ImportanceSeveral studies suggest that acetaminophen (paracetamol) use during pregnancy may increase risk of neurodevelopmental disorders in children. If true, this would have substantial implications for management of pain and fever during pregnancy.ObjectiveTo examine the associations of acetaminophen use during pregnancy with children’s risk of autism, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability.Design, Setting, and ParticipantsThis nationwide cohort study with sibling control analysis included a population-based sample of 2 480 797 children born in 1995 to 2019 in Sweden, with follow-up through December 31, 2021.ExposureUse of acetaminophen during pregnancy prospectively recorded from antenatal and prescription records.Main Outcomes and MeasuresAutism, ADHD, and intellectual disability based on International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes in health registers.ResultsIn total, 185 909 children (7.49%) were exposed to acetaminophen during pregnancy. Crude absolute risks at 10 years of age for those not exposed vs those exposed to acetaminophen were 1.33% vs 1.53% for autism, 2.46% vs 2.87% for ADHD, and 0.70% vs 0.82% for intellectual disability. In models without sibling control, ever-use vs no use of acetaminophen during pregnancy was associated with marginally increased risk of autism (hazard ratio [HR], 1.05 [95% CI, 1.02-1.08]; risk difference [RD] at 10 years of age, 0.09% [95% CI, −0.01% to 0.20%]), ADHD (HR, 1.07 [95% CI, 1.05-1.10]; RD, 0.21% [95% CI, 0.08%-0.34%]), and intellectual disability (HR, 1.05 [95% CI, 1.00-1.10]; RD, 0.04% [95% CI, −0.04% to 0.12%]). To address unobserved confounding, matched full sibling pairs were also analyzed. Sibling control analyses found no evidence that acetaminophen use during pregnancy was associated with autism (HR, 0.98 [95% CI, 0.93-1.04]; RD, 0.02% [95% CI, −0.14% to 0.18%]), ADHD (HR, 0.98 [95% CI, 0.94-1.02]; RD, −0.02% [95% CI, −0.21% to 0.15%]), or intellectual disability (HR, 1.01 [95% CI, 0.92-1.10]; RD, 0% [95% CI, −0.10% to 0.13%]). Similarly, there was no evidence of a dose-response pattern in sibling control analyses. For example, for autism, compared with no use of acetaminophen, persons with low (<25th percentile), medium (25th-75th percentile), and high (>75th percentile) mean daily acetaminophen use had HRs of 0.85, 0.96, and 0.88, respectively.Conclusions and RelevanceAcetaminophen use during pregnancy was not associated with children’s risk of autism, ADHD, or intellectual disability in sibling control analysis. This suggests that associations observed in other models may have been attributable to familial confounding.

中文翻译：

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怀孕期间使用对乙酰氨基酚与儿童患自闭症、多动症和智力障碍的风险

重要性多项研究表明，怀孕期间使用对乙酰氨基酚（扑热息痛）可能会增加儿童神经发育障碍的风险。如果属实，这将对怀孕期间疼痛和发烧的管理产生重大影响。目的检查怀孕期间使用对乙酰氨基酚与儿童患自闭症、注意力缺陷/多动障碍 (ADHD) 和智力障碍的风险之间的关系。设计、设置、这项全国性队列研究采用兄弟姐妹对照分析，包括 1995 年至 2019 年出生的 2 480 797 名瑞典儿童的人群样本，随访至 2021 年 12 月 31 日。 暴露根据产前和处方记录前瞻性记录怀孕期间对乙酰氨基酚的使用.主要成果和措施基于自闭症、多动症和智力障碍国际疾病分类，第九修订版和国际疾病分类，第十修订版结果总共有 185 909 名儿童 (7.49%) 在怀孕期间接触了对乙酰氨基酚。未接触对乙酰氨基酚的儿童与接触对乙酰氨基酚的儿童在 10 岁时患自闭症的粗绝对风险分别为 1.33% 和 1.53%，患 ADHD 的风险分别为 2.46% 和 2.87%，患智力障碍的风险分别为 0.70% 和 0.82%。在没有兄弟姐妹对照的模型中，怀孕期间使用对乙酰氨基酚与不使用对乙酰氨基酚与自闭症风险略有增加相关（风险比 [HR]，1.05 [95% CI，1.02-1.08]；10 年风险差异 [RD]年龄，0.09% [95% CI，-0.01% 至 0.20%]），ADHD（HR，1.07 [95% CI，1.05-1.10]；RD，0.21% [95% CI，0.08%-0.34%]）和智力障碍（HR，1.05 [95% CI，1.00-1.10]；RD，0.04% [95% CI，-0.04% 至 0.12%]）。为了解决未观察到的混杂问题，还分析了匹配的完整兄弟姐妹对。兄弟姐妹对照分析发现，没有证据表明怀孕期间使用对乙酰氨基酚与自闭症（HR，0.98 [95% CI，0.93-1.04]；RD，0.02% [95% CI，-0.14% 至 0.18%]）、注意力缺陷多动症（HR ，0.98 [95% CI，0.94-1.02]；RD，-0.02% [95% CI，-0.21% 至 0.15%]），或智力障碍（HR，1.01 [95% CI，0.92-1.10]；RD， 0% [95% CI, −0.10% 至 0.13%]）。同样，在同胞对照分析中没有证据表明存在剂量反应模式。例如，对于自闭症患者，与不使用对乙酰氨基酚相比，每日平均使用对乙酰氨基酚低（<25%）、中（25-75%）和高（>75%）的人的 HR 为分别为 0.85、0.96 和 0.88。 结论和相关性 在兄弟姐妹对照分析中，怀孕期间使用对乙酰氨基酚与儿童患自闭症、多动症或智力障碍的风险无关。这表明在其他模型中观察到的关联可能可归因于家族混杂因素。