By Rebecca H. Allen, MD, MPH, Editor
In this retrospective cohort study of 147,895 singleton births, epidural anesthesia was used in 74.2% of cases and the hazard ratio for the subsequent diagnosis of autism spectrum disorders was 1.37 (95% confidence interval, 1.23-1.53).
Chunyuan Q, Lin JC, Shi JM, et al. Association between epidural analgesia during labor and risk of autism spectrum disorders in offspring. JAMA Pediatr 2020; Oct. 12. doi: 10.1001/jamapediatrics.2020.3231. [Online ahead of print].
The authors of this study sought to evaluate the association between epidural analgesia for labor and delivery with the development of autism spectrum disorders in offspring. This was a retrospective cohort study that included vaginal deliveries between 28 and 44 weeks of gestation at Kaiser Permanente Southern California (KPSC) hospital system between Jan. 1, 2008, and Dec. 31, 2015. Children were followed in the KPSC system, and a screening checklist for autism was routinely administered to all children between ages 18 and 24 months. Clinical diagnosis of autism spectrum disorder (ASD) required a pediatric developmental specialist evaluation. The outcome variable was identified by using diagnosis codes for autism spectrum disorders from at least two separate visits. Children were followed until clinical diagnosis of autism, death, or study end date of Dec. 31, 2018. The exposure variable was epidural analgesia during labor and delivery, which was obtained through procedure notes. Data on the duration of epidural, any documented fever (38°C or higher) during labor, and any epidural-related maternal fever also were collected. Data on other confounders were recorded, including age, parity, educational level, self-reported race/ethnicity, median family household income based on census tract of residence, medical center of delivery, history of comorbidity, obesity, diabetes, preeclampsia or eclampsia, smoking, gestational age, birth weight, sex, and presence of birth defects.
There were 147,895 deliveries (50.3% male) during the study period with a mean gestational age of 39.8 (± 1.5) weeks, and 109,719 (74.2%) used epidural analgesia. The two groups were significantly different, with women using epidurals more likely to be younger, non-Hispanic, nulliparous, and of higher socioeconomic status based on education and income. Fever during labor occurred in 11.9% of those in the epidural group and 1.3% of those without epidural (P < 0.001). Fever occurred more commonly the longer the exposure was to the epidural, with a rate of 2.5% for less than four hours, 9.9% for four to eight hours, and 26.8% for more than eight hours. During follow-up, 2,524 children had diagnosis codes for autism spectrum disorders: 1.9% in the epidural group and 1.3% in the non-epidural group. In bivariable analysis adjusted for birth year, the hazard ratio (HR) of autism with epidural exposure was 1.48 (95% confidence interval [CI], 1.34-1.65). Adjusting for all confounding variables, including birth year, maternal age, parity, race/ethnicity, educational level, income, history of comorbidity, diabetes, smoking, preeclampsia or eclampsia, obesity, gestational age at delivery, birth weight, and medical center of delivery, the adjusted HR was 1.37 (95% CI, 1.23-1.53). There was no definitive relationship between the duration of epidural and the risk of autism. After excluding women who had fever prior to epidural placement, fever after epidural was not associated with risk of autism (adjusted HR, 1.03; 95% CI, 0.89-1.20). Excluding preterm deliveries and children with birth defects did not substantially change the results.
COMMENTARY
Not surprisingly, this study received a lot of media attention when it was published. ASD occurs in approximately 25 per 1,000 children, more commonly in boys, and is a diagnosis that prospective parents fear.1 The etiology of ASD is not fully known and there are many potential factors involved. The strongest etiology is believed to be genetic, given that family history is a strong risk factor and there is an increased prevalence in siblings and a high concordance in monozygotic twins. However, environmental factors also may contribute.
Epidural analgesia is the most common method of pain control for labor and delivery in the United States. Epidurals have been demonstrated to be safe for women and newborns in the perinatal period.2 Nevertheless, the authors of this study wanted to evaluate the long-term effects of epidurals, stating that standard doses of local anesthetics can produce neurotoxic effects and alter normal behavioral development in rhesus monkeys.
Additionally, they noted that a recent meta-analysis reported a higher risk of ASD after cesarean delivery (1.33; 95% CI, 1.25-1.41) compared to vaginal delivery.3 The authors speculated the mechanism of action to be potential neurotoxic effects of local anesthetic exposure to the fetus and possibly dysregulation of the maternal immune system by initiation of the epidural.
Although the study was large and attempted to control for many confounders, there are serious limitations. Observational studies cannot prove causality, and the strength of the association in this investigation, an HR of 1.37, is very weak. Generally, measures of association less than 2 could be the result of uncontrolled confounding. Confounders not controlled for in this study include family history of ASD, length of labor and rupture of membranes, fetal distress during labor, Apgar scores, and maternal or neonatal infection. In response to this publication, the Society for Obstetric Anesthesia and Perinatology (SOAP), the American Society of Anesthesiologists, the Society for Pediatric Anesthesia, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine released a statement to reassure women that this study did not prove causality.4 “Neuraxial analgesia is the gold standard for labor pain relief,” said Ruth Landau, Virginia Apgar Professor of Anesthesiology and president of SOAP. “We should not stop providing labor epidurals, and if anything, epidurals improve maternal and neonatal outcomes.”
The question is, what would be the alternative for pain control during labor and delivery or for anesthesia during cesarean delivery? Are women not supposed to have the option for pain relief during labor and delivery or not have cesarean delivery because of the possible link to future autism in their child? We should be careful not to blame childhood outcomes on women for their behaviors and choices during pregnancy and delivery. Although I do not think the authors were deliberately trying to be misogynistic and were just exploring a scientific hypothesis, their conclusions should have been more tempered. Given the weak association found in this study and the complexity of the pathogenesis of autism, I would interpret this as a negative study.
REFERENCES
- Kogan MD, Vladutiu CJ, Schieve LA, et al. The prevalence of parent-reported autism spectrum disorder among US children. Pediatrics 2018;142:e20174161.
- American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins – Obstetrics. ACOG Practice Bulletin No. 209: Obstetric analgesia and anesthesia. Obstet Gynecol 2019;133:e208-e225.
- Zhang T, Sidorchuk A, Sevilla-Cermeno L, et al. Association of cesarean delivery with risk of neurodevelopmental and psychiatric disorders in the offspring: A systematic review and meta-analysis. JAMA Netw Open 2019;2:e1910236.
- The American College of Obstetricians and Gynecologists. Labor epidurals do not cause autism; safe for mothers and infants, say anesthesiology, obstetrics, and pediatric medical societies. Oct. 13, 2020. https://www.acog.org/news/news-releases/2020/10/labor-epidurals-do-not-cause-autism-safe-for-mothers-and-infants
