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.

项目概要 对乙酰氨基酚（N-乙酰基-对氨基苯酚或 APAP）被推荐作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，美国有 45-65% 的孕妇摄入了 APAP，但也有 关于产前暴露的后代潜在健康影响的安全性数据很少。亚太经合组织 胎盘的 可以跨越 到达胎儿的屏障，在早期发育中代谢该化合物的能力有限。 最近的实验研究证明了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影响。母胎医学和美国食品协会 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安全性 APAP 在怀孕期间的使用。我们经验丰富的多学科团队建议利用收集到的丰富数据 丹麦国家出生队列 (DNBC) 以及丹麦人口医疗登记处的记录 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 儿童配对参加 DNBC，并调查产前接触 APAP 对广泛范围的影响 在从婴儿期到 18 岁的多个时间点确定的神经发育结果。六个领域 将检查结果，包括婴儿期的里程碑、颅面标志物、神经行为障碍、 运动功能、学校表现和心理健康。一系列丰富的混杂因素，包括母亲 疾病和家族/遗传风险，将在强大的多阶段分析框架中进行检查。此外，我们 将评估产后 APAP 暴露对神经发育的影响（目标 1a）、APAP 的影响 儿童 ADHD 的暴露，调整 ADHD 的遗传风险（目标 1b），并探讨 APAP 是否 暴露会影响童年和成年期间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，我们将研究产前联合用药暴露与 APAP 的影响 及其对神经发育的影响。我们将检查是否与 APAP 使用同时发生的药物 怀孕期间的 APAP 暴露与儿童神经发育之间的关联混淆了。我们也会 检查联合用药的联合影响。我们将重点关注常见药物清单（7 种主要药物） 和 15 个亚类），影响文献中记录的胎儿生长和/或大脑发育。这个及时 研究项目将提供强有力且科学严谨的数据，以告知早期生命的长期健康影响 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 母亲多药暴露对后代神经发育的影响。我们的研究结果将有助于 APAP（一种在怀孕期间广泛使用的药物）的监管建议和决策决定， 以及相关的联合用药。