Acetaminophen Use During Pregnancy and Neurodevelopmental Disorders

By Ahizechukwu C. Eke, MD, PhD, MPH

Synopsis: The synthesized evidence on prenatal acetaminophen exposure and neurodevelopmental outcomes highlights modest and inconsistent associations and emphasizes that causality remains unproven because of confounding and measurement biases. The authors conclude that, consistent with American College of Obstetricians and Gynecologists and Society for Maternal-Fetal Medicine guidance, acetaminophen remains appropriate in pregnancy when clinically indicated.

Source: Prada D, Ritz B, Bauer AZ, Baccarelli AA. Evaluation of the evidence on acetaminophen use and neurodevelopmental disorders using the Navigation Guide methodology. Environ Health. 2025;24(1):56.

Autism spectrum disorder (ASD) now affects approximately one in 31 U.S. 8-year-olds (3.2%), according to the 2022 Centers for Disease Control and Prevention (CDC) Autism and Developmental Disabilities Monitoring (ADDM) Network report, with a male-to-female ratio of roughly 3.4:1.¹

The etiology of ASD and related neurodevelopmental disorders (NDDs) is complex and multifactorial.² Highly heritable polygenic risk interacts with prenatal and perinatal environmental factors, such as maternal immune activation, metabolic diseases, infection, inflammation, or toxicant exposure, to influence early brain development.^2-4 The developing fetal brain demonstrates exquisite vulnerability to perturbations in oxidative balance, endocrine signaling, and immune regulation.^5,6 Mechanistic studies suggest that disruptions in neuroimmune cross-talk, mitochondrial metabolism, and synaptic pruning may converge to produce long-term neurobehavioral sequelae.^7,8 Thus, prenatal exposures that modulate these pathways, whether biologic, pharmacologic, or toxicologic, have justifiably drawn scrutiny as potential contributors to NDD risk.

Acetaminophen remains the most widely used analgesic-antipyretic in pregnancy, with 60% to 70% of U.S. women reporting some prenatal exposure.⁹ Multiple prospective cohorts have documented small but statistically significant associations between maternal acetaminophen use and subsequent attention-deficit or hyperactivity phenotypes and, more variably, ASD-related outcomes.^10-14 Several analyses report dose-response gradients, particularly with repeated or long-term use.^14-16

Preclinical models report some biological associations relating to acetaminophen’s reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), triggering oxidative stress, depleting glutathione in high doses, and altering endocannabinoid or serotonergic signaling critical to neuronal differentiation.^17-19 Yet, major interpretive caveats persist. Confounding by indication (underlying fever, infection, or pain) is incompletely controlled, exposure misclassification from recall bias or intermittent dosing may distort risk estimates, and outcome heterogeneity across eras and instruments limits synthesis. Recognizing these uncertainties, Prada and colleagues undertook the study evaluation of the evidence on acetaminophen use and neurodevelopmental disorders using the Navigation Guide methodology to rigorously appraise the available body of literature.²⁰

Prada et al applied the Navigation Guide systematic review framework, originally developed for environmental health, to synthesize human epidemiologic evidence on prenatal acetaminophen and NDDs.²⁰ Their research question defined the population as pregnant women, the exposure as prenatal acetaminophen (by self-report, medical records, or biomarkers), the comparator as no exposure or alternate medication, and the outcomes as ASD, attention-deficit hyperactivity disorder (ADHD), and related developmental domains. Inclusion criteria encompassed original human cohort or case-control studies with clearly ascertained prenatal exposure and validated child outcomes. Exclusions were postnatal-only exposure studies, in-vitro or animal experiments (reserved for secondary analysis), and duplicate reports from the same cohort, retaining the most complete publication. Most included cohorts were large national registries or longitudinal birth cohorts capable of detecting small effect sizes.

The primary outcomes were diagnoses or validated measures of ASD and ADHD in offspring. Secondary outcomes included related constructs, including attention, executive function, hyperactivity, and other NDD phenotypes. Heterogeneity in exposure ascertainment (self-report vs. biomarker) and confounder adjustment precluded reliable quantitative pooling. The team, therefore, prespecified a qualitative synthesis, emphasizing study quality over numerical aggregation.

Using a Grading of Recommendations, Assessment, Development, and Evaluation (GRADE)-like schema, each study was evaluated across selection bias, exposure/outcome assessment, confounding, missing data, and selective reporting. Sensitivity analyses sequentially excluded lower-quality studies and tested the stability of conclusions. Finally, a triangulation approach integrated evidence from observational, biomarker, and mechanistic domains, reflecting the Navigation Guide principle that converges across distinct bias structures.

Among 46 eligible human studies (approximately 20 examining ADHD, eight focusing on ASD, and 18 addressing other developmental outcomes), most were prospective in design. The majority reported positive associations between prenatal acetaminophen exposure and at least one neurodevelopmental endpoint. When quantitative estimates were extractable, effect sizes were modest. For example, a Taiwanese nationwide case-control study found an odds ratio (OR) of 1.20 (95% confidence interval [CI], 1.01-1.42) for any-trimester exposure and ADHD, a European multi-cohort pooled analysis yielded an OR of 1.21 (95% CI, 1.07-1.36) for ADHD-related behaviors, and in the Norwegian Mother and Child Cohort (MoBa), ≥ 29 days of exposure was associated with an adjusted hazard ratio (aHR) of 2.02 (95% CI, 1.17-3.25) for hyperkinetic disorder, while shorter courses were near null.^15,21,22

Sibling-comparison re-analyses typically attenuated associations toward the null (e.g., aHR 1.06 [95% CI, 0.51-2.05]). Biomarker studies using meconium or cord-blood metabolites demonstrated dose-response relationships in some datasets, although analytical variability remained high. Given methodological heterogeneity, the authors appropriately refrained from pooled meta-analysis, instead grading the overall human evidence as limited but suggestive for a causal link.

Commentary

Taken together, the literature indicates a potential association between prenatal acetaminophen exposure and neurodevelopmental outcomes. However, findings for core ASD phenotypes are less consistent and of smaller magnitude. Effect estimates cluster around relative risks of 1.1 to 1.3, values readily explainable by residual confounding, measurement error, or selective reporting.

Prospective cohort studies remain the cornerstone for investigating medication safety in pregnancy because they capture temporality and can adjust for numerous covariates. Yet, they are inherently limited in controlling unmeasured confounding. The Navigation Guide analysis by Prada and colleagues highlights this tension.²⁰ Although most cohorts demonstrate small positive associations, consistent directionality alone cannot confirm causality. Confounding by indication (for fever, pain, or infection) may generate spurious associations. Furthermore, exposure misclassification as the result of acetaminophen’s short half-life blurs dose-response, and outcome heterogeneity ranging from registry diagnoses to parental questionnaires adds noise. Moreover, selective publication and analytic flexibility inflate false-positive rates.

When investigators re-analyzed data using family-based designs (e.g., sibling comparisons) or genetically informed methods, associations weakened substantially, implying that shared familial or genetic liability may account for at least part of the observed signals in these studies.^12,15,23,24 Nonetheless, such within-family designs bring their own biases (e.g., collider bias, reduced generalizability). Prada et al’s emphasis on triangulation, comparing results across designs with distinct error structures, represents a sophisticated methodological evolution, advocating for coherence across evidence streams rather than overreliance on any single analytic paradigm, but its practical implementation can be constrained by several factors, including the interpretive framework across study designs.

Emerging biomarker studies using cord blood, maternal plasma, or meconium improve exposure classification and may detect cumulative or late-pregnancy use.^25-27 Some report monotonic relationships between acetaminophen metabolites and ADHD-related behaviors, bolstering biological gradient criteria. However, acetaminophen’s two- to four-hour half-life, rapid conjugation, and reliance on a single biological sample can misclassify intermittent use. Sibling designs elegantly control for stable familial factors, yet they may over-adjust by conditioning on factors (e.g., family size, birth spacing) linked to both exposure and outcome, and often they suffer low statistical power because only families with multiple children contribute informative contrasts.

Genetic approaches, including polygenic risk scoring and Mendelian randomization, help disentangle inherited liability from environmental exposure, but they depend on the completeness of variant discovery and may misattribute gene-environment correlations (e.g., parental neurobehavioral traits influencing both medication use and child outcome). Ultimately, no single design is definitive. Convergence of findings across these diverse methodologies, each with non-overlapping biases, offers a path toward causal understanding.

In summary, the jury remains out regarding whether prenatal acetaminophen causes neurodevelopmental disorders. The preponderance of evidence does not support causal links, since causal inference is constrained by several factors, including residual confounding, exposure misclassification, and heterogeneity in outcome measurement. Interestingly, randomized controlled trials are neither feasible nor ethical for this question, leaving the field reliant on increasingly sophisticated observational study designs to inch closer to the truth.

The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine recommendations endorse acetaminophen as a preferred first-line analgesic-antipyretic in pregnancy while emphasizing shared decision-making and ongoing surveillance for emerging data.^28,29 As with most medication-safety debates in obstetrics, nuance, not alarmism, best serves both science and public health.

Ahizechukwu C. Eke, MD, PhD, MPH, is Associate Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore.

References

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20. Prada D, Ritz B, Bauer AZ, Baccarelli AA. Evaluation of the evidence on acetaminophen use and neurodevelopmental disorders using the Navigation Guide methodology. Environ Health. 2025;24(1):56.

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28. American College of Obstetricians and Gynecologists. ACOG affirms safety and benefits of acetaminophen during pregnancy. Published Sept. 22, 2025. https://www.acog.org/news/news-releases/2025/09/acog-affirms-safety-benefits-acetaminophen-pregnancy

29. Society for Maternal-Fetal Medicine. SMFM statement on acetaminophen use during pregnancy and autism. Published Sept. 5, 2025. https://www.smfm.org/news/smfm-statement-on-acetaminophen-use-during-pregnancy-and-autism