Canadian Study Finds No Link Between Epidural Labor Analgesia and Autism Spectrum Disorders

In a new, population-based cohort study, Canadian researchers found no association between exposure to epidural labor analgesia and an increased risk of autism spectrum disorders (ASD) in children.

Epidural labor analgesia is given to 73% of pregnant women during labor in the U.S., but in a study published in October 2020, Qiu et al reported a 37% increased chance of ASD in offspring born to women electing epidural labor analgesia during labor.

“After publication, 5 medical societies that represent more than 100,000 physicians questioned the biologic plausibility of the reported association and expressed concern that the risk estimates were biased due to residual confounding. These findings may have created apprehension among pregnant women and maternal care professionals about the risk to the offspring from ELA exposure,” wrote Elizabeth Wall-Wieler, PhD, of the University of Manitoba, Winnipeg, Manitoba, Canada, and colleagues, in JAMA Pediatrics.

In this longitudinal study of vaginal deliveries of infants born from 2005-2016 (included in a population-based data set linking healthcare databases in Manitoba, Canada), Wall-Wieler and colleagues included 123,175 infants (maternal mean age: 28.2 years; 50.9% boys).

In all, 38.2% of the infants were exposed to epidural labor analgesia, of whom 2.1% were diagnosed with ASD during follow-up (HR: 1.25; 95% CI: 1.15-1.36), compared with 1.7% of unexposed infants.

After adjusting for maternal characteristics, including sociodemographic factors, prepregnancy, pregnancy, and perinatal covariates, Wall-Wieler and colleagues found no association between epidural labor analgesia and an offspring risk of ASD (inverse probability of treatment-weight HR: 1.08; 95% CI: 0.97-1.20).

Upon conducting an adjusted analysis within-siblings, they also found no association between epidural labor analgesia and ASD (inverse probability of treatment-weighted HR: 0.97; 95% CI: 0.78-1.22).

Despite its large sample size, the study did have limitations, including the lack of assessment for the accuracy of inpatient and outpatient ICD diagnostic codes for ASD and epidural labor analgesia, and the lack of data on epidural labor analgesia dosing regimens (i.e., doses used and duration of use).

In an accompanying editorial, Gillian E. Hanley, PhD, of the University of British Columbia, Vancouver, BC, Canada, and fellow authors considered these two studies, echoing the increased universal concern caused by results from Qiu et al:

“A recent population-based study by Qiu et al reported a 37% increased risk for a diagnosis of ASD in children of mothers receiving epidural labor analgesia (ELA) for labor and delivery. Given that ELA is widely accepted as a standard for labor analgesia, these findings led to widespread public and scientific concern. It thus comes with some relief that Wall-Wieler et al found no association when controlling for key maternal sociodemographic and perinatal factors. But does the finding of the absence of evidence put this issue to rest?” they queried.

However, Hanley and colleagues also stressed the difficulties inherent in the methodologic approaches necessary to address the potential confounders inherent in such studies, not the least of which include biological, cultural, and socioeconomic factors.

“Women who choose to use ELA during labor and delivery are conceivably different from women who do not in ways that can be measured and controlled for and by factors that are more difficult to measure in epidemiologic studies. Qiu et al reported substantial increased risk for ASD associated with ELA; however, they did not account for whether there was an induction of labor, presence of labor dystocia, fetal distress, or a maternal or family history of ASD. Accounting for these and other preconception and perinatal factors to address potential confounding bias, Wall-Wieler et al found no association, suggesting that positive associations might reflect incomplete or residual confounding,” they noted.

To this end, Wall-Wieler and colleagues included a wealth of variables to control for such confounding:

“Data linkages across multiple databases, including medical services, hospital abstracts, pharmaceutical dispensations, educational level, income assistance, and postpartum screens, allowed us to capture a wide set of sociodemographic, prepregnancy, pregnancy-related, and perinatal covariates for inclusion in our regression models,” they noted, and listed these as follows:

• Sociodemographic covariates: Maternal age, high school completion, marital status, and Employment and Income Assistance during pregnancy, and neighborhood socioeconomic status.
• Prepregnancy covariates: Diabetes, hypertension, anxiety, and depression.
• Pregnancy-related covariates: Parity, gestational diabetes, gestational hypertension or preeclampsia, drug use, smoking, alcohol use, premature membrane rupture, antepartum hemorrhage, amniotic sac and membrane infections, urogenital infections, antenatal mental health hospitalization, hypothyroidism, benzodiazepine use, antidepressant use, and antiepileptic use.
• Birth and perinatal covariates: Birth year, induction of labor, labor augmentation, labor dystocia, fetal distress, fetal macrosomia, gestational age at birth, sex of offspring and hospital type.

Hanley and colleagues applauded the careful methodology of Wall-Wieler, and concluded by stressing the need for a better understanding of the risks of epidural labor analgesia:

“Epidural labor analgesia is an extremely effective approach to obstetric analgesia, and we have a collective responsibility to understand whether it is safe option that sets a healthy developmental pathway well into childhood. Women have the right to make a truly informed choice about their pain relief during labor: for their health and that of her newborn,” they concluded.

1. In a large, population-based cohort study of 123,175 offspring born in Manitoba, Canada, from 2005 to 2016, Canadian researchers found no association between maternal exposure to epidural labor analgesia and their offspring’s risk of ASD, after accounting for maternal sociodemographic, preexisting, pregnancy-related, and birth-specific factors.

2. Results refute those from a previous study, which found a 37% increase in the chance of ASD in these infants, and may lay some concerns to rest.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

Cat ID: 191

Topic ID: 83,191,730,128,191,41,135,192,925