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 建议对乙酰氨基酚（N-乙酰基-P-氨基苯酚或APAP）作为安全治疗，以减轻疼痛和 怀孕期间发烧。估计有45-65％的孕妇报告了美国的APAP摄入量，但那里 在产前暴露的后代中潜在健康影响的安全性数据很少。 APAP 胎盘 可以越过 到达胎儿的障碍，该胎儿在早期发育中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 影响可能影响胎儿脑发育的影响。母亲医学和美国食品协会 药物管理局呼吁进行更彻底的调查和更好的数据，以指导 APAP在怀孕中使用。我们经验丰富的多学科团队建议利用收集的丰富数据 在丹麦国家出生队列（DNBC）中，以及丹麦人口医疗注册表的记录 研究APAP暴露对胎儿发育的潜在影响。在AIM 1中，我们将研究64,322个母亲 儿童成对参加了DNBC，并研究了产前暴露于APAP对广泛范围的影响 神经发育结果，从婴儿期到18岁的多个时间点确定。六个领域 将检查结果，包括婴儿期的里程碑，颅面标记，神经行为疾病， 运动功能，学校表现和心理健康。包括母亲在内的一系列混杂因素 疾病和家族/遗传风险将在强大的多阶段分析框架中检查。另外，我们 将评估产后APAP暴露对神经发育的影响（AIM 1A），APAP的影响 暴露于儿童多动症，调整ADHD的遗传风险（AIM 1B），并探索APAP是否是否 暴露会影响各个童年和/或行为轨迹的独特神经精神病学表型和/或 青春期（AIM 1C）。在AIM 2中，我们将研究与APAP的产前共同用途暴露的影响 及其对神经发育的影响。我们将检查与APAP共同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关联。我们也会 检查联合接触的联合影响。我们将专注于普通药物清单（7个专业 和15个子类）影响文献中记录的胎儿生长和/或大脑发育。这个及时 研究项目将提供强大且科学严格的数据，以告知早期生活的长期健康影响 暴露于儿童神经发育中的APAP。这也是调查最广泛的队列研究 母体多药对后代神经发育的影响。我们的发现将有助于 APAP的监管建议和决策决定，这是一种在怀孕中广泛消费的药物， 以及相关的共同用途。