The Interplay of Cesarean Section Delivery and First-Birth Order as Risk Factors in Acute Lymphoblastic Leukemia


 Background: Childhood B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) has been associated with early life exposures including birth by cesarean section (C-section), and a deficit of social exposure (first child). These exposures as proxies for microbiome acquisition in infancy are essential to prime the immune system and, restrain later dysregulated immune responses which can trigger ALL in susceptible individuals. We tested risk factors pertaining to immune stimulation that may impact BCP-ALL development. Methods: Cases comprised 1126 children (0-12 years) with ALL (BCP-ALL: 78.5%) from the EMiLI study group in Brazil (2002-2020). Age and sex-matched controls (n=2252) were randomly selected from healthy children whose mothers participated in the National Placental and Umbilical Cord Blood Bank donation. Multiple logistic regression was run fitted and adjusted for selected covariates models. Results: C-section delivery was associated with increased risk for ALL [Odds Ratio (OR)ALL:1.10, 95% Confidence Intervals (CIs):1.04-1.15; ORBCP-ALL:1.09, 95% CIs:1.03-1.14], as well as being the first-born child. Interaction analysis showed a significant effect of first birth on the observed C-section associations (p<0.0001). Indeed, high-risk children, namely first-born children delivered via C-section were at increased risk for ALL (OR: 2.33, 95% CIs:2.40-4.84) compared to non-first, vaginally born children. An increased risk was found for first-born children delivered by C-section and non-breastfed with ALL (ORALL:2.32, 95%CIs: 1.27-4.24; ORBCP-ALL:2.37, 95%CIs: 1.18-4.76). Conclusions: Our observations are in accord with the prediction that exposures determining microbiome composition and adrenal pathway in infancy contribute to the risk of BCP-ALL. Impact: These findings encourage the exploration of potential preventative interventions.