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

基本信息

批准号：
10522761
负责人：
MAGDALENA JANECKA
金额：
$ 68.07万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
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/10522761
关键词：
Accounting Address Affect Attention deficit hyperactivity disorder Benchmarking Biometry Cations Cerebral Palsy Chemical Structure Child Childhood Asthma Clinical Clinical Pharmacology Collaborations Combination Medication Data Demographic Factors Development Developmental Disabilities Disease Drug Kinetics Environmental Risk Factor Etiology Exposure to Family Fetus Finland Genetic Goals Health Incidence Individual Informatics 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 base congenital heart disorder delivery complications design disorder risk fetal genetic pedigree health data high risk innovation insight modifiable risk novel offspring population based prenatal prenatal exposure response sex trend

项目摘要

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.

项目概要在美国，每 54 名儿童中就有 1 名患有自闭症谱系障碍 (ASD)，但是该病的危险因素是可以改变的由于自闭症谱系障碍（ASD）可能在产前早期出现，因此该疾病仍然未知，因此产生了紧迫的公共卫生需求。的发展，确定此类可改变因素的努力重点关注孕期母亲的暴露，虽然某些药物已被证明与自闭症谱系障碍有关，但主要是危重药物。知识差距依然存在，包括：(1) 根本机制尚未阐明，(2) 影响尽管普遍使用处方药和过度使用药物，但大多数孕产妇药物对 ASD 风险的影响仍然未知。怀孕期间的非处方药（OTC）药物，其中大部分会穿过胎盘，对胎儿的影响未知为此，拟议研究的主要目标是确定孕妇服用的药物。影响后代 ASD 风险的因素，阐明这些关联中的混杂因素，并对其进行基准测试为了实现这些目标，我们提出了独立但协同的目标：目标 1：系统地研究孕产妇使用的各种处方药和非处方药的效果怀孕对自闭症谱系障碍 (ASD) 后代风险的影响，使用来自以色列的 120 万活产婴儿的有力样本，并具有完整的人口统计数据，我们将测试观察到的对 ASD 的影响是否因处方、医疗和血统信息而异。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：测试孕产妇药物使用与自闭症谱系障碍 (ASD) 之间关联的潜在机制，2A：检查家族混杂，使用兄弟姐妹比较和父亲暴露的阴性对照；以及 2B：识别通过（i）检查与由其定义的药物簇相关的自闭症谱系障碍（ASD）风险来进行临床混淆药理学特征（目标、化学结构）与适应症，(ii) 孕产妇健康指标的调整； (iii) 停药分析目标 3：确定孕产妇药物效应的特异性和普遍性。关于自闭症谱系障碍，3A：检查受同一母亲影响的其他（神经）发育结果的范围 ASD 和 3B 等药物：在瑞典、芬兰和美国进行复制研究。该项目有四个方面：（1）它可以识别新的、潜在可改变的自闭症谱系障碍风险因素；（2）它可以进行三角测量；辨别药物对自闭症谱系障碍 (ASD) 风险的因果影响和混杂影响的正交方法；(3) 它利用明确定义暴露的药物药理学和药代动力学数据；以及 (4) 提供了对不同不良发育结果中共同和独特的风险因素的新见解。完成后，我们的多维方法、严谨的方法和前所未有的研究力量掌握在我们的专家团队将提供孕期孕妇处方药和非处方药的系统清单与 ASD 相关，以及关于混杂因素在这些影响中的作用的有力证据。将有助于识别该疾病的潜在可改变风险因素，提供有关风险的高质量证据与母亲在怀孕期间使用某些药物有关，并描述 ASD 的病因学。