Cesarean Section Is Associated with an Increased Risk of Acute Lymphoblastic Leukemia and Hepatoblastoma in Children from Minnesota

Background: In recent decades, Cesarean section (C-section) rates have increased. C-section is hypothesized to negatively impact the developing immune system by altering activation of the hypothalamic-pituitary-adrenal axis and the infant microbiome, among other mechanisms, thereby potentially modulating childhood cancer risk.

Methods: Using linked birth and cancer registry data from Minnesota (1976-2014), we included individuals ages 0-14 at diagnosis with one of 19 cancers. Cases and controls were frequency matched by birth year. We used logistic regression to estimate ORs and 95% confidence intervals (95% CI) as the measure of association between C-section and cancer. We assessed sex-C-section interactions for each cancer and conducted stratified analyses in acute lymphoblastic leukemia (ALL) for birth year, age at diagnosis, and maternal race.

Results: There were 3,166 cases and 20,589 controls. One third (n = 1,174) of controls born during 2004-2014 were delivered via C-section compared with 42.2% of cases (n = 285). C-section was associated with ALL (n = 819; OR: 1.20; 95% CI: 1.01-1.43) and hepatoblastoma (n = 50; OR: 1.89; 95% CI: 1.03-3.48), particularly among females (ALL OR: 1.34; 95% CI: 1.04-1.72; hepatoblastoma OR: 3.87; 95% CI: 1.30-11.57). The risk of ALL was highest during 2005-2014 (OR: 1.62; 95% CI: 1.11-2.34) and among children ages 1-5 years (OR: 1.28; 95% CI: 1.02-1.61).

Conclusions: C-section was associated with an increased risk of ALL and hepatoblastoma.

Impact: These associations require investigation to determine causality and rule out confounding by indication or reverse causality. The mechanisms underlying these associations may depend on neonatal immune system processes altered during C-section deliveries.