Estimating the effect of cesarean delivery on long term childhood health across two countries

BackgroundPrevious studies have demonstrated cesarean delivery (CD) may influence a variety of long term childhood outcomes. However, assessing the impact of CD on long term outcomes is challenging, as conducting a randomized controlled trial is not feasible and inferring it from observational data may be biased. MethodsUtilizing over a decade of data obtained from electronic health records of 737,904 births, with a mean child follow-up of 5.66 (SD 2.96) years, we defined and emulated a target trial to estimate the effect of CD on several predefined long term pediatric outcomes. Causal effects were estimated using pooled logistic regression and standardized survival curves, leveraging data breadth to account for potential confounders. Diverse sensitivity analyses were performed including replication of results in an external validation set from the UK including 625,044 births with a mean child follow-up of 6.77 (SD 4.54) years. Findings10-year risk difference (95% CI) between infants born by CD versus vaginal delivery were 0.74% (-0.06, 1.52) for atopy, 0.64% (0.31, 0.98) for asthma and 0.47% (-0.32, 1.28) for allergy. Increased risk for these outcomes was also observed in the UK cohort. In addition, an average treatment effect of 0.10 (0.07-0.12) on body mass index (BMI) z-scores at age 5 years old and 0.92 (0.68-1.14) on the number of respiratory infection events until 5 years of age were observed for CD. For other examined outcomes, including autism and autoimmune diseases, an increased risk for infants born by CD was not observed consistently when employing different methods and across both countries. InterpretationOur findings add to a growing body of evidence on the long term effects of CD on pediatric morbidity, and may assist parents and clinicians in the decision to perform CD when not medically indicated. Furthermore, this study may pave the way to future research on the mechanisms underlying these effects and intervention strategies targeting them. FundingE.S. is supported by the Crown Human Genome Center; Larson Charitable Foundation New Scientist Fund; Else Kroener Fresenius Foundation; White Rose International Foundation; Ben B. and Joyce E. Eisenberg Foundation; Nissenbaum Family; Marcos Pinheiro de Andrade and Vanessa Buchheim; Lady Michelle Michels; Aliza Moussaieff; and grants funded by the Minerva foundation with funding from the Federal German Ministry for Education and Research and by the European Research Council and the Israel Science Foundation. H.R. is supported by the Israeli Council for Higher Education (CHE) via the Weizmann Data Science Research Center and by a research grant from Madame Olga Klein - Astrachan. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPrevious studies have investigated the relationship between CD and long term pediatric health. However, the majority of studies thus far have focused on the association of CD with pediatric outcomes, without accounting for possible confounding factors that might affect these associations. In addition, some of these studies were based on relatively small cohorts from a single geographic location, with a short follow-up period. Added value of this studyIn this study we emulated a target trial on a large nationwide dataset, to estimate the causal effect of CD on several long term pediatric health outcomes. Further, we validated our results using several sensitivity analyses and through replication in an external validation set originating from a different country and ethnicity. Implications of all the available evidenceGiven the increasing incidence of CD, a deeper understanding of its long term health effects on women and children is crucial. Our findings that CD confers an increased risk for several long term pediatric health outcomes contribute to the ongoing discussion on the optimal rate of CD, and may assist parents and caregivers in the decision to perform CD when not medically indicated. Moreover, studies on the mechanisms mediating these effects have the potential to inform novel prevention strategies.