Association Between Maternal Acetaminophen Use During Pregnancy and Autism in Children
Current evidence suggests there is a possible association between maternal acetaminophen use during pregnancy and increased risk of autism spectrum disorder (ASD) in offspring, particularly when ASD is accompanied by hyperkinetic symptoms, but the evidence remains inconclusive and has significant methodological limitations.
Current Evidence on the Association
Observational studies have found an association between prenatal acetaminophen exposure and increased risk of autism spectrum disorder (ASD), particularly when accompanied by hyperkinetic symptoms (hazard ratio = 1.51,95% CI 1.19-1.92), but not with ASD without hyperkinetic disorder (hazard ratio = 1.07,95% CI 0.92-1.24) 1
A large Danish National Birth Cohort study (n=64,322) showed that longer duration of acetaminophen use (>20 weeks in gestation) increased the risk of ASD with hyperkinetic symptoms almost twofold 1
Recent systematic reviews have found associations between prenatal acetaminophen exposure and ASD outcomes with risk ratios ranging from 1.093 to 1.19 2
The risk appears to be dose-dependent, with stronger associations observed with longer duration of exposure (≥28 days) 2
Limitations of Current Evidence
The FDA and Society for Maternal-Fetal Medicine (SMFM) 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" 2
Most studies have significant methodological limitations, including:
- Self-reported acetaminophen use with potential for recall bias 2
- Lack of information on dosage and duration of exposure 2
- Inability to control for all potential confounders such as the reason for acetaminophen use 2
- Outcome measurement using parental surveys rather than clinical assessment in some studies 2
While correlating exposures during pregnancy with childhood outcomes is challenging, it is especially difficult with neurobehavioral disorders whose definition and diagnosis continue to evolve 2
Potential Mechanisms
- Several hypothesized mechanisms may explain the potential association:
- Acetaminophen may indirectly activate the maternal immune system and fetal endocannabinoid system, which have been implicated in both ASD and ADHD etiology 2
- Animal studies have found links between acetaminophen exposure and lower levels of brain-derived neurotrophic factor (BDNF) in the striatum, with alterations in dopamine metabolism 2
- Disruption of rapid brain growth and structural differentiation during the third trimester 2
Clinical Recommendations
The Society for Maternal-Fetal Medicine advises that acetaminophen be considered a reasonable and appropriate medication choice for the treatment of pain and/or fever during pregnancy 3
Acetaminophen should be used at the lowest effective dose for the shortest possible duration, and excessive or prolonged use should be avoided 4, 3
Healthcare providers should closely monitor pregnant women who use acetaminophen across all trimesters 4, 3
Communication regarding the risks versus benefits of acetaminophen use should occur between patient and provider 3
Key Considerations for Clinical Practice
Acetaminophen remains the safest analgesic and antipyretic option during pregnancy, but should only be used when medically indicated 4
The risk appears higher with:
Male offspring may have a slightly higher risk than females, though effect sizes for gender differences are too small to draw firm conclusions 2
Recent comprehensive evaluation using the Navigation Guide methodology found that higher-quality studies were more likely to show positive associations between prenatal acetaminophen use and neurodevelopmental disorders 5