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Date: Sept 16, 2025

Reference: Prada et al. Evaluation of the evidence on acetaminophen use and neurodevelopmental disorders using the Navigation Guide methodology. Environ Health. August 2025

Guest Skeptic: Dr. Andrew Martin is an emergency physician practicing in Jacksonville, Florida. 

Case: A 27-year-old at 24 weeks’ gestation presents to the emergency department (ED) with fever (38.6 °C), myalgias, and sore throat. She took 650 mg of acetaminophen (Tylenol) six hours ago with partial relief. She hesitated to repeat the dose after reading online posts about “Tylenol and autism.” She has no abdominal pain, no vaginal bleeding, and normal fetal movement. Vitals otherwise stable; pharynx erythematous, no exudate. She asks, “Is it safe to take another dose, or could this hurt my baby’s brain later?”

Background: Acetaminophen (paracetamol) is the most used analgesic–antipyretic in pregnancy. A recent prospective cohort study suggests ~40 to 65% of pregnant people report using it. They are typically using acetaminophen for headache, myalgias, or fever, with most use being short and intermittent. Alternatives, particularly non-steroidal anti-inflammatory drugs (NSAIDs), carry well-described fetal risks in late gestation. This is one of the reasons why acetaminophen remains the default first-line choice [1,2].

Biologically, acetaminophen crosses the placenta and achieves fetal levels like maternal levels, making the developing brain theoretically exposed during critical windows [3]. This has motivated a large observational literature examining whether prenatal exposure is linked to later neurodevelopmental outcomes such as ADHD and autism. Meta-analyses generally report small associations (summary effects around 1.2 to 1.3) and signal stronger effects with longer duration of use, though heterogeneity in exposure measurement and outcome ascertainment is substantial. 

Professional bodies, including the American College of Obstetricians and Gynecologists (ACOG) and the Society of Obstetricians and Gynecologists of Canada [SOGC], continue to recommend acetaminophen for appropriate indications at the lowest effective dose and shortest duration. At the same time, they do acknowledge ongoing research and the limitations of observational data (including confounding by indication). For emergency clinicians, the practical tension is familiar. The dilemma is that untreated maternal fever and significant pain can themselves harm pregnancy, yet patients are increasingly asking about possible long-term neurodevelopmental potential harms of using acetaminophen. 

Clinical Question: Is acetaminophen exposure during pregnancy associated with ADHD, ASD, or other neurodevelopmental disorders (NDDs) in children?

Reference: Prada et al. Evaluation of the evidence on acetaminophen use and neurodevelopmental disorders using the Navigation Guide methodology. Environ Health. August 2025

  • Population: Observational studies assessing children of pregnant individuals for neurodevelopmental outcomes.
    • Excluded: Postnatal exposures, non-human studies for the primary analysis, non-original publications, and duplicate reports from the same cohort.
  • Exposure: Prenatal acetaminophen (maternal self-report, biomarkers such as meconium/cord blood, or medical records/prescription registries).
  • Comparison: Children who were not exposed prenatally to acetaminophen, or those exposed to alternative analgesics.
  • Outcome:
    • Primary Outcome: NDDs (particularly ADHD and ASD) and related symptomatology measured by clinical diagnoses, medication use, or validated behavioural scales.
    • Secondary Outcomes: Timing and dose–response patterns, broader cognitive/behavioural domains (language & executive function), and triangulation across design types.
  • Type of Study: Systematic review using the Navigation Guide methodology with a qualitative synthesis (no meta-analysis) due to substantial heterogeneity.

Authors’ Conclusions: “Our analyses using the Navigation Guide thus support evidence consistent with an association between acetaminophen exposure during pregnancy and increased incidence of NDDs. Appropriate and immediate steps should be taken to advise pregnant women to limit acetaminophen consumption to protect their offspring’s neurodevelopment.”

Quality Checklist for Systematic Review:

  1. The main question being addressed should be clearly stated. Yes
  2. The search for studies was detailed and exhaustive. Unsure
  3. Were the criteria used to select articles for inclusion appropriate? Yes
  4. Were the included studies sufficiently valid for the type of question asked? Unsure
  5. Were the results similar from study to study? No
  6. Were there any financial conflicts of Interest? Yes

Result: They searched PubMed (primary) through Feb 25, 2025, with confirmatory checks in Web of Science and Google Scholar. A total of 46 studies were included.  The studies consisted of a mix of prospective cohorts, retrospective/historical cohorts, sibling-controlled cohorts, and two case-control studies.  Sample sizes ranged from ~100 to a national registry scale (Sweden’s registry cohort included 2.5 million births).

Key Result: The preponderance of studies reported positive associations between prenatal acetaminophen exposure and ADHD/ASD or related symptoms, with dose–response suggested in several biomarker and prospective cohorts. However, some sibling-controlled analyses attenuated associations toward null, and overall heterogeneity was high.

  • Of 46 studies, 27 reported positive associations, 9 null, and 4 inverse (protective) associations.
  • Several higher-quality or biomarker-based studies suggested dose-response relationships.
  • No pooling into a meta-analysis due to heterogeneity

1) Exposure Misclassification: Most contributing cohorts ascertained prenatal acetaminophen exposure via maternal self-report during pregnancy or post‑partum recall, or from prescription/registry data that do not fully capture over-the-counter use. The authors’ own risk‑of‑bias summaries flag the exposure domain as a frequent concern, and they rate retrospective self-report, especially when collected after child diagnosis, as high risk for recall bias. In contrast, biomarker studies (meconium, cord blood, maternal plasma/urine) mitigate recall bias and, in several instances, suggest dose–response, but they remain snapshots that imperfectly reflect timing and cumulative dose. The review also highlights how low-sensitivity exposure measurement can deflate associations. An example is the large Swedish sibling‑analysis cohort that reported 7.5% use based on midwife interviews, despite contemporaneous sources indicating ~50 to 60% use. This implies substantial underascertainment (misclassification bias or ascertainment bias) that likely biases the estimate toward the null and compounds loss of power in within-family models. Together, these exposure‑measurement limitations should make us more cautious in both the direction and magnitude of observed associations in the qualitative synthesis.

2) Residual Confounding: Although many included studies adjusted for a broad set of factors (maternal age, socioeconomic status, smoking, alcohol, illness, fever, and infection) and some used negative‑control exposure periods or propensity approaches, the review acknowledges that unmeasured and residual confounding remain possible. Importantly, the authors did not implement a quantitative bias analysis (E‑values, probabilistic bias analysis) to bound the strength of confounding necessary to explain the findings. They explicitly list this as a limitation of the review. Given that indications for acetaminophen (fever, pain, intercurrent infection) may themselves relate to neurodevelopmental outcomes and can be difficult to measure with sufficient granularity, any qualitative conclusion about “persistence after adjustment” should be interpreted skeptically.

3) Outcome Heterogeneity & Variable Ascertainment:  The review pools evidence across disparate outcome definitions: registry-based clinical diagnoses (ICD‑coded ADHD/ASD), ADHD medication use, and multiple validated behavioural scales (CBCL, SDQ), often at different child ages and with parent vs teacher report. This heterogeneity in outcome measurement (plus differences in timing of assessment) creates non-comparability that complicates causal interpretation and precludes valid pooling. Appropriately, the authors do not conduct a meta-analysis, citing the substantial heterogeneity in exposure assessment, outcome measures, and confounder adjustment. Risk‑of‑bias summaries also show concerns in the outcome domain for some outcome types. Mixing clinical diagnoses, proxy markers (medication), and symptom scales across varied ages increases measurement error and between-study variability, limiting the precision and generalizability of the qualitative synthesis.

4) Search Scope & Evidence‑Grading: The search strategy relied on PubMed as the primary database with confirmatory checks in Web of Science and Google Scholar. No additional eligible studies were identified beyond PubMed, and no discussion of searching the grey literature.  Heavy reliance on a single primary database risks missing studies indexed elsewhere or gray literature, potentially introducing retrieval bias.[4] In addition, while the Navigation Guide offers a structured approach, the authors note that its numeric domain‑averaging can imply unwarranted precision and assign equal weight to domains even when certain biases (confounding, exposure error) likely dominate. They attempted sensitivity analyses (excluding lowest‑scoring papers and up-weighting confounding) but acknowledge the framework’s default “moderate” rating for observational evidence could skew certainty assessments. These methodological choices reasonably reflect transparency but also represent limitations of the review’s grading and synthesis.

5) Design‑Specific Biases: The review “triangulates” across prospective cohorts, biomarker studies, and sibling‑comparison designs, arguing that convergence strengthens causal inference. In practice, however, the sibling‑control analyses, intended to address shared familial confounding, are highly vulnerable to reduced power (only discordant pairs count) and to magnified effects of exposure misclassification. The authors specifically cite small discordant samples for long-duration exposure and simulations demonstrating that measurement error can push within-family estimates toward the null. Conversely, conventional cohorts that show positive associations remain susceptible to residual confounding. This bidirectional bias structure (familial confounding vs. measurement error/non-shared confounders) means that different designs can reasonably point in different directions. While the authors discuss these issues and justify a qualitative approach, the design‑level tensions are unresolved and limit how definitively one can move from “association” to “causation” in the overall conclusion

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree that this data suggests a small association between prenatal acetaminophen exposure and later NDD outcomes, but causality is not established.

SGEM Bottom Line: Do not change ED analgesic/antipyretic practice in pregnancy based on this review alone. Continue to use acetaminophen judiciously to treat significant fever/pain and discuss uncertainties transparently.

Case Resolution: You counsel the patient that treating fever in pregnancy matters, that acetaminophen remains the first-line option when clinically indicated, and that research signals a possible small association with later behavioural diagnoses but cannot prove causation. After shared decision‑making, she takes another 650 mg dose, you obtain a rapid strep/viral panel and provide reasons to return to the ED.

Dr. Andrew Martin

Clinical Application: Acetaminophen remains the ED analgesic/antipyretic of choice in pregnancy. Continue to avoid routine NSAIDs in late pregnancy. Aim for the lowest effective dose and shortest duration. While observational studies show small associations with later ADHD/ASD, confounding and misclassification limit causal inference.

What Do I Tell the Patient? Based on current best evidence, acetaminophen is still the safest first-choice medicine for fever or significant pain in pregnancy. You should use the lowest effective dose for the shortest time. Some studies have found a small link with later attention or behaviour problems, but they can’t prove cause and effect. Not treating fever and pain also has risks. Please return to the ED if you are feeling worse, develop new symptoms (coughing blood, “water breaks”, contractions, etc) or are worried.

Keener Kontest: Last week’s winner was Tim Kolosionek, a Medical toxicology fellow at Lehigh Valley Health Network in Allentown, PA. He knew potassium was discovered in 1807 by Humphry Davy.

Listen to the SGEM podcast to hear this episode’s trivia question. If you think you know the answer, send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will get a shoutout on the next episode.

Other SGEM on the Topic:

  • Science-Based Medicine -Tylenol and Autism
  • Swedish Study with Sibling Controls – Acetaminophen Use During Pregnancy and Children’s Risk Of Autism, ADHD, And Intellectual Disability. Ahlqvist Vh, Et Al. Jama. 331(14):1205-1214. April, 2023
  • Hepatitis B and Autism – Gallagher CM, Goodman MS. Hepatitis B Vaccination of Male Neonates and Autism Diagnosis, NHIS 1997–2002. J Toxicol Environ Health A. 2010;73:1665-1677.
  • Henry Ford Vax vs UnVax Study – Lamerato et al. Impact of Childhood Vaccination on Short and Long-Term Chronic Health Outcomes in Children: A Birth Cohort Study. Unpublished Henry Ford Study
  • Danish Aluminum & Autism Study – Niklas Worm Andersson, Ingrid Bech Svalgaard, Stine Skovbo Hoffmann, et al. Aluminum-Adsorbed Vaccines and Chronic Diseases in Childhood: A Nationwide Cohort Study. Ann Intern Med. [Epub 15 July 2025]. doi:10.7326/ANNALS-25-00997
  • Florida 9-Year-Old Children Medicaid – Mawson & Jacob. Vaccination and Neurodevelopmental Disorders: A Study of Nine-Year-Old Children Enrolled in Medicaid. January 2025 Science, Public Health Policy, and the Law Volume: v6.2019-2025

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

References:

  1. Bandoli G, Palmsten K, Chambers C. Acetaminophen use in pregnancy: Examining prevalence, timing, and indication of use in a prospective birth cohort. Paediatr Perinat Epidemiol. 2020 May;34(3):237-246. doi: 10.1111/ppe.12595. Epub 2019 Nov 7. PMID: 31696962; PMCID: PMC7192766.
  2. ACOG September 2021. https://www.acog.org/news/news-articles/2021/09/response-to-consensus-statement-on-paracetamol-use-during-pregnancy  Accessed September 8, 2025
  3. Levy G, Garrettson LK, Soda DM. Letter: Evidence of placental transfer of acetaminophen. Pediatrics. 1975 Jun;55(6):895. PMID: 1134892.
  4. MacDonald H, Comer C, Foster M, Labelle PR, Marsalis S, Nyhan K, Premji Z, Rogers M, Splenda R, Stansfield C, Young S. Searching for studies: A guide to information retrieval for Campbell systematic reviews. Campbell Syst Rev. 2024 Sep 10;20(3):e1433. doi: 10.1002/cl2.1433. PMID: 39258215; PMCID: PMC11386270.