Paracetamol during pregnancy and the risk of neurodevelopmental disorders in children

A systematic review using the strict Navigation Guide protocol was published in Environmental Health (August 14, 2025): the authors assessed the association of prenatal use of paracetamol (acetaminophen) with neurodevelopmental development in children. Of the 46 studies selected, most showed a positive association with the risk of ADHD, ASD, and other NDD (neurodevelopmental disorders); moreover, higher-quality studies more often found a connection. Meta-analysis was not performed due to heterogeneity, but the overall conclusion is that the data are consistent with an increased risk and require a restrictive approach to use during pregnancy (minimum effective dose, shortest course, for medical reasons).

Background

Why is there even a debate about paracetamol during pregnancy?
Paracetamol (acetaminophen, APAP) is the most widely used painkiller and fever reducer in pregnant women; it is used by many women around the world. However, some epidemiological studies have found a link between prenatal APAP use and an increased risk of neurodevelopmental disorders in children (primarily ADHD and ASD) for many years, while others have not confirmed such a link. So the question is between the risks of untreated pain/fever and the hypothetical risks of the drug, which requires a balanced, transparent assessment of the totality of evidence.

What did the key observational studies show?

• Several large cohort studies have reported an association between APAP use during pregnancy and increased risk of behavioral problems/ADHD in children (JAMA Pediatrics, 2014, is a classic example). More recently, biomarker studies have linked cord blood levels of APAP metabolites to ADHD and ASD risk in a dose-response manner. These studies have increased attention to the topic because they are less dependent on recall bias.
• At the same time, sibling-control analyses (2024) found no association between prenatal APAP use and ADHD/ASD/intellectual disability risk, pointing to a possible role for familial confounding (genetics, environment, reasons for taking the drug). This highlights that the results depend on the design and control of confounding factors.

Possible mechanisms (why is this even possible?)
APAP freely crosses the placenta and blood-brain barrier; its metabolism is altered during pregnancy, which could theoretically affect fetal vulnerability. Pathways via endocrine effects, oxidative stress, and effects on placental trophoblasts are discussed; preclinical models provide biological plausibility for this.

Why it matters how exactly to summarize the evidence
The Navigation Guide methodology (transferring the “rules” of evidence-based medicine to environmental/reproductive epidemiology) specifies pre-registration protocol, systematic search, rigorous risk assessment of bias, and separation of scientific part from values/preferences. This reduces the arbitrariness of “narrative” reviews and makes conclusions more reproducible.

What the new review adds to Environmental Health (2025)
The authors conducted a systematic search (February 2025), included 46 original studies and, due to significant heterogeneity, performed a qualitative synthesis without meta-analysis. Conclusion: the overall picture is consistent with an increased risk of neurodevelopmental disorders in children with prenatal APAP use, with higher quality studies more likely to find an association. In practice, a precautionary approach is recommended: use paracetamol only when indicated, at the lowest effective dose and for the shortest course.

How does this fit with clinical guidelines?
Professional societies (e.g., ACOG) emphasize the lack of proven cause-and-effect relationship with “judicious” use of APAP and still consider it the preferred analgesic/antipyretic in pregnancy - with informed choice and consultation with a physician. The consensus position today is: do not self-medicate, but do not tolerate dangerous fever/pain; if necessary - briefly and at a minimum dose.

Context conclusion
The field remains controversial: there are signals from biomarker and cohort studies in favor of an association, and there is a “null” with strict control for family factors. A new systematic review of the Navigation Guide neatly formulates the conclusion: caution is appropriate now, in parallel, multicenter prospective cohorts with precise measurement of dose/duration and biomarkers, as well as designs that minimize confounding by indication are needed.

What exactly did they do?

The researchers conducted a search and screening funnel (PubMed until 25.02.2025 + verification in Web of Science/Google Scholar), including only original observational studies in humans on the exposure "paracetamol during pregnancy → neurodevelopment of the child". The quality and risk of systematic errors were assessed according to the Navigation Guide/GRADE scale (blinding, exposure/outcome measurement, confounding, selective reporting, etc.). Due to the heterogeneity of designs and metrics, the authors conducted a qualitative synthesis instead of a meta-analysis.

Key Results

• Forty-six studies were included in the final sample; of these, 27 reported a significant positive association (more NRRs in children with prenatal paracetamol use), 9 reported a null association, and 4 reported a negative (protective) association.
• Predictor of quality: Authors rated high-quality studies as more likely to show an association than studies with a higher risk of systematic errors (e.g. retrospective surveys after a child's diagnosis are subject to recall bias).
• The review summary: the data are consistent with the association "paracetamol during pregnancy → ↑ risk of adverse drug reactions in offspring" (including ADHD and ASD). The authors suggest immediate practical steps to inform pregnant women: use the drug only as indicated, in the minimum dose, and for the shortest course.

Why is this important?

Paracetamol is the most commonly used over-the-counter analgesic/antipyretic during pregnancy (>50-60% of pregnant women report using it). Amid long-standing reassuring language about “safety,” pregnant women and doctors are receiving conflicting signals. The new Navigation Guide assessment is a transparent, structured framework for observational evidence that adds weight to the precautionary stance: the precautionary principle until definitive causal clarity.

Context: Why Opinions Differ

• In 2021, a group of experts called for precautions regarding paracetamol in pregnancy (minimum doses/timings, as indicated).
• Professional societies, including ACOG, responded by emphasizing the lack of proven cause-and-effect relationship with “prudent” use and did not change clinical guidelines, citing the risks of alternatives (fever, pain).
• We add that some large cohorts and sibling analyses have also yielded null results, raising the issue of confounding by indication (e.g., the reason for admission itself - infection/fever). This is another reason why the authors of the current review are concerned about quality assessment and triangulation of different types of studies.

What does this mean in practice?

• Do not self-medicate. Any medication during pregnancy - after consultation.
• If paracetamol is really needed for the indications (fever, severe pain), stick to the principles of the minimum effective dose and the shortest course. This is consistent with both the "precaution" position and the current recommendations.
• For chronic pain/recurring headaches, discuss non-drug strategies and alternatives with your obstetrician/gynecologist.

Restrictions

This is a systematic review of observational studies: it strengthens the evidence consistency but does not prove causality. The authors deliberately avoided meta-analysis due to exposure/outcome heterogeneity and differences in confounder control; the final conclusion relies on qualitative assessment and risk of bias. Prospective cohorts with biomarkers, better measurement of dose/duration, and analytical designs that reduce confounding by indication are needed.

Source: Prada D., Ritz B., Bauer AZ, Baccarelli AA et al. Evaluation of the evidence on acetaminophen use and neurodevelopmental disorders using the Navigation Guide methodology, Environmental Health, August 14, 2025 (open access). doi.org/10.1186/s12940-025-01208-0