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

Christina Ricci^1,2, Carmela Melina Albanese¹, Lesley A Pablo³

¹Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

Paediatric and Perinatal Epidemiology

|March 20, 2023

Insights

In utero acetaminophen exposure is linked to an increased risk of attention deficit/hyperactivity disorder (ADHD) in children. This association persists even after accounting for reasons for acetaminophen use during pregnancy.

Area of Science:

Neuroscience
Developmental Pediatrics
Pharmacology

Background:

Acetaminophen is a common analgesic for pain and fever.
Concerns exist regarding potential adverse neurodevelopmental outcomes from in utero acetaminophen exposure.
The role of indication for use versus direct drug effects remains unclear.

Purpose of the Study:

To systematically review the literature on the association between prenatal acetaminophen exposure and child neurodevelopmental outcomes.
To evaluate the impact of confounding by indication on this association.

Main Methods:

Comprehensive literature search across OVID (Medline, Embase, PsycINFO) and EBSCO (CINAHL) databases up to August 2022.
Inclusion of peer-reviewed, English-language studies on in utero acetaminophen exposure and child neurodevelopment.
Meta-analysis of risk ratios for outcomes in at least three studies; narrative synthesis for others, with quality assessment using the Systematic Assessment of Quality in Observational Research.

Main Results:

Twenty-two studies (n=367,775) were included, primarily prospective cohorts from Europe and the US.
In utero acetaminophen exposure showed an association with increased ADHD risk (unadjusted pooled RR 1.32; adjusted RR 1.34).
The association remained consistent after adjusting for confounders, including indications for acetaminophen use.

Conclusions:

Confounding by indication does not fully explain the observed association between prenatal acetaminophen exposure and childhood ADHD.
Further high-quality research is necessary to elucidate the relationship between in utero acetaminophen exposure and various neurodevelopmental outcomes.

Read full 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.

Keywords:

acetaminophen attention deficit disorder with hyperactivity child development meta-analysis pregnancy outcome

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