Prolonged Acetaminophen Use During Pregnancy Linked to Modest Increase in ADHD and ASD Risk

Summary: A comprehensive systematic review and meta-analysis from the Hebrew University of Jerusalem finds that prolonged maternal use of acetaminophen (paracetamol) during pregnancy is associated with a modestly higher relative risk of offspring being diagnosed with attention deficit hyperactivity disorder (ADHD) and autistic spectrum disorder (ASD). The pooled analysis indicates an approximately 30% increased relative risk for ADHD and about a 20% increased relative risk for ASD compared to no acetaminophen exposure.

Source: The Hebrew University of Jerusalem.

Overview

Acetaminophen (paracetamol) is commonly recommended for treating pain and fever during pregnancy and is widely regarded as safe for short-term use. However, growing observational evidence has raised concerns that prolonged exposure during pregnancy could affect fetal neurodevelopment. To clarify the existing evidence, researchers at the Hebrew University’s Institute for Drug Research conducted a systematic review and meta-analysis examining the association between prolonged prenatal acetaminophen exposure and later diagnoses of ADHD and ASD in children.

The study, led by Dr. Ilan Matok with doctoral student Reem Masarwa and collaborators, pooled data from seven eligible retrospective cohort studies covering 132,738 mother–child pairs with follow-up periods ranging from three to eleven years. The analysis appeared in the American Journal of Epidemiology.

Key Findings

The pooled estimates from the meta-analysis were as follows:

• ADHD: pooled relative risk (RR) = 1.32 (95% CI 1.18–1.45), indicating about a 30% relative increase compared with no acetaminophen exposure.
• ASD: pooled RR = 1.23 (95% CI 1.13–1.32), indicating about a 20% relative increase.
• Hyperactivity symptoms: pooled RR = 1.23 (95% CI 1.01–1.49).

Meta-regression suggested that the association with ADHD strengthened with older child age at follow-up and with longer average duration of prenatal acetaminophen exposure. However, heterogeneity across studies was noted, particularly for hyperactivity outcomes.

Study Strengths and Limitations

This is the first and most comprehensive meta-analysis to date addressing prolonged prenatal acetaminophen exposure and later neurodevelopmental diagnoses. Strengths include the large combined sample size and the systematic approach to study identification and data synthesis.

Important limitations temper interpretation of the results: all included studies were observational, leaving findings susceptible to confounding and bias. Studies differed substantially in how exposure and outcomes were measured, and residual confounding (for example, by indication—why the medication was taken—or by maternal health, genetics, or environmental factors) cannot be ruled out. Because of these limitations, causal conclusions cannot be drawn from the pooled estimates alone.

Clinical Context and Practical Guidance

Authors and participating clinicians emphasize that pain and fever during pregnancy can themselves harm the developing fetus, and short-term acetaminophen use remains an accepted option for treatment when clinically indicated. The research team advises caution about prolonged, unnecessary medication use during pregnancy but recommends that pregnant women do not avoid acetaminophen entirely when it is needed for fever or significant pain.

If pain or fever persists beyond short-term use, pregnant patients should consult their health care provider to evaluate the underlying cause and consider appropriate alternative treatments or further management.

Concluding Remarks

The meta-analysis identifies an association between prolonged prenatal acetaminophen exposure and modestly increased relative risks for ADHD and ASD in children. While these associations are concerning and warrant further high-quality research, the current evidence comes from observational studies with significant variability in exposure and outcome assessment. Clinicians and pregnant women should balance the small observed increased risks against the known harms of untreated fever and pain, following individualized clinical guidance.

Research team: Reem Masarwa, Hagai Levine, Einat Gorelik, Shimon Reif, Amichai Perlman, Ilan Matok, and collaborators at the Hebrew University of Jerusalem and Hadassah Medical Center.

Publication: American Journal of Epidemiology (published April 24, 2018). Title: “Prenatal Exposure to Acetaminophen and Risk for Attention Deficit Hyperactivity Disorder and Autistic Spectrum Disorder: A Systematic Review, Meta-Analysis, and Meta-Regression Analysis of Cohort Studies.”

DOI: 10.1093/aje/kwy086

Source: The Hebrew University of Jerusalem. Publisher: NeuroscienceNews.com. Image source: NeuroscienceNews.com (public domain).

Abstract (Condensed)

Acetaminophen is the most commonly used analgesic and antipyretic during pregnancy. Observational evidence suggests potential neuro-disruptive effects after prenatal exposure. The authors searched major databases through January 2017 and identified seven retrospective cohort studies including 132,738 mother–child pairs with 3–11 years of follow-up. Pooled relative risks indicated modestly higher risks for ADHD, ASD, and hyperactivity symptoms following prolonged maternal acetaminophen use during pregnancy. Given the observational design and heterogeneity among studies, results should be interpreted cautiously and prompt further rigorous investigation.

This summary synthesizes published observational data and does not replace individualized medical advice. Pregnant women with concerns about medication use should discuss risks and benefits with their healthcare provider.