Association of Prenatal Acetaminophen Exposure Measured in Meconium With Risk of Attention-Deficit/Hyperactivity Disorder Mediated by Frontoparietal Network Brain Connectivity
Association of Prenatal Acetaminophen Exposure Measured in Meconium With Risk of Attention-Deficit/Hyperactivity Disorder Mediated by Frontoparietal Network Brain Connectivity
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DOI：
10.1001/jamapediatrics.2020.3080
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发表时间：
2020-09-28
期刊：
影响因子：
26.1
通讯作者：
Baccarelli, Andrea A.
中科院分区：
文献类型：
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作者：
Baker, Brennan H.;Lugo-Candelas, Claudia;Baccarelli, Andrea A.
重要性尽管有证据表明产前对乙酰氨基酚暴露与后代注意力缺陷/多动障碍（ADHD）之间存在关联，但该药物在妊娠期间并不禁忌，可能是因为之前的研究依赖于母亲的自我报告，未能量化对乙酰氨基酚的剂量，目的探讨胎粪中测定的产前对乙酰氨基酚暴露与妊娠结局之间的关系。（以下称为胎粪对乙酰氨基酚）和ADHD在6至7岁儿童中的作用，沿着通过功能性脑连接进行调解的潜力。设计、设置和参与者这项来自加拿大魁北克Sherbrooke的Sherbrooke大学中心医院的前瞻性出生队列研究包括394名合格儿童，其中345人在分娩时采集了胎粪样本，并提供了ADHD诊断信息。从2007年9月25日至2009年9月10日，母亲们在第一次产前检查或分娩时登记，并在孩子6至7岁时进行随访。当儿童年龄在9至11岁时，通过磁共振成像评估静息态大脑连接。本研究的数据收集于2007年9月25日至2020年1月18日，分析时间为2019年1月7日至2020年1月22日。暴露胎粪中测定的对乙酰氨基酚水平。主要结果和指标ADHD的医生诊断在随访时确定，当儿童年龄为6至7岁或从医疗记录。静息状态下的大脑连接进行了评估，磁共振成像，注意力问题和多动症进行了评估与儿童行为评估系统家长报告量表。胎粪对乙酰氨基酚水平和结果之间的关系通过线性和逻辑回归进行估计，对治疗的逆概率进行加权，以解释潜在的混杂因素。采用因果中介分析法，通过静息态脑连接检测产前对乙酰氨基酚暴露与多动之间关联的中介作用（男生177人[51.3%];平均[SD]年龄6.58 [0.54]岁），在199例胎粪样本中检测到对乙酰氨基酚（57.7%），33例儿童（9.6%）被诊断为ADHD。与未检测到对乙酰氨基酚相比，胎粪中检测到对乙酰氨基酚与ADHD的几率增加相关（比值比[OR]，2.43; 95%CI，1.41-4.21）。检测到剂量反应相关性;暴露量每增加一倍，ADHD的几率增加10%（OR，1.10; 95%CI，1.02-1.19）。在胎粪中检测到对乙酰氨基酚的儿童表现出额顶叶和默认模式网络节点与感觉运动皮质簇之间的负连接增加，这间接影响了儿童多动症的增加（百分之十四;结论和相关性与大量其他显示与产前对乙酰氨基酚暴露相关的不良神经发育的队列研究一起，这项工作建议在怀孕期间服用醋氨酚时应谨慎。研究孕妇的替代疼痛管理策略可能是有益的。
IMPORTANCE Despite evidence of an association between prenatal acetaminophen exposure and attention-deficit/hyperactivity disorder (ADHD) in offspring, the drug is not contraindicated during pregnancy, possibly because prior studies have relied on maternal self-report, failed to quantify acetaminophen dose, and lacked mechanistic insight.OBJECTIVE To examine the association between prenatal acetaminophen exposure measured in meconium (hereinafter referred to as meconium acetaminophen) and ADHD in children aged 6 to 7 years, along with the potential for mediation by functional brain connectivity.DESIGN, SETTING, AND PARTICIPANTS This prospective birth cohort study from the Centre Hospitalier Universite de Sherbrooke in Sherbrooke, Quebec, Canada, included 394 eligible children, of whom 345 had meconium samples collected at delivery and information on ADHD diagnosis. Mothers were enrolled from September 25, 2007, to September 10, 2009, at their first prenatal care visit or delivery and were followed up when children were aged 6 to 7 years. When children were aged 9 to 11 years, resting-state brain connectivity was assessed with magnetic resonance imaging. Data for the present study were collected from September 25, 2007, to January 18, 2020, and analyzed from January 7, 2019, to January 22, 2020.EXPOSURES Acetaminophen levels measured in meconium.MAIN OUTCOMES AND MEASURES Physician diagnosis of ADHD was determined at follow-up when children were aged 6 to 7 years or from medical records. Resting-state brain connectivity was assessed with magnetic resonance imaging; attention problems and hyperactivity were assessed with the Behavioral Assessment System for Children Parent Report Scale. Associations between meconium acetaminophen levels and outcomes were estimated with linear and logistic regressions weighted on the inverse probability of treatment to account for potential confounders. Causal mediation analysis was used to test for mediation of the association between prenatal acetaminophen exposure and hyperactivity by resting-state brain connectivity.RESULTS Among the 345 children included in the analysis (177 boys [51.3%]; mean [SD] age, 6.58 [0.54] years), acetaminophen was detected in 199 meconium samples (57.7%), and ADHD was diagnosed in 33 children (9.6%). Compared with no acetaminophen, detection of acetaminophen in meconium was associated with increased odds of ADHD (odds ratio [OR],2.43; 95% CI, 1.41-4.21). A dose-response association was detected; each doubling of exposure increased the odds of ADHD by 10% (OR,1.10; 95% CI, 1.02-1.19). Children with acetaminophen detected in meconium showed increased negative connectivity between frontoparietal and default mode network nodes to clusters in the sensorimotor cortices, which mediated an indirect effect on increased child hyperactivity (14%; 95% CI, 1%-26%).CONCLUSIONS AND RELEVANCE Together with the multitude of other cohort studies showing adverse neurodevelopment associated with prenatal acetaminophen exposure, this work suggests caution should be used in administering acetaminophen during pregnancy. Research into alternative pain management strategies for pregnant women could be beneficial.