1. In a Canadian population-based birth cohort study, no association was found between epidural labor analgesia (ELA) exposure and risk of autism spectrum disorder (ASD) in offspring.
2. In the sibling cohort, adjusting for baseline covariates, ELA was not associated with an increased offspring risk of ASD.
Evidence Rating Level: 2 (Good)
Study Rundown: Due to a rise in the US incidence of ASD in the past two decades, there has been substantial interest in identifying potential genetic, maternal, and neurological factors for ASD. It is known that perinatal morbidities and interventions, including birth injury, low birth weight, and cesarean delivery, may lead to neonatal neurological vulnerability and, thus, increase the offspring risk of ASD. More recent research has focused on associations between intrapartum interventions, such as ELA, and the risk of ASD. However, these studies often do not account for the risk estimate biases due to residual confounding and have been questioned on the biologic plausibility of their reported associative findings. This longitudinal cohort study sought to examine the association between ELA and offspring risk of ASD in Manitoba, Canada, adjusting for a large set of potential confounders. The primary outcome of the study was a diagnosis of ASD in the offspring, classified by the presence of at least 1 inpatient or outpatient diagnosis of ASD after the offspring reached at least 18 months of age. Using the inclusion and exclusion criteria, 123,175 offspring from singleton live vaginal births were included in the study. 47,011 (38.2%) offspring were exposed to ELA during delivery and of these, 985 (2.1%) were diagnosed with ASD in the follow-up period. In contrast, 1,272 of the 76,164 (1.7%) unexposed offspring were diagnosed with ASD. Upon adjusting for potential confounders including maternal sociodemographic, pre-pregnancy, pregnancy, and perinatal covariates, no association was found between ELA and offspring risk of ASD. This was further confirmed in the sibling cohort analysis after adjusting for baseline covariation. Importantly, a limitation of this study was the lack of information on ELA drug dosing regimens and the duration of ELA exposure at the time of delivery to women in labor. Thus, it could not be determined whether drug effects were potential factors in the observed association between ELA and ASD risk.
In-Depth [prospective cohort]: This longitudinal population-based birth cohort study was performed in the province of Manitoba, Canada between 2005 and 2016 using data reported from four healthcare databases. Vaginal deliveries of singleton live infants born during the study period were screened and followed from birth until 2019 or censored by death or emigration. The study included 123,175 eligible offspring (62,647 boys, 50.9%) and the mean (SD) age of mothers at delivery was 28.2 (5.8) years. The mean follow-up period (SD) for each offspring was 7.9 (3.4) years. In total, 47,011 (38.2%) offspring were exposed to ELA during delivery and of these, 985 (2.1%) were diagnosed with ASD in the follow-up period. Comparatively, 1,272 of the 76,164 (1.7%) unexposed offspring were diagnosed with ASD (HR, 1.25; 95%CI, 1.15-1.36). After adjusting for potential confounders including maternal sociodemographic, pre-pregnancy, pregnancy, and perinatal covariates, ELA was not associated with an offspring risk of ASD (inverse probability of treatment-weighted HR, 1.08; 95%CI, 0.97-1.20). Furthermore, in the sibling cohort analysis, after adjusting for the same potential confounders and addition of family fixed effects, ELA exposure was not associated with ASD, confirming the results of the study’s primary outcome (inverse probability of treatment-weighted HR, 0.97; 95%CI, 0.78-1.22). Lastly, results of the sensitivity analyses on the population-based models restricted to women without missing information who delivered at or after 37 weeks of gestation, firstborn infants only, and offspring with ASD classified with at least 2 diagnostic codes were consistent with those from the study’s main findings.
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