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: 10051330
• 负责人: Kelsey Kathleen Wiggs
• 金额: $ 3.31万
• 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 2021-07-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10051330
• 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; 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 safety; comparison group; conditioning; design; fetus at risk; genetic risk factor; high dimensionality; high risk; improved; lamotrigine; maternal condition; migration; nervous system disorder; neuronal growth; neuropsychopharmacology; offspring; premature; prenatal exposure; safety study; sociodemographic factors; 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).

项目概要 几项观察性研究已将怀孕期间使用抗癫痫 (AED) 与后代出生缺陷联系起来 （BD）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些关联可能是因果关系， 因为有证据表明 AED 会穿过人类胎盘，并且动物模型显示出异常的大脑 暴露后的发育和行为。然而，对于关联的重要非因果解释 在我们得出人类之间的关联是因果关系的结论之前，需要排除这一点。具体来说，产妇 AED 使用指征（例如癫痫）、遗传因素（例如 BD、NDD 和癫痫发作常见的）、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 使用 AED 后，后代患 BD 和 NDD 的风险增加。了解是否存在关联 因果关系对于医生和患者在权衡使用 AED 的潜在风险和益处时非常重要 怀孕。具体来说，虽然 AED 暴露可能会伤害胎儿，但使用 AED 是主要治疗方法 怀孕期间的癫痫和癫痫发作会使胎儿和母亲面临危险。该提案的目的是测试 产前接触 AED 会导致这些结果的假设。我会完成这个目标 通过分析瑞典的大型国家数据集并追求两个目标来提出建议：（1）估计 怀孕期间使用 AED 后出现 BD 的风险，以及 (2) 估计怀孕期间使用 AED 后出现 NDD 的风险 妊娠与混杂因素无关。在目标 1 中，我将利用迄今为止最大的样本来检验 AED 和后代 BD 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 患有癫痫的女性，同时调整许多先前研究未考虑到的测量协变量 为了。在目标 2 中，我将使用边际模型（例如倾向得分匹配）和几个比较组来 帮助排除对关联的其他解释。该提案意义重大，因为它将告知 调查 BD 和 NDD 机制的基础研究以及治疗期间的最佳实践指南 怀孕。我有独特的能力来回答这个提案中的问题，因为我将分析最大的 迄今为止的研究（n =约210万），可以访问瑞典的综合登记册以及跨越多个国家的预测因子 分析的领域和层次，并将使用多种先进的设计来测试因果推论。这个提议 还结合了我之前的工作，其中我调查了 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，包括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、病因和评估 NDD 和专业发展（例如道德和传播培训）。

项目成果

A nationwide study of initiation of antidepressant pharmacotherapy and the risk of seizures.

一项关于开始抗抑郁药物治疗和癫痫发作风险的全国性研究。

• DOI: 10.1016/j.eplepsyres.2023.107134
• 发表时间: 2023
• 期刊: Epilepsy research
• 影响因子: 2.2
• 作者: Wiggs,KelseyK;Lagerberg,Tyra;Quinn,PatrickD;Öberg,ASara;Larsson,Henrik;Chang,Zheng;D'Onofrio,BrianM
• 通讯作者: D'Onofrio,BrianM

Antiseizure medication use during pregnancy and risk of ASD and ADHD in children.

• DOI: 10.1212/wnl.0000000000010993
• 发表时间: 2020-12-15
• 期刊: Neurology
• 影响因子: 9.9
• 作者: Wiggs KK;Rickert ME;Sujan AC;Quinn PD;Larsson H;Lichtenstein P;Oberg AS;D'Onofrio BM
• 通讯作者: D'Onofrio BM

Maternal Serotonergic Antidepressant Use in Pregnancy and Risk of Seizures in Children.

孕产妇血清素能在妊娠中使用抗抑郁药和儿童癫痫发作的风险。

• DOI: 10.1212/wnl.0000000000200516
• 发表时间: 2022-06-06
• 期刊: Neurology
• 影响因子: 9.9