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: 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
• 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

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.

项目总结