Association between cesarean delivery and pediatric leukemia: A case-control study using a Japanese administrative claims database.
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BACKGROUND: The etiology of pediatric leukemia remains incompletely understood. The delayed infection hypothesis suggests that reduced microbial exposure in early infancy may contribute to leukemia development through dysregulated immune responses. Because cesarean delivery may alter early-life microbial colonization and immune development, several studies have examined its association with pediatric leukemia, but findings remain inconsistent, particularly in Asian populations. METHODS: We conducted a case-control study using a large Japanese administrative claims database (2008-2024). Children with Down syndrome were excluded from the primary analysis given its strong, well-established association with leukemia. Cases were matched 1:4 with controls by age, sex, birth year, and observation period using risk-set sampling. Multivariable conditional logistic regression was used to evaluate the association between cesarean delivery and pediatric leukemia, adjusting for maternal and perinatal factors. A sensitivity analysis including children with Down syndrome was also performed. RESULTS: In the primary analysis, 197 cases were matched with 778 controls. Cesarean delivery was recorded in 10 cases (5.1%) and 48 controls (6.2%; p = 0.56). In multivariable analysis, cesarean delivery was not significantly associated with pediatric leukemia (OR, 0.7; 95% CI, 0.3-1.4; p = 0.32). Pediatric complex chronic conditions were associated with leukemia risk (OR, 3.9; 95% CI, 2.6-6.0; p < 0.001), although this finding should be interpreted with caution given the heterogeneous nature of this construct. In the sensitivity analysis, 226 cases were matched with 894 controls. The association between cesarean delivery and leukemia remained non-significant, whereas Down syndrome was strongly associated with leukemia (OR, 30.3; 95% CI, 4.3-216; p = 0.001). CONCLUSIONS: In this Japanese case-control study, cesarean delivery was not significantly associated with pediatric leukemia after excluding children with Down syndrome and adjusting for maternal and perinatal factors. Further studies with detailed information on planned versus emergency cesarean delivery, genetic predisposition, and clinical factors are warranted.