Association of Labour Epidural Analgesia with the Risks of Autism Spectrum Disorders and Other Neurodevelopmental Disorders in Offspring: A Population-Based Cohort Study

Abstract

Background: Recently, concern has been raised regarding the impact of labor epidural analgesia (LEA) on offspring risk of autism spectrum disorders (ASD). We explored the association between exposure to LEA and ASD, as well as specific developmental disorder (SDD), attention deficit hyperactivity disorder (ADHD), intellectual disability (ID), and epilepsy in offspring. Methods: This nationwide population-based cohort study included 671,709 live-born singletons delivered by women who intended to have a vaginal birth (i.e., vaginal and intrapartum cesarean deliveries) in Denmark from 2005 to 2017. A total of 91,627 siblings discordant for exposure to LEA were analyzed in a sibling-matched analysis. Both full-cohort and sibling-matched analyses were performed to estimate hazard ratios[HRs] of neurodevelopmental outcomes according to exposure to LEA. Findings: In the full cohort analysis, we observed a 15% increased risk of ASD in offspring exposed to LEA (HR, 1.15 [95% CI, 1.09-1.22]) regardless of LEA duration. In the sibling-matched analysis, we found no association between maternal LEA and offspring ASD (1.02 [0.84-1.24]). No association was found between LEA and other neurodevelopmental disorders in the full cohort (HR for SDD, 1.06 [0.98-1.15]; HR for ADHD, 1.00 [0.95-1.06]; HR for ID, 0.98 [0.86-1.13]; HR for epilepsy, 0.92 [0.83-1.03]) or in the sibling-matched analyses. Interpretation: The association between maternal LEA and ASD did not persist in the sibling-matched analysis. No association was found between maternal LEA and SDD, ADHD, ID, or epilepsy. Our findings accord with a lack of causal effect of LEA on the risk of neurodevelopmental disorders. Funding Statement: This study was supported by grants from the Danish Council for Independent Research (DFF-6110- 00019B and 9039-00010B), the Nordic Cancer Union (R275-A15770), the Karen Elise Jensens Fond (2016), Novo Nordisk Fonden (NNF18OC0052029 and NNF18OC0054457), the National Nature Science Foundation of China (82073570), and Shanghai Municipal Health Commission (GWV-10.1-XK07 and 2020CXJQ01). Declaration of Interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work. Ethics Approval Statement: The study was approved by the Danish Data Protection Agency (Record No. 2013-41- 2569). By Danish law, no informed consent is required for a registry-based study using anonymized data.