In utero acetaminophen exposure and child neurodevelopmental outcomes: Systematic review and meta‐analysis

Abstract

Background Acetaminophen is a frequently used analgesic for pain and fever. There have been reports of adverse neurodevelopmental outcomes associated with in utero acetaminophen exposure. However, it is unclear whether this association is related directly to acetaminophen use, or the reasons for use. Objectives To summarise the literature on the association between in utero acetaminophen exposure and child neurodevelopmental outcomes, and assess the extent to which the association is due to confounding by indication. Data Sources OVID for Medline, Embase, and PsycINFO, and EBSCO for CINAHL, from inception to August 18, 2022. Study Selection and Data Extraction We searched for peer‐reviewed, English‐language studies on in utero acetaminophen exposure and child neurodevelopmental outcomes. Data were extracted using a standardised form created a priori, and quality was assessed using the Systematic Assessment of Quality in Observational Research. Synthesis We generated pooled risk ratios (RR) for outcomes examined by ≥3 studies using random‐effects models; outcomes that could not be meta‐analysed were narratively summarised following Synthesis Without Meta‐Analysis guidelines. Results Twenty‐two studies including 23 cohorts were eligible (n = 367,775 total participants; median: 51.7% with acetaminophen exposure). Studies were primarily prospective cohort studies from Europe and the US, with attention deficit/hyperactivity disorder (ADHD) being the most common outcome. Quality assessments resulted in 13.6% of studies being classified as high, 59.1% as medium, 22.7% as low, and 4.5% as very low quality. In utero acetaminophen exposure was associated with an elevated risk of ADHD (unadjusted pooled RR 1.32, 95% confidence interval [CI] 1.20, 1.44; I2 = 47%, n = 7 studies), with little difference after adjusting for confounders, including indications for acetaminophen use (adjusted pooled RR 1.34, 95% CI 1.15, 1.55; I2 = 50%, n = 4 studies). Conclusions Confounding by indication did not explain the association between in utero acetaminophen exposure and child ADHD. Further, high‐quality research is needed on this and other neurodevelopmental outcomes.