Is acetaminophen (paracetamol) safe to use during pregnancy in women at high risk of having a child with autism spectrum disorder?

Acetaminophen Use During Pregnancy and Autism Risk

Acetaminophen should be considered a reasonable medication choice for necessary pain or fever during pregnancy, but should be used at the lowest effective dose for the shortest duration possible due to inconclusive but concerning evidence regarding potential associations with neurodevelopmental disorders including autism spectrum disorder. 1

Current Guidelines and Evidence

The Society for Maternal-Fetal Medicine (SMFM) and the American College of Obstetricians and Gynecologists (ACOG) maintain that acetaminophen remains the safest medication option during pregnancy for necessary pain or fever relief 1. However, several important considerations should guide its use:

• The weight of evidence regarding a possible causal relationship between acetaminophen use during pregnancy and autism spectrum disorder is currently inconclusive 1
• 40-65% of pregnant women use acetaminophen at some point during pregnancy 1
• Multiple studies have found associations between maternal acetaminophen use and increased risk of neurodevelopmental disorders, particularly when used for longer durations 1, 2

Risk Factors and Considerations

Duration of Use

• Longer duration of acetaminophen use appears to increase risk:
  • Use for >20 weeks in gestation may increase the risk of ASD with hyperkinetic symptoms almost twofold 2
  • Use for ≥28 days is associated with a higher risk (RR = 1.63) 1

Specific Neurodevelopmental Concerns

• Prenatal acetaminophen exposure has been associated with:
  • ASD with hyperkinetic disorder (hazard ratio of 1.51,95% CI 1.19-1.92) 1, 2
  • ADHD outcomes (risk ratios of 1.08-1.34) 1, 3

Confounding Factors

• The conditions requiring acetaminophen (fever, inflammation) may themselves contribute to neurodevelopmental outcomes 1
• One pivotal study adjusted for pain, infection, inflammation, and fever to reduce confounding by indication and still found a dose-dependent risk 3

Clinical Recommendations

1. Risk-Benefit Assessment

   • Discuss risks versus benefits with patients at high risk of having a child with autism spectrum disorder
   • Untreated pain or fever may pose greater risks than acetaminophen use 1

2. Usage Guidelines

   • Use acetaminophen at the lowest effective dose for the shortest possible time 1
   • Avoid prolonged use without periodic evaluation of continued need 1
   • Exercise particular caution with prolonged use, especially in second and third trimesters 1

3. Alternative Approaches

   • Consider non-pharmacological approaches for mild to moderate pain when appropriate 1
   • For severe pain or fever that requires treatment, acetaminophen remains the preferred medication during pregnancy 1

Common Pitfalls to Avoid

• Overuse without indication: Avoid routine or prolonged use without clear medical necessity
• Failure to consider alternatives: Non-pharmacological pain management should be considered first for mild pain
• Causing unnecessary anxiety: While discussing risks, emphasize that the evidence is inconclusive and that untreated fever or pain may pose greater risks
• Ignoring dose and duration: The risk appears to increase with longer duration and higher doses of acetaminophen use 1, 2

While concerns exist about acetaminophen use during pregnancy and autism risk, the current evidence does not support withholding acetaminophen when clinically indicated. Instead, judicious use following a careful risk-benefit assessment is recommended, particularly in women at high risk of having a child with autism spectrum disorder.