Systematic Review and Meta-Analysis: Acetaminophen Use During Pregnancy and the Risk of Neurodevelopmental Disorders in Childhood - 01/11/25

Doi : 10.1016/j.jaac.2025.09.031

Anick Bérard, PhD ^a,^b,^⁎ , Judith Cottin, PharmD ^c, Lisiane F. Leal, ScD ^b, Cyndie Picot, PhD ^c, Justine Pleau, MA ^a,^b, Jan M. Friedman, MD, PhD ^d, Per Damkier, PhD ^e,^f, Michel Cucherat, MD, PhD ^c, Sura Alwan, PhD ^d, Lucie Jurek, MD, PhD ^g,^h, Louise M. Winn, PhD ⁱ, Bruce C. Carleton, PharmD ^d,^j, Andréa D. Bertoldi, ScD ^k, Sonia M. Grandi, PhD ^l,^m, Reem Masarwa, PharmD, PhD ⁿ, Philippe Dodin, MA ^o, Michael Ceulemans, PharmD, PhD ^p,^q,^r, Robert W. Platt, PhD ^s, Mikail Nourredine, MD, MSc ^c,^t, Erika Björkström Gram, MD ^f, Areti Angeliki Veroniki, PhD ^m,^u, Jérôme Massardier, MD, MSc ^c, Andrea C. Tricco, PhD, MSc ^m,^u
^a University of Montreal, Montréal, Quebec, Canada
^b Centre de Recherche Azrieli du CHU Sainte-Justine, Montréal, Quebec, Canada
^c Hospices Civils de Lyon, Lyon, France
^d University of British Columbia, Vancouver, British Columbia, Canada
^e Odense University Hospital, Odense, Denmark
^f University of Southern Denmark, Odense, Denmark
^g CH Le Vinatier, Bron, France
^h Université Claude Bernard Lyon 1, Lyon, France
ⁱ Queen's University, Kingston, Ontario, Canada
^j BC Children’s Hospital and Research Institute, Vancouver, British Columbia, Canada
^k Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
^l The Hospital for Sick Children, Toronto, Ontario, Canada
^m University of Toronto, Toronto, Ontario, Canada
ⁿ PPD (Part of Thermo-Fisher Scientific), Saint-Laurent, Quebec, Canada
^o CHU Sainte-Justine, Montréal, Quebec, Canada
^p KU Leuven, Leuven, Belgium
^q Research Foundation Flanders (FWO), Brussels, Belgium
^r KU Leuven Child and Youth Institute, Leuven, Belgium
^s McGill University, Montréal, Quebec, Canada
^t Université Claude Bernard Lyon 1, Lyon, France
^u St. Michael’s Hospital, Toronto, Ontario, Canada

^∗Correspondence to Anick Bérard, PhD, 3175 Chem. de la Côte-Sainte-Catherine, Montréal, QC H3T 1C5, Canada3175 Chem. de la Côte-Sainte-CatherineMontréalQC H3T 1C5Canada

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Saturday 01 November 2025

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; CRD42024566964; osfstorage

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.

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Key words : neurodevelopmental disorders, attention deficit disorder with hyperactivity, autism spectrum disorder, acetaminophen, systematic review

Plan

Method

Data Sources and Search Strategy

Eligibility Criteria

Study Selection

Data Extraction and Quality Assessment

Comparison With Existing Literature

CRediT authorship contribution statement

	This research was funded by the Center for Truth in Science (No award number to Anick Bérard). The funder was not involved in the design, analyses, and interpretation of findings.
	A summary of the results of this study is published online as an infographic for lay public summarizing the results is published online in the website: les-effets-de-lacetaminophene-pendant-la-grossesse/.
	This study abstract was orally presented at 2025 Society of Toxicology meeting; March 19th, 2025; Orlando, Florida.
	Data Sharing: This systematic review does not include original data. Data were extracted from the literature and are publicly available. Any request can be made directly to the corresponding author.
	Anick Bérard, Michel Cucherat, Robert W. Platt, and Areti-Angeliki Veroniki served as the statistical experts for this research.
	Disclosure: Bruce Carleton is a Rare Disease Foundation Board of Directors (nonprofit) and has received grant funds from the following federal and provincial agencies: CIHR, Genome Canada, BC PHSA, BC Children's Hospital, Health Canada, Genome, BC. He has served as a consultant to Dynacare and Neopharm Diagnostic and Analytical Laboratories on pharmacogenetic testing, unrelated to the current project. Robert W. Platt has served as a consultant to Merck on various topics unrelated to current project. He is a member of study advisory committee of Pfizer and holds the Albert Boehringer I Chair in pharmacoepidemiology from Boehringer Ingelheim. Anick Bérard, Judith Cottin, Lisiane F. Leal, Cyndie Picot, Justine Pleau, Jan M. Friedman, Per Damkier, Michel Cucherat, Sura Alwan, Lucie Jurek, Louise M. Winn, Andréa D. Bertoldi, Sonia M. Grandi, Reem Masarwa, Philippe Dodin, Michael Ceulemans, Mikail Nourredine, Erika Björkström Gram, Areti Angeliki Veroniki, Jérôme Massardier, and Andrea C. Tricco have reported no biomedical financial interests or potential conflicts of interest.