects; Affect; Antiepileptic Agents; Area; Benefits and Risks; Caring; Cause of Death; Cesarean section; Cessation of life; Child; Clinical; Cognition; Congenital Abnormality; Data; Databases; Drug Exposure; Drug usage; Epilepsy; Ethics; Etiology; Exposure to; Fetus; Frequencies; Fright; General Population; Genetic; Hospitalization; Link; Literature; Maternal Health; Mental disorders; Methodology; Methods; Molecular; Morbidity - disease rate; Mothers; Observational Study; Outcome; Pain Disorder; Patients; Persons; Pharmaceutical Preparations; Pharmacoepidemiology; Phenotype; Population Database; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnant Women; Premature Labor; Prevalence; Public Health; Randomized Controlled Trials; Recommendation; Reporting; Research; Risk; Risk Estimate; Risk Reduction; Safety; Sample Size; Sampling; Seizures; Selection Bias; Self-Injurious Behavior; Siblings; Statistical Methods; Status Epilepticus; Sweden; Techniques; Time; Tonic - clonic seizures; United Kingdom; Woman; autism spectrum disorder; clinical database; clinical practice; computerized; disorder risk; epidemiology study; evidence base; health data; improved; interest; mortality risk; motor impairment; nervous system disorder; neurodevelopment; population based; prenatal exposure; prevent; risk benefit ratio; simulation; stillbirth; valproate

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.

项目摘要 在瑞典和英国的一项跨国流行病学研究中，我们旨在研究产妇 怀孕期间癫痫和使用抗癫痫药（AED）与自闭症的风险增加有关 频谱障碍（ASD）。此外，我们将研究与AED使用相关的孕产妇健康结果 提供有关怀孕期间持续药物使用的风险效益比的数据。癫痫是 最常见的严重神经系统疾病会影响怀孕期间女性，并与10倍有关 分娩期间死亡的风险增加。抗癫痫药是癫痫控制所必需的，但是AED的影响 怀孕期间的使用仍在研究。尽管有充分的证据链接了AED的使用 怀孕对先天性畸形，关于不利的高质量证据 神经发育结果。两项研究发现 怀孕和ASD，但两项研究都少于10例ASD病例。而且，许多 对AED和神经发育结果的研究存在方法论问题。两次对过去研究的评论 暴露于AED的儿童中的神经发育结果发现了实质性问题 关于AED暴露的不利影响的确定性结论。主要问题包括：混淆， 选择偏差和统计能力有限的小样本量。我们提出了一项流行病学研究， 在瑞典出生的近300万儿童的总样本中解决了这些问题中的每一个 英国。 所有暴露，混杂因素和结果数据均来自瑞典和 英国。在AIM 1中，我们将估计母亲癫痫和儿童ASD的关联。在AIM 2中，我们评估了 AED使用的安全性和特定AED在怀孕期间与儿童ASD有关。在AIM 3中，我们将估计 怀孕期间与AED使用相关的怀孕和递送结果的风险或风险降低 作为癫痫发作，自我伤害或死亡。在所有分析中，因果推理技术将采用 确定发现的有效性。方法包括倾向得分匹配，同级和负面对照， 以及未观察到的混杂因素的模拟。