Systematic Review and Meta-Analysis: Acetaminophen Use During Pregnancy and the Risk of Neurodevelopmental Disorders in Childhood

Abstract

Objective: To explore the association between acetaminophen use during pregnancy and the risk of neurodevelopmental disorders (NDDs) in children.

Method: We conducted a comprehensive search of major bibliographic databases and gray literature to identify human studies evaluating the association between prenatal acetaminophen exposure and the risk of NDDs in offspring. Pooled odds ratios (OR_pooled) with 95% confidence intervals were calculated in random-effects meta-analysis by type of NDD. We performed sensitivity analysis including a bounding method (E-value) and probabilistic bias analysis.

Results: Of 2,002 studies retrieved, 16 studies met eligibility criteria, and were included in the meta-analysis. The majority of studies assessing the risk of NDDs associated with gestational exposure to acetaminophen were on attention-deficit disorders with or without hyperactivity (ADHD, 6 studies, N = 2,668,689), followed by language disorders (5 studies, N = 31,104) and psychomotor developmental disorders/delay (3 studies, N = 30,824). Acetaminophen use during pregnancy was associated with an increased risk of ADHD, when ADHD was assessed with a physician-based diagnosis or psychometric tests (OR_pooled = 1.17, 95% CI = 1.08-1.27). The estimated E-value of 1.61 suggests that the observed association may be partly due to unmeasured confounders. Non-differential exposure misclassification biased results toward the null and differential misclassification potentially biased them away from the null. Similar results were observed when assessing outcome misclassification. Acetaminophen use during pregnancy was not associated with the risk of autism spectrum disorder (ASD) when considering physician-based diagnoses (OR = 1.10, 95% CI = 0.98, 1.24; 2 studies; ASD 69,611, n exposed 222,096, E-value = 1.43). No significant increase in the risk of other NDDs was observed.

Conclusion: Gestational exposure to acetaminophen was associated with a small increased risk of ADHD, which was attenuated in sensitivity analyses. Further studies are needed to examine this association more robustly.

Study registration information: Acetaminophen use during pregnancy and the risk of neurodevelopmental disorders (NDDs) in childhood: A Systematic Review and Meta-Analysis Protocol; https://www.crd.york.ac.uk/PROSPERO/view/CRD42024566964; https://osf.io/7rcqe DIVERSITY & INCLUSION STATEMENT: One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list.

Keywords: acetaminophen; attention deficit disorder with hyperactivity; autism spectrum disorder; neurodevelopmental disorders; systematic review.