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Acetaminophen in Pregnancy and Attention-Deficit and Hyperactivity Disorder and Autism Spectrum Disorder
Per Damkier1, Erika B Gram, Michael Ceulemans
1Department of Clinical Pharmacology, Odense University Hospital, and the Department of Clinical Research, University of Southern Denmark, Odense, Denmark; Clinical Pharmacology & Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; Radboud University Medical Center, Nijmegen, the Netherlands; Service of Pharmacy, Lausanne University Hospital and University of Lausanne, Lausanne, and the Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland; the Pharmacy Department, Rotunda Hospital and School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland; the Department of Pediatrics, University of California San Diego, La Jolla, California; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Pharmakovigilanzzentrum, Embryonaltoxikologie, Institut für Klinische Pharmakologie und Toxikologie, Berlin, Germany; Mothersafe, University of New South Wales, Australia; UK Teratology Information Service and the Directorate of Women's Services, Royal Victoria Infirmary, Newcastle Upon Tyne, United Kingdom; the Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, Washington; the Israeli Teratology Information Service, Ministry of Health, and the Hebrew University Hadassah Medical School, Jerusalem, Israel; the Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, Florida; and the Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Insights
Maternal acetaminophen use during pregnancy is unlikely to increase a child's risk for attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD). Current evidence suggests biases in studies showing a link, not a true clinical risk.
Area of Science:
- Perinatal pharmacology and neurodevelopmental disorders.
Background:
- Acetaminophen (paracetamol) is a widely used analgesic and antipyretic during pregnancy.
- Concerns exist regarding potential neurodevelopmental effects, specifically attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), following in utero exposure.
Purpose of the Study:
- To critically evaluate the existing scientific literature on the association between maternal acetaminophen use during pregnancy and the risk of ADHD and ASD in children.
- To assess the quality of evidence and identify limitations in published studies.
Main Methods:
- Systematic review and critical appraisal of published studies and meta-analyses.
- Inclusion criteria focused on studies with validated ADHD or ASD outcome definitions.
- Analysis of nine original data studies and three meta-analyses, with particular attention to confounding factors.
Main Results:
- Many studies reporting a positive association between acetaminophen exposure and ADHD/ASD risk suffer from significant biases, including selection bias and inadequate control for confounders.
- When familial confounding (shared genetics and environment) was addressed using sibling analyses, the observed associations substantially weakened.
- The current body of evidence suggests that in utero acetaminophen exposure does not confer a clinically significant increased risk for childhood ADHD or ASD.
Conclusions:
- The existing scientific evidence does not support a clinically important link between maternal acetaminophen use in pregnancy and increased risk of ADHD or ASD in children.
- Current clinical guidelines for managing pain or fever during pregnancy do not require revision based on this evidence.
- Further prospective research is needed to investigate potential confounding factors, including familial and psychosocial influences on both maternal medication use and child neurodevelopment.
Abstract:
Acetaminophen is a common over-the-counter medication that recently gained substantial media attention regarding its use by pregnant individuals. In this clinical perspective, we discuss the strengths and limitations of the published literature on the effect of maternal acetaminophen use in pregnancy on the child's risk of developing attention-deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Studies included were specifically selected on the basis of the quality and validity of ADHD or ASD outcome definitions. From a total of 56 identified studies, commentaries, and editorials of relevance, we critically reviewed nine studies with original data that satisfied our inclusion criteria and three meta-analyses. Most studies that have reported positive findings are difficult to interpret because they have important biases, notably a high degree of selection bias, variability in selection and adjustment for various potential confounders, and unmeasured familial confounding. When unobserved familial confounding through sibling analysis was controlled for, associations weakened substantially. This suggests that residual confounding from shared genetic and environmental factors may have caused an upward bias in the original observations. According to the current scientific evidence, in utero exposure to acetaminophen is unlikely to confer a clinically important increased risk of childhood ADHD or ASD. The current level of evidence does not warrant changes to clinical guidelines on the treatment of fever or pain in pregnancy. Prospective research designed to account for familial and psychosocial environmental factors related to both maternal use of acetaminophen and children's neurodevelopment should be undertaken.
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