By Maria F. Gallo, PhD
Professor, Chair, and Associate Dean of Research, College of Public Health, Division of Epidemiology, The Ohio State University, Columbus
SYNOPSIS: Use of epidural analgesia by pregnant women in labor was not associated with an increased risk of autism spectrum disorder or attention-deficit/hyperactivity disorder in the resulting children after controlling for confounding factors, including familial risks.
SOURCE: Hegvik T-A, Klungsøyr K, Kuja-Halkola R, et al. Labor epidural analgesia and subsequent risk of offspring autism spectrum disorder and attention-deficit/hyperactivity disorder: A cross-national cohort study of 4.5 million individuals and their siblings. Am J Obstet Gynecol 2022; Aug 13. doi: 10.1016/j.ajog.2022.08.016. [Online ahead of print].
Epidural, spinal, or combined spinal-epidural analgesia is a safe and effective method of pain relief for pregnant people in labor. Because of this, the American College of Obstetricians and Gynecologists (ACOG) recommends that epidural analgesia be provided to any patient, regardless of their insurance status, who chooses it for pain relief during labor unless there is a medical contraindication.1 Its use is common: About 73% of women who were in labor in the United States in 2015 used epidural or spinal analgesia.2
In 2020, Qui et al published a study showing an association between the use of epidural analgesia during labor and autism spectrum disorder (ASD) in the resulting children.3 Their analysis was based on administrative records on almost 148,000 singleton, term, live births in the Kaiser Permanente Southern California hospital system. After controlling for numerous confounders related to maternal demographics, health behaviors, medical and obstetrical history, labor, delivery, and offspring characteristics, they found a hazard ratio of ASD of 1.37 (95% confidence interval [CI], 1.23-1.53) for the children whose birth had involved epidural analgesia during labor compared to those without this exposure. Furthermore, there appeared to be a dose-response relationship between the duration of epidural analgesia and the risk of ASD.
The strength of the association, though, was modest and could be completely the result of uncontrolled confounding. That is, women with more depressive and anxiety symptoms might be more likely to decide to use epidural analgesia during labor compared to those with lower scores for depression or anxiety.4 At the same time, the offspring of someone with depression and anxiety could be genetically predisposed to have a higher risk of ASD. In this way, the use of epidural analgesia during labor might be associated with having a child with ASD without the exposure to epidural analgesia being the cause of ASD in the child. In response to this methodological limitation, several researchers since have conducted similar analyses using other data sources.
To date, Hegvik and colleagues have published the largest study that attempted to replicate these earlier findings. Hegvik et al analyzed almost 4.5 million singleton, term, live births occurring in 1987-2005 in Finland, in 1999-2015 in Norway, and in 1987-2011 in Sweden. They used birth registers to determine whether epidural analgesia was used during labor. They then were able to link the births to population and patient registries, which they reviewed for a mean follow-up period of 13.6 to 16.8 years to see whether the resulting children were diagnosed with ASD or attention-deficit/hyperactivity disorder (ADHD). They based the diagnoses of ASD or ADHD on codes from the International Classification of Diseases (ICD-9 or ICD-10, depending on the timing during follow-up) or else documentation of at least one prescription medication for treating ADHD. They analyzed the data separately for ASD and ADHD for each of the three countries and then pooled the country data together in meta-analyses, which weigh the individual effect estimates according to their relative statistical power.
Overall, 24% of the births had epidural analgesia use during labor. ASD diagnoses were higher in children whose birth had involved epidural analgesia during labor (1.20%) compared to those without this exposure (1.07%). This difference appeared to be statistically significant. The pooled hazard ratio, which was adjusted for infant sex, birth year, and birth order, was 1.12 (95% CI, 1.10-1.14). However, the investigators then repeated the analysis for each country after restricting the samples to include only full-sibling births in which at least one sibling was exposed to epidural analgesia during labor and at least one sibling did not have this exposure. This allowed the investigators to compare the risk of ASD between differentially exposed full-siblings and, thus, control for unmeasured confounding involving shared familial risks, such as genetic risks of ASD. With these restricted samples, the pooled adjusted hazard ratio of ASD was 0.98 (95% CI, 0.93-1.03). That is, epidural analgesia use during labor and ASD no longer were statistically significantly associated.
The analyses on the time to ADHD diagnosis showed similar patterns. ADHD diagnoses were higher in children whose birth had involved epidural analgesia during labor (3.95%) compared to those without this exposure (3.32%). The pooled adjusted hazard ratio for having ADHD was 1.20 (95% CI, 1.19-1.21), suggesting that exposure to epidural analgesia during labor led to a higher risk of ADHD in the resulting children. However, again, when the investigators restricted the samples to full-siblings who were differentially exposed to epidural analgesics during labor, the pooled adjusted hazard ratio (0.99) no longer was statistically significant (95% CI, 0.96-1.02).
COMMENTARY
The publication in 2020 by Qui and colleagues showing an association between the use of epidural analgesia during labor and ASD in the resulting children was followed by numerous critiques.3 Notably, five professional associations quickly issued a joint statement that the study failed to provide “credible scientific evidence” that epidural analgesia during labor causes autism.5 A primary criticism was that the modest association potentially could be completely artificial. They argued that it instead could be explained by the failure to control for important confounding related to both the likelihood of using epidural analgesics during labor and the risk of ASD.
Furthermore, the biological mechanism by which exposure to epidural analgesia during labor could cause ASD is unknown. We lack evidence on how the low levels of exposure to analgesia during labor theoretically could cause harm to the infant’s brain. While we do not always have the knowledge to identify a plausible mechanism, this is one of the nine criteria established by Bradford Hill for epidemiologic evidence of a causal relationship between an exposure and outcome.6
The analysis by Hegvik and colleagues was a response to address the methodological issues that were present in the earlier study. First, Hegvik et al used a much larger sample size: 4,498,462 mother-child pairs compared to 147,895 mother-child pairs in the earlier study. Consistency across settings is another of the nine criteria for causality, and Hegvik et al analyzed data in three countries, which appeared consistent.6 That is, the effect estimates from the individual countries appeared to consistently follow the pattern in which the hazard ratio was attenuated in the analysis using the full-sibling comparisons relative to the analysis based on the larger population sample. However, this qualitative assessment would be strengthened had the authors followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines by also reporting the measures of statistical heterogeneity for their pooled analyses.7
The primary strength of the Hegvik et al study was that they accounted for shared familial risks by limiting their analysis to study children with full-siblings who did not have epidural analgesia used during labor. This might not have controlled completely for confounding, since some important factors still could have differed between the births. However, it likely controlled for much of the residual confounding, including the genetic risks shared between the full-siblings. The consistency in the attenuation between the full and restricted analyses in each of the three states supports the importance of this approach. Finally, the authors also evaluated ADHD because its prevalence is much higher than that of ASD and, thus, could help shed more light on a link if epidural analgesia use were causally associated with neurodevelopmental disorders. The similarities in the patterns of findings between both outcomes suggests that a causal relationship was not overlooked.
The study by Hegvik and colleagues should reassure clinicians and pregnant people that evidence does not support a causal relationship between the use of epidural analgesia during labor and the development of ASD or ADHD in the resulting child. Clinicians should continue to offer epidural analgesia during labor to patients who want to use this for pain relief.
REFERENCES
- [No authors listed]. Practice Bulletin No. 177 summary: Obstetric analgesia and anesthesia. Obstet Gynecol 2017;129:766-768.
- Butwick AJ, Bentley J, Wong CA, et al. United States state-level
variation in the use of neuraxial analgesia during labor for pregnant women. JAMA Netw Open 2018;1:e186567.
- Qiu C, Lin JC, Shi JM, et al. Association between epidural analgesia during labor and risk of autism spectrum disorders in offspring. JAMA Pediatr 2020;174:1168-1175.
- Alder J, Fink N, Bitzer J, et al. Depression and anxiety during pregnancy: A risk factor for obstetric, fetal and neonatal outcome? A critical review of the literature. J Matern Fetal Neonatal Med 2007;20:189-209.
- American Society of Anesthesiologists. Labor epidurals do not cause autism; safe for mothers and infants, say anesthesiology, obstetrics, and pediatric medical societies. Published Oct. 12, 2020. https://www.asahq.org/about-asa/newsroom/news-releases/2020/10/labor-epidurals-and-autism-joint-statement
- Hill AB. The environment and disease: Association or causation? 1965. J R Soc Med 2015;108:32-37.
- Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021;372:n71.
