Neurodevelopmental Effect of Acetaminophen Exposures

对乙酰氨基酚暴露对神经发育的影响

• 批准号: 10736409
• 负责人: Zeyan Liew
• 金额: $ 53.04万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736409
• 关键词: Acetaminophen; Address; Adolescence; Adverse effects; Affect; Age; Aminophenols; Analgesic and Antipyretic; Asia; Attention deficit hyperactivity disorder; Behavioral; Birth; Brain; Child; Childhood; Clinical Trials; Cohort Studies; Consumption; Data; Data Sources; Databases; Decision Making; Development; Diagnosis; Disease; Dose; Enrollment; Ethics; Europe; Exposure to; Fetal Development; Fetal Growth; Fetus; Fever; Genetic Risk; Guidelines; Health; Intake; Interview; Investigation; Joints; Knowledge; Life; Link; Literature; Maternal-fetal medicine; Medical; Mental Health; Modeling; Mothers; Motor; Observational Study; Outcome; Performance; Persons; Pharmaceutical Preparations; Pharmacoepidemiology; Phenotype; Policy Making; Polypharmacy; Population; Pregnancy; Property; Prospective, cohort study; Randomized; Recommendation; Records; Registries; Reporting; Research; Research Design; Research Project Grants; Review Literature; Risk; Role; Safety; Sampling; Schools; Societies; Symptoms; Systematic Bias; Time; United States Food and Drug Administration; androgenic; cognitive function; cohort; craniofacial; early life exposure; executive function; experience; experimental study; fetal; infancy; maternal serum; multidisciplinary; neurobehavior; neurobehavioral disorder; neurodevelopment; neurodevelopmental effect; neuropsychiatry; offspring; pain reduction; postnatal; pregnant; prenatal; prenatal exposure; prenatal influence; prospective; time interval

Project Summary Acetaminophen (N-acetyl-p-aminophenol or APAP) is recommended as a safe treatment to reduce pain and fever during pregnancy. An estimated 45-65% of pregnant people reported intake of APAP in the U.S., but there has been little data on safety for potential health effects in the prenatally exposed offspring. APAP placental can cross the barrier reaching the fetus which has limited capacity to metabolize the compound in early development. Recent experimental studies demonstrated compelling evidence suggesting APAP can induce anti-androgenic effects potentially affecting fetal brain development. The Society for Maternal-Fetal Medicine and the U.S. Food and Drug Administration have called for a more thorough investigation and better data to guide the safety of APAP use in pregnancy. Our experienced and multidisciplinary team proposes to leverage the rich data collected in the Danish National Birth Cohort (DNBC) and records from the Danish population medical registries to investigate the potential effects of APAP exposures on fetal development. In Aim 1, we will study 64,322 mother- child pairs enrolled in the DNBC and investigate the effects of prenatal exposure to APAP on a wide spectrum of neurodevelopmental outcomes, ascertained at multiple time points from infancy through age 18. Six domains of outcomes will be examined, including milestones in infancy, craniofacial markers, neurobehavioral disorders, motor function, school performance, and mental health. A rich set of confounding factors, including maternal illnesses and familial/genetic risks, will be examined in a robust multi-stage analytical framework. In addition, we will evaluate the effect of post-natal APAP exposure on neurodevelopment (aim 1a), the effect of APAP exposures on childhood ADHD, adjusting for the genetic risk of ADHD (aim 1b), and explore whether APAP exposures affect distinct neuropsychiatric phenotypes and/or behavioral trajectories across childhood and adolescence (aim 1c). In Aim 2, we will investigate the influence of prenatal co-medication exposures with APAP and their impacts on neurodevelopment. We will examine whether medications that co-occur with APAP use during pregnancy confound the associations between APAP exposure and child neurodevelopment. We will also examine the joint effects of co-medications exposures. We will focus on a list of common medications (7 major and 15 subclasses) that impact fetal growth and/or brain development documented in the literature. This timely research project will provide strong and scientifically rigorous data to inform long-term health effects of early life exposure to APAP on child neurodevelopment. This is also the most extensive cohort study investigating maternal polypharmacy exposure effects on offspring neurodevelopment. Our findings will contribute to regulatory recommendations and policymaking decisions for APAP, a widely consumed medication in pregnancy, as well as related co-medication use.

项目摘要 醋氨酚(N-乙酰-对氨基酚或APAP)被推荐为一种安全的治疗方法，以减轻疼痛和 怀孕期间发烧。据估计，在美国有45%-65%的孕妇报告摄入了APAP，但 在产前暴露的后代中，关于潜在健康影响的安全性的数据很少。APAP 胎盘 可以跨过 到达胎儿的屏障，在发育早期代谢化合物的能力有限。 最近的实验研究表明，令人信服的证据表明，APAP可以诱导抗雄激素 可能影响胎儿大脑发育的因素。母胎医学学会与美国食品 和药品监督管理局呼吁进行更彻底的调查和更好的数据来指导 APAP在妊娠中的应用。我们经验丰富的多学科团队建议利用收集到的丰富数据 在丹麦国家出生队列(DNBC)和丹麦人口医疗登记处的记录中 研究APAP暴露对胎儿发育的潜在影响。在目标1中，我们将研究64,322名母亲- 在DNBC登记的儿童对，并调查产前暴露于APAP的广泛影响 从婴儿期到18岁，在多个时间点确定的神经发育结果。 包括婴儿期的里程碑、颅面标志、神经行为障碍、 运动功能、学习成绩和心理健康。一组丰富的混杂因素，包括母体 将在一个强有力的多阶段分析框架中对疾病和家族/遗传风险进行审查。此外，我们 将评估出生后暴露于APAP对神经发育的影响(目标1a)，APAP的影响 儿童ADHD的暴露，调整ADHD的遗传风险(目标1b)，并探索APAP是否 暴露会影响儿童和青少年不同的神经精神表型和/或行为轨迹 青春期(目标1c)。在目标2中，我们将调查产前联合用药暴露对APAP的影响。 以及它们对神经发育的影响。我们将检查与APAP同时发生的药物是否使用 在怀孕期间，APAP暴露与儿童神经发育之间的联系被混淆。我们还将 检查联合用药暴露的联合影响。我们将重点介绍常见药物的清单(7种主要药物 和15个子类)，影响文献中记载的胎儿生长和/或脑发育。这来得正是时候 研究项目将提供强有力和科学严谨的数据，以告知早期生活对长期健康的影响 暴露于APAP对儿童神经发育的影响。这也是最广泛的队列研究调查 母亲接触多种药物对子代神经发育的影响。我们的发现将有助于 APAP是一种广泛使用的妊娠期药物，其监管建议和政策决策 以及相关的联合用药。