Testing Claimed Associations of Prenatal Acetaminophen with Neurodevelopmental Disorders: Re-analysis Using Bias-Correction Methods
- 1Harvard Medical School
Abstract
ImportanceA 2025 systematic review concluded there was "strong evidence of a likely relationship" between prenatal acetaminophen exposure and neurodevelopmental disorders (NDDs), directly informing a federal health advisory, based on qualitative synthesis without quantitative pooling or bias correction.
ObjectiveTo determine, via meta-analysis, whether the association claimed between prenatal acetaminophen exposure and attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and other NDDs survives publication-bias correction and sensitivity methods applied to the same underlying studies.
Data SourcesThe 46 studies identified in a 2025 Navigation Guide systematic review, based on a PubMed search (through February 25, 2025) supplemented by Web of Science and Google Scholar searches that yielded no additional studies; no additional search was performed for this reanalysis.
Study SelectionOf the 46 studies, 24 (52%) reported a ratio measure (hazard ratio, odds ratio, relative risk, or incidence rate ratio) and were retained; studies reporting only continuous outcomes were excluded.
Data Extraction and SynthesisEstimates were collapsed to 1 per study, outcome group, and design to correct a unit-of-analysis error in the original review. Random-effects meta-analysis was used. We assessed eight bias-correction methods, a credibility ceiling analysis, and 5 quality-filtered subsets, then repeated the analyses after harmonizing odds and hazard ratios onto a common risk ratio scale.
Main Outcomes and MeasuresPooled ratio and 95% CI for ADHD, ASD, and other NDDs under each method, before and after harmonization.
ResultsAmong 30 estimates from 24 studies (sample sizes, 307-2,480,797), the ASD association lost statistical significance (pooled ratio, 1.08; 95% CI, 0.97-1.19) from corrected weighting alone, before any further bias correction. The ADHD association remained positive under most methods but lost statistical significance under a 15% credibility ceiling. The other NDD association was not robust under bias correction, reversing sign under 1 method and failing a test for evidential value (p-curve, P = .71).
Conclusions and RelevanceThe claim of "strong evidence" for an acetaminophen-NDD association was not supported by meta-analysis of the same studies. A modest, method-dependent ADHD signal persisted with most methods, but the ASD and other-NDD associations did not survive bias-correction and sensitivity methods.
Key Points
QuestionDoes the "strong evidence" verdict linking prenatal acetaminophen exposure to attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) survive standard meta-analytic and bias-correction methods applied to the same underlying studies?
FindingsIn this meta-analysis of 30 study-level estimates from a 2025 systematic review,1 the ASD association was not significant after corrected study weighting alone, and the association with other neurodevelopmental disorders was not robust under scrutiny. The ADHD association survived most, but not all, of eight publication-bias-correction methods and was not statistically significant under a modest 15% credibility ceiling.
MeaningThese findings suggest that the original reviews claim of strong evidence linking prenatal acetaminophen use to neurodevelopmental disorders is not supported by quantitative reanalysis of the same underlying studies.
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BibTeX
@misc{grover2026testing,
title = {{Testing Claimed Associations of Prenatal Acetaminophen with Neurodevelopmental Disorders: Re-analysis Using Bias-Correction Methods}},
author = {A. Grover and J. Reis-Pardal and R. J. Ellis and J. Ioannidis and C. J. Patel},
howpublished = {medRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.28.26361666},
url = {https://www.medrxiv.org/content/10.64898/2026.08.28.26361666v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Testing Claimed Associations of Prenatal Acetaminophen with Neurodevelopmental Disorders: Re-analysis Using Bias-Correction Methods
AU - A. Grover
AU - J. Reis-Pardal
AU - R. J. Ellis
AU - J. Ioannidis
AU - C. J. Patel
PY - 2026
DA - 2026/08/28
PB - medRxiv
DO - 10.64898/2026.08.28.26361666
UR - https://www.medrxiv.org/content/10.64898/2026.08.28.26361666v1
AB - ImportanceA 2025 systematic review concluded there was "strong evidence of a likely relationship" between prenatal acetaminophen exposure and neurodevelopmental disorders (NDDs), directly informing a federal health advisory, based on qualitative synthesis without quantitative pooling or bias correction. ObjectiveTo determine, via meta-analysis, whether the association claimed between prenatal acetaminophen exposure and attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and other NDDs survives publication-bias correction and sensitivity methods applied to the same underlying studies. Data SourcesThe 46 studies identified in a 2025 Navigation Guide systematic review, based on a PubMed search (through February 25, 2025) supplemented by Web of Science and Google Scholar searches that yielded no additional studies; no additional search was performed for this reanalysis. Study SelectionOf the 46 studies, 24 (52%) reported a ratio measure (hazard ratio, odds ratio, relative risk, or incidence rate ratio) and were retained; studies reporting only continuous outcomes were excluded. Data Extraction and SynthesisEstimates were collapsed to 1 per study, outcome group, and design to correct a unit-of-analysis error in the original review. Random-effects meta-analysis was used. We assessed eight bias-correction methods, a credibility ceiling analysis, and 5 quality-filtered subsets, then repeated the analyses after harmonizing odds and hazard ratios onto a common risk ratio scale. Main Outcomes and MeasuresPooled ratio and 95% CI for ADHD, ASD, and other NDDs under each method, before and after harmonization. ResultsAmong 30 estimates from 24 studies (sample sizes, 307-2,480,797), the ASD association lost statistical significance (pooled ratio, 1.08; 95% CI, 0.97-1.19) from corrected weighting alone, before any further bias correction. The ADHD association remained positive under most methods but lost statistical significance under a 15% credibility ceiling. The other NDD association was not robust under bias correction, reversing sign under 1 method and failing a test for evidential value (p-curve, P = .71). Conclusions and RelevanceThe claim of "strong evidence" for an acetaminophen-NDD association was not supported by meta-analysis of the same studies. A modest, method-dependent ADHD signal persisted with most methods, but the ASD and other-NDD associations did not survive bias-correction and sensitivity methods. Key Points QuestionDoes the "strong evidence" verdict linking prenatal acetaminophen exposure to attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) survive standard meta-analytic and bias-correction methods applied to the same underlying studies? FindingsIn this meta-analysis of 30 study-level estimates from a 2025 systematic review,1 the ASD association was not significant after corrected study weighting alone, and the association with other neurodevelopmental disorders was not robust under scrutiny. The ADHD association survived most, but not all, of eight publication-bias-correction methods and was not statistically significant under a modest 15% credibility ceiling. MeaningThese findings suggest that the original reviews claim of strong evidence linking prenatal acetaminophen use to neurodevelopmental disorders is not supported by quantitative reanalysis of the same underlying studies.
ER -