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

母亲妊娠期间使用抗癫痫药物及后代出生缺陷和神经发育障碍

• 批准号: 9910999
• 负责人: Kelsey Kathleen Wiggs
• 金额: $ 4.5万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910999
• 关键词: Animal Model; Animals; Antiepileptic Agents; Attention deficit hyperactivity disorder; Basic Science; Behavior; Benefits and Risks; Birth; Brain; Carbamazepine; Characteristics; Child; Clinical; Congenital Abnormality; Data Set; Demographic Factors; Development; Diagnosis; Drug Exposure; Drug usage; Environmental Risk Factor; Epidemiologic Methods; Epilepsy; Ethics; Etiology; Evidence based intervention; Exposure to; Fetal health; Fetus; Functional disorder; Genetic; Genetic Risk; Goals; Guidelines; Human; Individual; Investigation; Link; Maternal Health; Measures; Mental disorders; Methods; Modeling; Mothers; Neurodevelopmental Disorder; Observational Study; Outcome; Perinatal; Pharmaceutical Preparations; Pharmacoepidemiology; Pharmacotherapy; Physicians; Placenta; Population; Population Registers; Practice Guidelines; Pregnancy; Pregnant Women; Process; Research; Resources; Risk; Risk Estimate; Risk Factors; Rodent; Role; Sampling; Seizures; Socioeconomic Factors; Sweden; Testing; Training; Weighing patient; Woman; Women' s Health; Work; adverse outcome; autism spectrum disorder; base; career; clinical care; clinical practice; clinically relevant; cohort; comparative; comparison group; conditioning; design; fetus at risk; genetic risk factor; high dimensionality; high risk; improved; lamotrigine; migration; nervous system disorder; neuronal growth; neuropsychopharmacology; offspring; premature; prenatal exposure; safety study; sociodemographics; socioeconomics; treatment guidelines; valproate

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).

项目摘要 几项观察性研究将妊娠期间使用抗癫痫药（AED）与后代出生缺陷联系起来 (BDs)和神经发育障碍（NDD），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关系， 因为有证据表明AED可以穿过人类胎盘，动物模型显示异常的大脑 暴露后的发展和行为。然而，重要的非因果关系的解释， 在我们得出结论人类中的关联是因果关系之前需要排除。具体来说，产妇 AED使用的适应症（例如，癫痫），遗传因素（例如，常见于BD、NDD和癫痫发作），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使用后后代中BD和NDD的风险增加。了解关联是否 对于医生和患者来说，在治疗过程中权衡AED使用的潜在风险和益处是很重要的。 怀孕具体来说，虽然AED暴露可能会伤害胎儿，但AED使用是治疗胎儿缺氧的主要方法。 癫痫和怀孕期间的癫痫发作使胎儿和母亲处于危险之中。本提案的目的是测试 产前暴露于AED导致这些结果的假设。我会完成这个目标 通过分析瑞典的一个大型国家数据集，提出了一项建议，并追求两个目标：（1）估计 妊娠期间使用AED后的BD风险，以及（2）估计妊娠期间使用AED后的NDD风险 妊娠不受混杂因素影响。在目标1中，我将利用迄今为止最大的样本来检查 AEDs和后代BDs之间的关联。我将通过比较暴露和未暴露的后代来做到这一点。 女性癫痫患者，同时调整了许多先前研究没有考虑的测量协变量， for.在目标2中，我将使用边际模型（例如，倾向评分匹配）和几个比较组， 有助于排除对这种关联的其他解释。这一建议意义重大，因为它将告知 基础研究调查BD和NDD的机制以及治疗期间的最佳实践指南 怀孕我是唯一有能力回答这个问题的建议，因为我将分析最大的 迄今为止的研究（n = ~ 210万），可访问瑞典联合登记册，预测因子涵盖多个 领域和分析水平，并将使用多种先进的设计来测试因果推理。这项建议 我还将我以前的工作结合在一起，在这些工作中，我调查了NDD的产前和围产期危险因素 并使用药物流行病学方法来调查癫痫发作的风险。该项目将促进 我的长期培训目标是发展研究NDD风险因素的职业生涯，包括在以下方面的广泛培训： 流行病学方法，妇女健康和神经精神药理学， NDD和专业发展（例如，道德和传播方面的培训）。