Association of labor epidural analgesia exposure with long-term risk of autism spectrum disorder in offspring: A meta-analysis of observational studies

Abstract

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, I2 = 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, I2 = 0%, five studies) and children delivered vaginally (hazard ratio: 1.11, 95% confidence interval: 1.06–1.17, I2 = 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. Lay abstract A previous meta-analysis has demonstrated a superior analgesic efficacy of epidural analgesia (e.g. labor epidural analgesia) in comparison with non-epidural approaches. The widely accepted safety of labor epidural analgesia also endorses its current popularity in obstetric practice. However, the results of a recent large-scale longitudinal study that demonstrated a significant increase in risk of autism spectrum disorder in offspring from mothers with labor epidural analgesia exposure have raised some concerns over the safety of its use. The current meta-analysis aimed at examining the strength of evidence regarding this issue based on updated clinical data. Through systematically reviewing seven eligible observational studies involving 4,021,406 children from electronic databases, our results showed a slight but statistically significant increase in risk of autism spectrum disorder in children with exposure to labor epidural analgesia compared with those without. The finding was consistent in subgroup analysis focusing on siblings and children delivered vaginally. Nevertheless, despite the tendency of an increased risk of autism spectrum disorder in children exposed to labor epidural analgesia <4 h, this effect was not observed in those exposed to labor epidural analgesia >8 h (data from two studies). In conclusion, the level of evidence linking labor epidural analgesia to autism spectrum disorder development in offspring was very low based on the latest data because of the small effect size and the finding of a lack of cumulative dose–response effect in the current analysis. Further studies are warranted to provide an insight into this issue.

Decoding labour epidural analgesia and autism

“…However, upon accounting for potential confounders, the effect diminished, yet remained statistically significant [hazard ratio 1.13, 95% CI, 1.03 to 1.25, and hazard ratio 1.11, 95% CI, 1.06 to 1.165] 16 . Nevertheless, when only studies using a sibling-matched design were analysed, this meta-analysis concluded that there was no significant association (hazard ratio 1.07, 95% CI, 0.99 to 1.16), 13,16 whereas another demonstrated a significant association in sibling-matched designed studies [hazard ratio 1.10, 95% CI, 1.02 to 1.18], 13 with, however, no dose–response effect. It was concluded that the small statistically significant association between LEA and ASD may be elucidated by selection bias and residual (unmeasured) confounders, such as genetic factors 16 …”

“…Meta-analyses conducted on this topic present an intriguing picture. [13][14][15][16] On one hand, they reveal an association between neuraxial labour analgesia and autism when no confounding variables are considered. However, a critical turning point emerges when confounders are pondered, resulting in a very weak association.…”

“…It is, therefore, crucial to approach the findings of Qiu et al 1 and related meta-analyses [13][14][15][16] with caution. The presence of an association without confounders does not imply causation.…”

“…Meta-analyses conducted on this topic present an intriguing picture 13–16 . On one hand, they reveal an association between neuraxial labour analgesia and autism when no confounding variables are considered.…”