Prenatal and postnatal exposure to acetaminophen in relation to autism spectrum and attention-deficit and hyperactivity symptoms in childhood:
Meta-analysis in six European population-based cohorts

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The results of our meta-analysis representing more than 70,000 children of six European population-based birth/child cohorts indicated that children prenatally exposed to acetaminophen were 19% and 21% more likely to subsequently have ASC and ADHD symptoms within the borderline/clinical range, respectively, compared with non-exposed children. The association with ASC was attenuated after omitting the largest cohort but remained positive. When stratifying by sex, these associations were slightly stronger among boys compared to girls but positive associations with effect sizes of similar magnitude were observed in both strata, especially in the case of ADHD. Postnatal exposure to acetaminophen was not associated with either of the outcome, thought there was evidence of between-study heterogeneity for the association with ASC symptoms.

The most consistent pattern of results was observed for the association between prenatal acetaminophen exposure and ADHD symptoms. The positive associations were observed in all the cohorts and of similar magnitude regardless of the cohort excluded in the leave-one-out analysis. This finding is in agreement with previous meta-analysis which reported likelihood increases of 25% and 34% for ADHD in relation to prenatal acetaminophen exposure [12, 13]. Our findings are consistent with previous single cohort studies conducted in ALSPAC [7], DNBC [1, 9] and INMA [6] cohorts, which were included in our meta-analysis. Despite the overlap of samples included, this agreement supports the robustness of the findings since analytical strategies and outcome definitions were harmonized for the present meta-analysis.

The association between prenatal acetaminophen use and ASC symptoms was consistently positive even after omitting the largest cohort. Previous findings in DNBC only found this association in ASC cases with hyperactive symptoms [9], however, in our meta-analysis the association remained after excluding ADHD cases. Overall our findings provide support for the association between prenatal acetaminophen and ASC symptoms in line with a previous meta-analysis [12].


Associations between postnatal acetaminophen exposure and both ASC and ADHD symptoms were close to the null and different directions of associations around the null were observed across cohorts. Heterogeneity was high in the case of ASC, with about 50% of the variation in odds of ASC symptoms being explained by between study differences. The high prevalence of the exposure to acetaminophen when combining pre- and post-natal across studies made it impossible to explore cumulative effects combining prenatal and postnatal exposures. Previous studies examining postnatal acetaminophen exposure have focused on ASC and results are mixed [17, 32, 33]. We do not find evidence supporting this association in either ASC or ADHD symptoms but further research in larger samples is required.

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