Prenatal medication exposure in autism, birth complications and developmental disabilities

自闭症、出生并发症和发育障碍的产前药物暴露

• 批准号: 10704111
• 负责人: MAGDALENA JANECKA
• 金额: $ 69.41万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704111
• 关键词: Accounting; Address; Affect; Attention deficit hyperactivity disorder; Benchmarking; Biometry; Cerebral Palsy; Chemical Structure; Child; Childhood Asthma; Clinical; Collaborations; Combination Medication; Data; Demographic Factors; Development; Developmental Disabilities; Dimensions; Disease; Drug Kinetics; Environmental Risk Factor; Epidemiology; Etiology; Exposure to; Family; Fetus; Finland; Genetic; Goals; Health; Incidence; Individual; Intellectual functioning disability; Israel; Knowledge; Link; Live Birth; Maternal Age; Maternal Exposure; Maternal Health; Medical; Methods; Mothers; Outcome; Paternal Exposure; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Placenta; Polypharmacy; Pregnancy; Pregnant Women; Premature Birth; Prevalence; Prevention; Prevention strategy; Property; Prospective cohort; Proxy; Psychiatric epidemiology; Public Health; Registries; Risk; Risk Factors; Role; Sampling; Siblings; Source; Specificity; Structure; Subgroup; Sweden; System; Testing; Time; autism spectrum disorder; congenital heart disorder; delivery complications; design; disorder risk; fetal; genetic pedigree; health data; high risk; innovation; insight; modifiable risk; novel; offspring; pharmacologic; population based; prenatal; prenatal exposure; response; sex; trend

PROJECT SUMMARY Autism spectrum disorder (ASD) affects 1 in 54 children in the US, however the modifiable risk factors for this disorder remain unknown, creating a pressing public health need. As ASD likely arises early in prenatal development, efforts in identifying such modifiable factors have focused on maternal exposures in pregnancy, including medications. While some medications have been shown to be associated with ASD, major critical knowledge gaps remain, including: (1) the underlying mechanisms have not been elucidated, and (2) the effects of most maternal medications on ASD risk are still unknown — despite pervasive use of prescription and over- the-counter (OTC) medications in pregnancy, most of which cross the placenta, with unknown effects on the fetus. In response, the key objectives of the proposed study are to identify medications taken by pregnant women that influence offspring ASD risk, elucidate confounding factors in these associations, and benchmark their generalizability and specificity. To achieve these objectives, we propose independent, but synergistic aims: Aim 1: Systematically investigate the effects of the full range of maternal prescription and OTC medications used in pregnancy on ASD offspring risk, using well-powered sample of 1.2M live births from Israel with full demographic, prescription, medical and pedigree information. We will test if the observed effects on ASD differ depending on the timing or duration of the exposure, concurrent use of other medications, indication or offspring sex. Aim 2: Test the mechanisms underlying the associations between maternal medication use and ASD, 2A: examining familial confounding, using sibling comparisons and negative control of paternal exposure; and 2B: identifying clinical confounding by (i) examining risk of ASD associated with clusters of medications defined by their pharmacological features (target(s), chemical structure) vs indication, (ii) adjustment for maternal health proxies; (iii) discontinuation analysis. Aim 3: Establish the specificity and generalizability of maternal medication effects on ASD, by 3A: examining the range of other (neuro)developmental outcomes affected by the same maternal medications as ASD, and 3B: performing a replication study in Sweden, Finland and the US. The innovation of this project is four-fold: (1) it can identify novel, potentially modifiable risk factors for ASD; (2) it triangulates orthogonal approaches to discern causal vs confounded effects of medications on ASD risk; (3) it leverages pharmacological and pharmacokinetic data on medications to unambiguously define exposure; and (4) it provides new insights into shared and distinct risk factors in different adverse developmental outcomes. Upon completion, our multi-dimensional approach, rigorous methods and unprecedented study power in the hands of our expert team will deliver a systematic list of the maternal prescription and OTC medications in pregnancy associated with ASD, and robust evidence regarding the role of the confounding factors in these effects. This will help identify potential modifiable risk factors for the disorder, contribute high-quality evidence about the risks associated with maternal use of certain medications during pregnancy, and delineate the etiology of ASD.

项目摘要 自闭症谱系障碍（ASD）在美国影响54名儿童中有1个，但是可改变的风险因素 疾病仍然未知，产生了紧迫的公共健康需求。由于ASD可能在产前早期出现 开发，确定此类可修改因素的努力集中在孕妇的孕妇暴露上， 包括药物。虽然某些药物已被证明与ASD相关，但主要关键 知识差距仍然存在，包括：（1）尚未阐明基本机制，以及（2）影响 在大多数关于ASD风险的母亲药物中，尽管普遍地使用处方和过度使用 怀孕中大多数跨越斑点的特征（OTC）药物，对 胎儿。作为回应，拟议的研究的关键目标是确定孕妇服用的药物 这会影响后代ASD风险，阐明这些关联中的混杂因素，并基准测试 概括性和特异性。为了实现这些目标，我们提出了独立的目标，但协同目标是：目标 1：系统地研究了使用的所有母体处方和OTC药物的影响 怀孕是ASD后代风险的怀孕，使用以色列的120万个活生生样本，具有完全人口统计学， 处方，医学和谱系信息。我们将测试观察到的对ASD的影响是否不同 暴露的时间或持续时间，同时使用其他药物，适应症或后代性别。目标2： 测试使用物质药物使用与ASD之间关联的机制，2A：检查 家族性混淆，使用同胞比较和对父亲暴露的负面对照；和2b：识别 临床混淆（i）检查与其定义的药物簇相关的ASD风险 药理学特征（靶，化学结构）与指示，（ii）对母亲健康代理的调整； （iii）中断分析。目标3：确定母体药物效应的特异性和概括性 在ASD上，按3A：检查受同一母体影响的其他（神经）发育结果的范围 ASD和3B的药物：在瑞典，芬兰和美国进行复制研究。创新 该项目是四倍：（1）它可以识别ASD的新颖，可能修改的风险因素； （2）它是三角枪 辨别因果与药物对ASD风险的混杂作用的正交方法； （3）它的利用 有关药物的药理和药代动力学数据，以明确定义暴露； （4） 在不同的不良发展结果中，提供了有关共同且独特的风险因素的新见解。之上 完成，我们的多维方法，严格的方法和前所未有的学习能力 我们的专家团队将提供孕妇处方和OTC药物的系统清单 与ASD相关，以及关于混杂因素在这些影响中的作用的强大证据。这 将有助于确定该疾病的潜在可修改风险因素，为风险提供高质量的证据 与孕妇在怀孕期间使用某些药物有关，并描述ASD的病因。