Chunyuan Qiu1, Jane C Lin2, Jiaxiao M Shi2, Ting Chow2, Vimal N Desai1, Vu T Nguyen1,3, Robert J Riewerts4, R Klara Feldman5, Scott Segal6, Anny H Xiang2. 1. Department of Anesthesiology, Kaiser Permanente Baldwin Park Medical Center, Baldwin Park, California. 2. Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena. 3. Department of Internal Medicine, Kaiser Permanente Baldwin Park Medical Center, Baldwin Park, California. 4. Department of Pediatrics, Kaiser Permanente Baldwin Park Medical Center, Baldwin Park, California. 5. Department of Obstetrics & Gynecology, Kaiser Permanente Baldwin Park Medical Center, Baldwin Park, California. 6. Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
Abstract
Importance: Although the safety of labor epidural analgesia (LEA) for neonates has been well documented, the long-term health effects of LEA on offspring remain to be investigated. Objective: To assess the association between maternal LEA exposure and risk of autism spectrum disorders (ASDs) in offspring. Design, Setting, and Participants: Data for this retrospective longitudinal birth cohort study were derived from electronic medical records from a population-based clinical birth cohort. A total of 147 895 singleton children delivered vaginally between January 1, 2008, and December 31, 2015, in a single integrated health care system were included. Children were followed up from the age of 1 year until the first date of the following occurrences: clinical diagnosis of ASD, last date of health plan enrollment, death, or the study end date of December 31, 2018. Exposures: Use and duration of LEA. Main Outcomes and Measures: The main outcome was clinical diagnosis of ASD. Cox proportional hazards regression analysis was used to estimate the hazard ratio (HR) of ASD associated with LEA exposure. Results: Among the cohort of 147 895 singleton children (74 425 boys [50.3%]; mean [SD] gestational age at delivery, 38.9 [1.5] weeks), 109 719 (74.2%) were exposed to maternal LEA. Fever during labor was observed in 13 055 mothers (11.9%) in the LEA group and 510 of 38 176 mothers (1.3%) in the non-LEA group. Autism spectrum disorders were diagnosed in 2039 children (1.9%) in the LEA group and 485 children (1.3%) in the non-LEA group. After adjusting for potential confounders, including birth year, medical center, maternal age at delivery, parity, race/ethnicity, educational level, household income, history of comorbidity, diabetes during pregnancy, smoking during pregnancy, preeclampsia or eclampsia, prepregnancy body mass index, gestational weight gain, gestational age at delivery, and birth weight, the HR associated with LEA vs non-LEA exposure was 1.37 (95% CI, 1.23-1.53). Relative to the unexposed group, the adjusted HR associated with LEA exposure of less than 4 hours was 1.33 (95% CI, 1.17-1.53), with LEA exposure of 4 to 8 hours was 1.35 (95% CI, 1.20-1.53), and with LEA exposure of more than 8 hours was 1.46 (95% CI, 1.27-1.69). Within the LEA group, there was a significant trend of ASD risk associated with increasing duration of LEA exposure after adjusting for covariates (HR for linear trend, 1.05 [95% CI, 1.01-1.09] per 4 hours). Adding fever to the model did not change the HR estimate associated with LEA exposure (adjusted HR for LEA vs non-LEA, 1.37 [95% CI, 1.22-1.53]). Conclusions and Relevance: This study suggests that maternal LEA may be associated with increased ASD risk in children. The risk appears to not be directly associated with epidural-related maternal fever.
Importance: Although the safety of labor epidural analgesia (LEA) for neonates has been well documented, the long-term health effects of LEA on offspring remain to be investigated. Objective: To assess the association between maternal LEA exposure and risk of autism spectrum disorders (ASDs) in offspring. Design, Setting, and Participants: Data for this retrospective longitudinal birth cohort study were derived from electronic medical records from a population-based clinical birth cohort. A total of 147 895 singleton children delivered vaginally between January 1, 2008, and December 31, 2015, in a single integrated health care system were included. Children were followed up from the age of 1 year until the first date of the following occurrences: clinical diagnosis of ASD, last date of health plan enrollment, death, or the study end date of December 31, 2018. Exposures: Use and duration of LEA. Main Outcomes and Measures: The main outcome was clinical diagnosis of ASD. Cox proportional hazards regression analysis was used to estimate the hazard ratio (HR) of ASD associated with LEA exposure. Results: Among the cohort of 147 895 singleton children (74 425 boys [50.3%]; mean [SD] gestational age at delivery, 38.9 [1.5] weeks), 109 719 (74.2%) were exposed to maternal LEA. Fever during labor was observed in 13 055 mothers (11.9%) in the LEA group and 510 of 38 176 mothers (1.3%) in the non-LEA group. Autism spectrum disorders were diagnosed in 2039 children (1.9%) in the LEA group and 485 children (1.3%) in the non-LEA group. After adjusting for potential confounders, including birth year, medical center, maternal age at delivery, parity, race/ethnicity, educational level, household income, history of comorbidity, diabetes during pregnancy, smoking during pregnancy, preeclampsia or eclampsia, prepregnancy body mass index, gestational weight gain, gestational age at delivery, and birth weight, the HR associated with LEA vs non-LEA exposure was 1.37 (95% CI, 1.23-1.53). Relative to the unexposed group, the adjusted HR associated with LEA exposure of less than 4 hours was 1.33 (95% CI, 1.17-1.53), with LEA exposure of 4 to 8 hours was 1.35 (95% CI, 1.20-1.53), and with LEA exposure of more than 8 hours was 1.46 (95% CI, 1.27-1.69). Within the LEA group, there was a significant trend of ASD risk associated with increasing duration of LEA exposure after adjusting for covariates (HR for linear trend, 1.05 [95% CI, 1.01-1.09] per 4 hours). Adding fever to the model did not change the HR estimate associated with LEA exposure (adjusted HR for LEA vs non-LEA, 1.37 [95% CI, 1.22-1.53]). Conclusions and Relevance: This study suggests that maternal LEA may be associated with increased ASD risk in children. The risk appears to not be directly associated with epidural-related maternal fever.
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