Is there a link between Tylenol (acetaminophen) use and the development of autism?

Tylenol and Autism: Current Evidence and Recommendations

The weight of evidence is currently inconclusive regarding a causal relationship between acetaminophen (Tylenol) use and autism spectrum disorder (ASD), though some studies suggest a potential association that requires further investigation. 1

Evidence on Acetaminophen and Neurodevelopmental Outcomes

• Recent systematic reviews have found associations between prenatal acetaminophen exposure and ASD outcomes with risk ratios ranging from 1.09 to 1.19 2
• The risk appears to be dose-dependent, with stronger associations observed with longer duration of exposure (≥28 days) 1, 2
• Prenatal acetaminophen use was associated with an increased risk specifically for ASD with hyperkinetic disorder (hazard ratio 1.51; 95% CI 1.19-1.92), but not for ASD without hyperkinetic disorder (hazard ratio 1.07; 95% CI 0.92-1.24) 1, 3
• Longer duration of use (>20 weeks in gestation) increased the risk of ASD with hyperkinetic symptoms almost twofold 3
• The third trimester may present the highest risk for increased neurodevelopmental outcomes 1

Limitations of Current Evidence

• The FDA and Society for Maternal-Fetal Medicine have evaluated these studies and determined that "the weight of evidence is inconclusive regarding a possible connection between acetaminophen use in pregnancy and neurodevelopmental disorders" 1, 2
• Most studies have significant methodological limitations, including:
  • Self-reported acetaminophen use with potential for recall bias 1
  • Lack of quantification of doses 1
  • Measurement of outcomes using parental surveys rather than clinical assessments 1
  • Inability to control for all potential confounders 1
• Studies show heterogeneity in both measures and outcomes 1

Potential Mechanisms

• Acetaminophen may indirectly activate the maternal immune system and fetal endocannabinoid system, which have been implicated in both ASD and ADHD etiology 1, 2
• Animal studies have found links between acetaminophen exposure and lower levels of brain-derived neurotrophic factor (BDNF) in the striatum and alterations in dopamine metabolism 1
• Prenatal acetaminophen exposure has been associated with affected frontoparietal brain connectivity in children 1
• Acetaminophen may influence inflammatory and immunologic mechanisms and may predispose to oxidative stress 4, 5

Clinical Recommendations

• The Society for Maternal-Fetal Medicine advises that acetaminophen can still be considered a reasonable and appropriate medication choice for the treatment of pain and/or fever during pregnancy 1
• If acetaminophen is used during pregnancy, it should be at the lowest effective dose for the shortest possible duration 2
• Communication regarding the risks versus benefits of acetaminophen use should occur between patient and provider 1
• Use caution particularly with long-term use (>28 days) and during the third trimester 1, 2

Key Points for Clinical Practice

• The strongest evidence suggests a possible link between acetaminophen and ASD specifically with hyperkinetic symptoms, rather than ASD broadly 1, 3
• While some studies suggest male offspring may have a slightly higher risk than females, effect sizes for gender differences are too small to draw firm conclusions 1, 2
• The definition and diagnosis of neurodevelopmental disorders continues to evolve, making it difficult to establish clear causal relationships 1
• Multiple potential confounders exist, including environmental exposures and genetic predisposition 1