Association Between Maternal Infection During Pregnancy and the Risk of Childhood Acute Lymphoblastic Leukemia in Offspring: A Systematic Review and Meta‐Analysis

OBJECTIVE: To systematically evaluate the association between maternal infection during pregnancy and the risk of childhood acute lymphoblastic leukemia (ALL) in offspring through a comprehensive meta-analysis of adjusted and pathogen-specific data. METHODS: We systematically searched PubMed, Web of Science, Embase, and Cochrane Library from inception to January 7, 2025. Two reviewers performed data extraction and assessed study quality using the Joanna Briggs Institute (JBI) checklist. Pooled odds ratios (ORs) were calculated for any infection, specific pathogen infection, and anatomical sites of infection. Sensitivity analyses and the GRADE approach were employed to evaluate the robustness and certainty of the evidence. RESULTS: A total of 26 studies were included. The pooled adjusted OR for "any infection" was 1.18 (95% confidence interval [CI]: 1.03-1.35) after sensitivity analysis. Influenza demonstrated the most robust association (adjusted odds ratio [OR] 1.90; 95% CI: 1.27-2.83). In contrast, Epstein-Barr virus (adjusted OR 1.45; 95% CI: 1.00-2.09) and respiratory tract infections (adjusted OR 1.18; 95% CI: 1.00-1.39) showed only borderline significance. Analysis by anatomical site revealed a significant but likely artifactual signal for combined genitourinary infections (OR 1.44; 95% CI: 1.03-2.01), which was not replicated in more populous, tract-specific syntheses. CONCLUSIONS: Maternal infections during pregnancy, particularly influenza, are associated with an increased risk of childhood ALL, and borderline associations were observed for EBV and respiratory infections. The observed risk from genitourinary infections may have come from confounding. These findings emphasize the clinical importance of influenza prevention and the timely management of prenatal infections.