Prenatal medication exposure in autism, birth complications and developmental disabilities

项目摘要 自闭症谱系障碍（ASD）影响美国54名儿童中的1名，然而， 疾病仍然未知，造成了紧迫的公共卫生需求。由于ASD可能在产前早期出现， 在发展过程中，确定这些可改变因素的工作主要集中在孕妇怀孕期间的暴露， 包括药物。虽然一些药物已被证明与ASD有关，但主要的关键是 知识差距仍然存在，包括：（1）基本机制尚未阐明，（2）影响 大多数母体药物对ASD风险的影响仍然未知-尽管广泛使用处方药和过度使用， 非处方（OTC）药物在怀孕期间，其中大部分穿过胎盘，对胎儿的影响未知。 胎儿作为回应，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，阐明这些关联中的混杂因素，并对其进行基准测试。 一般性和特殊性。为了实现这些目标，我们提出了独立但协同的目标： 1：系统地调查在妊娠中使用的所有产妇处方药和OTC药物的影响， 妊娠对ASD后代风险的影响，使用来自以色列的120万活产婴儿的有效样本， 处方、医疗和血统信息。我们将测试观察到的对ASD的影响是否因 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。目标二： 测试母体药物使用与ASD之间相关性的潜在机制，2A：检查 家族混杂，使用同胞比较和父亲暴露的阴性对照;和2B：鉴定 通过（i）检查与药物簇相关的ASD风险， 药理学特征（靶点、化学结构）与适应症，（ii）调整孕产妇健康代理; (iii)停药分析。目的3：确定母体用药效应的特异性和普遍性 在ASD上，通过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药物：在瑞典、芬兰和美国进行重复研究。的创新 这个项目有四个方面：（1）它可以识别新的，潜在的可改变的ASD风险因素;（2）它三角测量 正交方法来辨别药物对ASD风险的因果与混杂效应;（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） 为不同不良发育结果中的共同和独特风险因素提供了新的见解。后 完成，我们的多维方法，严谨的方法和前所未有的研究力量在手中， 我们的专家团队将提供一份系统的孕妇处方和OTC药物清单， 与ASD相关，以及关于这些影响中混杂因素作用的有力证据。这 将有助于确定潜在的可改变的风险因素，为风险提供高质量的证据 与母亲在怀孕期间使用某些药物有关，并描述ASD的病因。

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.