Prenatal medication exposure in autism, birth complications and developmental disabilities

项目总结 自闭症谱系障碍(ASD)在美国每54个儿童中就有1个受到影响，然而，导致这一疾病的可改变的危险因素 混乱仍不为人所知，造成了紧迫的公共卫生需求。由于自闭症可能在产前早期出现 在发展方面，在确定这些可改变因素方面的努力侧重于孕妇在怀孕期间的暴露， 包括药物治疗。虽然一些药物已被证明与ASD有关，但主要的关键 知识差距仍然存在，包括：(1)根本机制尚未阐明；(2)影响 大多数孕妇服用的药物对自闭症风险的影响仍不清楚--尽管处方药和过度使用普遍存在。 怀孕期间的非处方药(OTC)，其中大多数穿过胎盘，对 胎儿。因此，这项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 概括性和特殊性。为了实现这些目标，我们提出了独立但协同的目标：目标 1：系统调查全系列产妇处方和非处方药在 怀孕对自闭症后代风险的影响，使用了来自以色列的120万名活产婴儿的高质量样本， 处方、医疗和血统信息。我们将测试观察到的对ASD的影响是否不同，具体取决于 暴露的时间或持续时间、同时使用其他药物、适应症或后代性行为。目标2： 测试母体用药与自闭症之间联系的潜在机制， 家庭混杂，使用兄弟姐妹比较和对父亲暴露的负面控制；以及2B：识别 临床混杂通过(I)检查ASD与由其定义的药物簇相关的风险 药理特征(靶标(S)、化学结构)与适应症；(2)对孕产妇保健替代品的调整； (三)停产分析。目标3：建立母体用药效应的特异性和概括性 关于自闭症，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等药物：在瑞典、芬兰和美国进行复制研究。创新之处 这个项目有四个方面：(1)它可以识别ASD的新的、潜在的可修改的风险因素；(2)它可以三角测量 辨别药物对自闭症风险的因果和混杂影响的正交方法；(3)它利用 明确界定暴露的药物的药理学和药代动力学数据；和(4) 对不同不利发展结果中共同和不同的风险因素提供了新的见解。vt.在.的基础上 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了 我们的专家团队将提供孕妇处方和怀孕期间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强有力的证据。这 将有助于确定疾病的潜在可修改风险因素，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，并描绘了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.