Maternal antiepileptic drug use during pregnancy and offspring birth defects and neurodevelopmental disorders

项目摘要 一些观察性研究已将孕期使用抗癫痫药(AED)与后代出生缺陷联系起来 (BDS)和神经发育障碍(NDDS)，包括注意力缺陷多动障碍(ADHD)和 自闭症谱系障碍(ASD)。对人类和动物的研究表明，这种联系可能是因果的， 由于有证据表明AEDs穿过人类胎盘，动物模型显示大脑异常 暴露后的发展和行为。然而，对联想的重要的非因果解释 在我们得出结论认为人类的这种关联是因果关系之前，需要排除这种可能性。具体地说，母性 使用AED的适应症(例如癫痫)、遗传因素(例如BDS、NDDS和癫痫的共同症状)、其他 环境因素(例如，社会经济资源)或这些因素的组合可以解释 暴露于AED后，子代BDS和NDDS的风险增加。了解协会是否 因果关系对于医生和患者权衡使用AED的潜在风险和好处是重要的 怀孕了。具体地说，尽管接触AED可能会损害胎儿，但使用AED是治疗 癫痫和怀孕期间的癫痫发作将胎儿和母亲置于危险之中。这项提议的目标是测试 这一假设认为，产前暴露于抗癫痫药物会导致这些结果。我会实现这一目标的 通过分析瑞典的一个大型国家数据集提出建议，并追求两个目标：(1)估计 在妊娠期间使用AED后发生BDS的风险，以及(2)估计在怀孕期间使用AED后发生NDDS的风险 独立于混乱的怀孕。在目标1中，我将利用迄今为止最大的样本来检查 抗癫痫药物与子代BDS之间的关系。我将通过比较暴露和未暴露的后代来实现这一点 女性癫痫患者，同时调整了许多以前研究没有考虑到的测量协变量 为。在目标2中，我将使用边际模型(例如，倾向分数匹配)和几个比较组来 帮助排除对这些联系的其他解释。这项建议意义重大，因为它将使 BDS和NDDS的基础研究调查机制和治疗的最佳实践指南 怀孕了。我是唯一有能力回答这个问题的人，因为我将分析最大的 到目前为止的研究(n=~210万)，可以访问具有跨越多个预测值的组合瑞典寄存器 分析的领域和水平，并将使用多种先进的设计来测试因果推论。这项建议 我还结合了我以前的工作，其中我调查了NDDS的产前和围产期风险因素 并使用药物流行病学方法调查癫痫发作的风险。这个项目将促进 我的长期培训目标是发展研究非处方药风险因素的职业，包括在 流行病学方法，妇女健康和神经精神药理学，病因和评估 NDDS和专业发展(例如，道德培训和传播)。

Project Summary Several observational studies have linked antiepileptic (AED) use during pregnancy to offspring birth defects (BDs) and neurodevelopmental disorders (NDDs), including attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Research in humans and animals suggest the associations might be causal, as there is evidence that AEDs cross the human placenta and animal models show aberrant brain development and behavior following exposure. However, important non-causal explanations for associations need to be ruled out before we can conclude that the association in humans is causal. Specifically, maternal indications for AED use (e.g., epilepsy), genetic factors (e.g., common to BDs, NDDs, and seizures), other environmental factors (e.g., socioeconomic resources), or a combination of these factors may explain the increased risk for BDs and NDDs in offspring after exposure to AED use. Understanding whether associations are causal is important for doctors and patients weighing the potential risks and benefits of AED use during pregnancy. Specifically, although AED exposure may harm the fetus, AED use is the primary treatment for epilepsy, and seizures during pregnancy put fetus and mother at risk. The objective of this proposal is to test the hypothesis that prenatal exposure to AEDs causes these outcomes. I will accomplish the objective of this proposal through the analysis of a large, national dataset from Sweden and pursuing two aims: (1) estimate the risk of BDs following AED use during pregnancy, and (2) estimate the risk of NDDs following AED use during pregnancy independent of confounding. In aim 1, I will leverage the largest sample to date to examine associations between AEDs and offspring BDs. I will do this by comparing exposed and unexposed offspring of women with epilepsy, while adjusting for many measured covariates that previous research has not accounted for. In aim 2, I will use marginal models (e.g., propensity score matching) and several comparison groups to help rule out alternative explanations for the associations. This proposal is significant because it will inform basic research investigating mechanisms for BDs and NDDs and best-practice guidelines for treatment during pregnancy. I am uniquely equipped to answer the question in this proposal because I will analyze the largest study to date (n = ~2.1 million), have access to combined Swedish registers with predictors spanning multiple domains and levels of analysis, and will use multiple advanced designs to test causal inferences. This proposal also weaves together my previous work in which I have investigated pre- and perinatal risk factors for NDDs and used pharmaco-epidemiologic approaches to investigate the risks for seizures. This project will facilitate my long-term training goal to develop a career researching risk factors for NDDs, including extensive training in epidemiologic methods, women’s health and neuropsychopharmacology, the etiology and assessment of NDDs, and professional development (e.g., training in ethics and dissemination).