Association of Labor Epidural Analgesia Exposure with Long-Term Risk of Autism Spectrum Disorder in Offspring: A Meta-Analysis of Observational Studies

To investigate the association between labor epidural analgesia exposure and the risk of autism spectrum disorder in offspring, this meta-analysis reviewed relevant literature from Medline, Cochrane Library, Google Scholar, and EMBASE databases from inception to May 2022 to evaluate the overall adjusted risk of autism spectrum disorder in offspring (primary outcome) and adjusted risks of autism spectrum disorder focusing on sibling-matched data, children who were delivered vaginally, and duration of labor epidural analgesia exposure (secondary outcomes). Pooled results of seven eligible observational studies involving 4,021,406 children revealed slightly higher risks of autism spectrum disorder in children with labor epidural analgesia exposure than those without (hazard ratio = 1.11, 95% confidence interval: 1.06-1.16, I[superscript 2] = 67%, seven studies, level of evidence: very low). Consistent findings were found in subgroup analysis focusing on sibling data (hazard ratio: 1.10, 95% confidence interval: 1.02-1.18, I[superscript 2] = 0%, five studies) and children delivered vaginally (hazard ratio: 1.11, 95% confidence interval: 1.06-1.17, I[superscript 2] = 64%, seven studies). The tendency of an increased risk of autism spectrum disorder in children exposed to labor epidural analgesia <4 h was not observed in those exposed to labor epidural analgesia >8 h (two studies). Although our results demonstrated a slightly increased risk of autism spectrum disorder in offspring with previous labor epidural analgesia exposure, the small effect size and lack of cumulative dose-response effect precluded tangible evidence supporting the association.