Highlight
– An umbrella review of nine systematic reviews (40 primary studies) found possible associations between maternal paracetamol use and autism or ADHD in offspring, but overall confidence in the evidence was low to critically low.
– High study overlap, residual confounding (especially by indication and familial factors), and methodological limitations weaken causal inference.
– Sibling-controlled analyses in the few studies that used them largely attenuated the observed associations to null, suggesting family-level confounding.
– Clinical implication: paracetamol remains an option in pregnancy for indicated pain or fever, using the lowest effective dose and duration; unnecessary chronic use should be avoided while better evidence is generated.
Background
Paracetamol (acetaminophen) is the most commonly used analgesic and antipyretic in pregnancy worldwide because of perceived safety compared with alternatives. Over the last decade, several observational studies have reported associations between maternal paracetamol use during pregnancy and offspring neurodevelopmental outcomes, notably autism spectrum disorder (autism) and attention deficit/hyperactivity disorder (ADHD). These findings prompted multiple systematic reviews and meta-analyses and generated public anxiety, clinical uncertainty, and research efforts to clarify causality.
Study design and scope of the umbrella review
The article by Sheikh and colleagues (BMJ, 2025) is an umbrella review that synthesised systematic reviews examining maternal paracetamol use during pregnancy and subsequent diagnosis of autism or ADHD in offspring. The authors searched major bibliographic databases and grey literature through 30 September 2025 and included systematic reviews of randomised trials and observational designs (cohort, case-control, cross-sectional studies) that reported relevant neurodevelopmental outcomes.
Key methodological steps included extracting details of primary studies (n=40 across reviews), appraisal with AMSTAR 2 to rate review quality, assessment of study overlap (corrected covered area, CCA), and examination of whether primary studies adjusted for critical confounders (maternal characteristics, indication for use, familial factors) or used family-based designs to address unmeasured confounding.
Key findings
The umbrella review incorporated nine systematic reviews that together reported on 40 primary studies: six studies addressing autism and 17 addressing ADHD (some studies contributed to both outcomes). Four of the reviews performed meta-analyses. Main empirical findings were:
- Reported associations: Across reviews, pooled estimates generally suggested a possible to strong association between prenatal paracetamol exposure and increased odds or hazards of autism and ADHD in offspring in conventional cohort analyses.
- Review quality and overlap: Confidence in the systematic review conclusions was low (two reviews) to critically low (seven reviews) using AMSTAR 2. There was substantial overlap among primary studies (corrected covered area 23%), increasing the risk that multiple reviews summarised the same limited evidence base.
- Confounding and bias concerns: Most primary studies were observational with potential for recall bias (when exposure was self-reported), exposure misclassification, incomplete or inconsistent adjustment for indication (maternal fever, infection or pain), and limited control for familial confounding (shared genetic and environmental factors).
- Family-controlled (sibling) analyses: Only a single review included sibling-controlled studies (two primary studies) able to adjust for unmeasured family-level confounders. In conventional whole-cohort analyses these studies reported small increased risks: autism hazard ratio (HR) 1.05 (95% CI 1.02–1.08) and ADHD HRs 1.07 (1.05–1.10) and 2.02 (1.17–3.25). However, when sibling-controlled analyses were used, estimates attenuated to approximate null: autism HR 0.98 (0.93–1.04); ADHD HRs 0.98 (0.94–1.02) and 1.06 (0.51–2.05), the latter with wide confidence intervals that cross unity.
- Interpretation by reviewers: Seven of nine systematic reviews explicitly cautioned about interpreting pooled associations as causal given the limitations above. The umbrella review authors concluded that existing evidence does not clearly link maternal paracetamol use in pregnancy with autism or ADHD in offspring.
What the results mean for causality
Triangulation of evidence is vital to assess causality from observational data. Key issues that weaken causal claims here include:
- Confounding by indication: Maternal fever or infection during pregnancy are themselves associated with adverse neurodevelopmental outcomes, so failure to account for the reason paracetamol was used can generate spurious associations.
- Familial confounding: Shared genetic or environmental factors that predispose both to maternal paracetamol use and child neurodevelopmental risk (for example, parental psychiatric traits) can produce associations in cohort analyses. Sibling designs control for shared familial confounders and, in the limited sibling analyses available, associations largely dissipated.
- Exposure measurement: Many studies rely on maternal recall or registry-recorded prescriptions, which poorly capture dose, timing (trimester-specific), indication, or over-the-counter use. Misclassification tends to bias effect estimates unpredictably.
- Residual confounding and multiple testing: Incomplete adjustment for socioeconomic factors, comorbidities, concurrent medication use, and postnatal exposures can produce spurious associations. Heterogeneity in outcome ascertainment and diagnostic criteria further complicates interpretation.
Clinical implications and practice guidance
At present, the totality of the evidence does not justify advising pregnant patients to avoid paracetamol when it is indicated. Important practical points for clinicians:
- Balance maternal and fetal risks: Untreated fever — particularly high or prolonged fever — and pain can harm pregnancy and fetal neurodevelopment; treating these conditions is clinically appropriate.
- Use minimal effective therapy: When paracetamol is indicated, recommend the lowest effective dose for the shortest necessary duration. Avoid routine or chronic use without clear indication.
- Individualised counselling: Discuss the current uncertainty with pregnant patients — explain that observational studies suggest associations but causal links are unproven and that sibling- and family-based analyses reduce previously observed associations.
- Address underlying indications: Prioritise treating causes of symptoms (e.g., managing infection) and consider non-pharmacologic options when appropriate.
Research priorities
The umbrella review highlights several research gaps that must be addressed to reach firmer conclusions:
- Stronger designs: Larger family-based studies (sibling and cousin comparisons), negative-control analyses, and within-individual longitudinal designs that better account for unmeasured confounding.
- Improved exposure measurement: Prospective capture of dose, timing (trimester and cumulative exposure), indication, and biologic markers where feasible to reduce misclassification.
- Mechanistic studies: Preclinical work and human translational studies to evaluate plausible biological pathways (for example, prostaglandin-mediated neurodevelopmental effects, oxidative stress, endocrine disruption) and whether effects vary by dose/timing.
- Data triangulation: Combining epidemiology, genetics (Mendelian randomisation where applicable), and experimental biology to clarify causality.
- Reporting standards: Harmonised reporting of confounders, indication data, and analytic approaches to improve comparability and enable high-quality meta-analyses.
Expert commentary
Several expert groups have cautioned against overinterpreting associations from observational studies linking widely used medications and neurodevelopmental outcomes. The results of the BMJ umbrella review align with a conservative scientific interpretation: signal detection in observational data warrants investigation, but does not equate to proof of harm. Clinicians should avoid alarmist messaging and instead provide balanced, evidence-informed counselling, emphasising the known maternal benefits of treating fever and pain and the limitations of current evidence.
Limitations of the umbrella review
While the umbrella review rigorously appraised existing systematic reviews and primary study features, its conclusions are constrained by the quality and designs of included studies. The high overlap of primary studies across reviews reduces the increment of information provided by multiple reviews. Also, sibling-controlled analyses were available from only a small subset of cohorts, and those analyses may be underpowered for less common outcomes or for dose–response effects.
Conclusion
The best available synthesis to date — an umbrella review of systematic reviews — finds that the evidence linking maternal paracetamol use during pregnancy to offspring autism or ADHD is inconclusive. Observed associations in conventional cohort analyses may reflect residual confounding, confounding by indication, or other biases; family-based analyses that better account for shared confounders attenuate associations. For clinical practice, paracetamol remains an option for treating maternal fever and pain during pregnancy, used judiciously at the lowest effective dose and for the shortest necessary duration. High-quality prospective studies with improved exposure measurement, family-based designs, and mechanistic research are needed to resolve remaining uncertainty.
Funding and registration
The umbrella review reported registration with PROSPERO (CRD420251154052). Details on funding and competing interests are reported in the original BMJ article.
References
Sheikh J, Allotey J, Sobhy S, Plana MN, Martinez-Barros H, Naidu H, Junaid F, Sofat R, Mol BW, Kenny LC, Gladstone M, Teede H, Zamora J, Thangaratinam S. Maternal paracetamol (acetaminophen) use during pregnancy and risk of autism spectrum disorder and attention deficit/hyperactivity disorder in offspring: umbrella review of systematic reviews. BMJ. 2025 Nov 9;391:e088141. doi: 10.1136/bmj-2025-088141. PMID: 41207796.
Note: This article summarises and interprets the BMJ umbrella review findings for clinicians and policy-makers. It is not a guideline. Clinicians should continue to follow local and international guidance on medication use in pregnancy and individualise care.
