Acetaminophen (Tylenol) in Pregnancy: Relief or Risk?

Acetaminophen has long been considered the safest option for pain and fever relief during pregnancy, but new research suggests its widespread use may carry hidden risks. A recent review found “consistent associations” between prenatal acetaminophen exposure and neurodevelopmental disorders, like ADHD and autism. The findings raise important questions about balancing maternal health needs with potential long-term impacts on child development.

The Study at a Glance

A total of 46 studies were incorporated in the analysis, 20 involving acetaminophen and attention-deficit/hyperactivity disorder (ADHD), 8 involving autism spectrum disorder (ASD), and 18 involving neurodevelopmental disorders (NDDs)

Large prospective studies, constituting most of the evidence base, demonstrated moderate bias. Studies with a high risk of bias, i.e., those involving retrospective recall or poor control of confounders, were down-weighted, not discarded. Sibling-comparison studies mitigated but did not eliminate genetic impacts; however, their small number served more to strengthen than to make a causal inference. Biomarker studies added biological plausibility and dose-response support, improving the researcher’s confidence in their conclusions. However, in each case, the researcher's judgment categorizes the risk and application of weighting, introducing an inevitable degree of subjectivity.

They found: 

• “Higher-quality studies were more likely to show positive associations… evidence supports an association between prenatal acetaminophen use and ADHD.”
• “The majority of studies reported positive associations of prenatal acetaminophen use with ASD, … though fewer in number compared to ADHD.”
• “The majority of studies reported positive associations of prenatal acetaminophen use with neurodevelopmental deficits (NDDs), … While residual confounding cannot be excluded, triangulation of evidence supports concern for adverse neurodevelopmental impacts beyond ADHD and ASD.”

Methodology

Meta-analysis is at its best when evidence is plentiful and the underlying data are homogeneous, allowing for direct comparisons. Meta-analysis remains a statistical technique that provides a quantitative summary of the effect. While meta-analysis may be more statistically certain,its greatest weakness is that of “garbage in, garbage out,” where poor-quality studies or highly heterogeneous data can bias the aggregated results.

The current study uses the Navigation Guide Systematic Review (NGSR), a different methodology of meta-analysis, serving a different master. NGSR, developed by researchers in environmental health, provides a broader view when the data is divergent, heterogeneous, and gold-standard randomized controlled trials are sparse, making indirect, apples-to-oranges comparisons more sound. NGSR paints with a less certain brush; it works well in providing a transparent, reproducible qualitative gist, and may be more useful in guidance rather than guidelines or rules.

NGSR considers multiple lines of evidence, such as human, animal, and cellular studies, and, like meta-analysis, weighs the “risk of bias” and “strength of evidence” in reaching its conclusions. Meta-analysis assessment of bias and evidence strength is less structured, making it more susceptible to criticism. 

When examining the link between acetaminophen and ADHD, a meta-analysis would gather relevant studies, calculate a combined effect size, and report a percentage change in risk, e.g., acetaminophen use was associated with a X% increase or decrease in the risk of ADHD. It would also account for study quality, variability, and subgroup differences. Advocates highlight the precision of a numeric estimate, while critics argue that the numbers can give a false sense of certainty when the underlying data is uneven.

Using NGSR, researchers first define the population, exposure, comparison, and outcomes (PECO) [1]. They then assess studies across humans, animals, and cells, rating limitations and weighing the strength of evidence. Instead of a numeric risk, NGSR offers a qualitative judgment that acetaminophen exposure is linked to a low, medium, or high level of evidence of an association with ADHD. 

Grains of Salt

An immediate concern is whether the acetaminophen use was simply an intermediary mark of an underlying illness that was more causal than the acetaminophen – a confounding concern. The researchers acknowledge this central limitation and do their best to limit the grains of salt we might apply. They argued that the studies not fully accounting for the confounding of “maternal illness and indication for acetaminophen use” were balanced by other studies that did attempt to account for confounding, and the biomarker studies further strengthen their findings. 

We are left with a statement that both advocates and critics can point to: 

“Residual confounding by maternal illness and indication for acetaminophen use cannot be entirely ruled out, yet triangulation across prospective, biomarker, and sibling-comparison designs strengthens confidence that the observed associations are not wholly explained by confounding.” [Emphasis added]

The overall pattern of consistent associations led them to conclude:

“Our analysis demonstrated evidence consistent with an association between exposure to acetaminophen during pregnancy and offspring with NDDs, including ASD and ADHD, though observational limitations preclude definitive causation.”

The Clinical Crossroads

Pregnant women experience pain and fevers during pregnancy. Acetaminophen is the first-line medication for symptomatic relief because all other choices have a greater potential for “congenital disabilities” and miscarriage. That is why the American College of Obstetricians and Gynecologists recommends its use. The researchers note that one study estimated that 60% of women use acetaminophen while pregnant, and that some 20% used it for more than 20 days, a significant exposure. But that same study noted that the increased use of acetaminophen was associated with confounders not considered in the current NGSR study, specifically “tobacco use, obesity, self-reported depression or anxiety, and antidepressant use.”

So, what’s a woman to do? Last word on this to the researchers.

“While this association warrants caution, untreated maternal fever and pain pose risks such as neural tube defects and preterm birth, necessitating a balanced approach. We recommend judicious acetaminophen use—lowest effective dose, shortest duration—under medical guidance, tailored to individual risk–benefit assessments, rather than a broad limitation.”

The emerging evidence surrounding acetaminophen use in pregnancy underscores the uncomfortable truth of modern medicine: there are few risk-free choices. Scientific research provides crucial information about potential risks, but it does not offer a simple "yes" or "no" answer for individual health decisions. The safest path forward lies not in fear or avoidance, but in nuanced decision-making—using the lowest effective dose for the shortest necessary time, guided by individualized medical advice. Ultimately, the choice rests on careful conversations between women and their physicians, weighing both the relief of the present and the long-term health implications.

[1] Population: Pregnant women and offspring; Exposure: Acetaminophen exposure during pregnancy; Comparator: No acetaminophen exposure; Outcome: ADHD diagnosis or symptoms

[2] Confounding, exposure misclassification, outcome assessment, and selective reporting

Source: Evaluation of the evidence on acetaminophen use and neurodevelopmental disorders using the Navigation Guide methodology Environmental Health DOI: 10.1186/s12940-025-01208-0