Maternal infection during pregnancy and the risk of childhood cancer: a systematic review and meta-analysis.
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BACKGROUND: Maternal infections during pregnancy may increase the risk of childhood cancer (CC) in offspring by affecting foetal immunity and genetics. Existing evidence seems inconclusive, necessitating a comprehensive review to understand this association. We aimed to evaluate the risk of various CC outcomes following prenatal exposure to different types of maternal infections. METHODS: We searched Medline, Web of Science, Embase, Cochrane Library, and bibliographies for relevant studies from inception to October 2025. The study protocol was registered in PROSPERO (ID:CRD42023483706). We included original human epidemiological studies that examined the association between maternal infections during pregnancy and CC with appropriate reference groups and no language restrictions. We excluded studies if they were reviews or reports, if they did not assess individual-level infection or if they used therapies for infections (e.g., antibiotics) as markers of infection exposure. Two independent reviewers extracted data and assessed methodological quality following PRISMA guidelines. Pooled estimates (ES) and 95% confidence intervals (95%CIs) were calculated using random-effect models. Heterogeneity was examined in subgroup analyses. Publication bias was evaluated using Egger's tests and Funnel plots. RESULTS: From 9284 studies identified by the search, 46 studies (39 case-control,7 cohort) with over nine million participants were included, covering 33 analyses of 12 types of infection and five CC sites. Overall, maternal infection during pregnancy was associated with increased risk of CC (ES = 1.36;95%CI,1.17-1.59). Sexually transmitted infections (STIs) were associated with increased overall CC risk (ES = 2.86;95%CI,1.88-4.33). Viral infections were also associated with increased risk of overall CC (ES = 1.43;1.18,1.74), with cytomegalovirus and rubella virus infections showing positive associations upon stratification by pathogen-type. Genitourinary tract infections (GUTIs) were associated with increased risk of leukaemia (ES = 1.49;95%CI,1.05-2.12) and solid tumours (ES = 1.60, 95%CI;1.06-2.42) and viral infections with the risk of acute lymphoblastic leukaemia (ES = 1.58;95%CI,1.15-2.18). CONCLUSIONS: Maternal STIs, GUTIs, and viral infections during pregnancy are associated with increased risk of CC, with GUTIs and viral infections specifically associated with increased risk of leukaemia. Targeted prevention strategies towards specific infections during pregnancy may protect against CC. Large-scale prospective studies with precise infection assessment and stratification by pathogen-type, and mechanistic considerations are needed to deepen knowledge in this area.