Male Sex and the Risk of Childhood Cancer: The Mediating Effect of Birth Defects

Abstract

Background There is a persistent, unexplained disparity in sex ratio among childhood cancer cases, whereby males are more likely to develop most cancers. This male predominance is also seen for most birth defects, which are strongly associated with risk of childhood cancer. We conducted mediation analysis to estimate whether the increased risk of cancer among males is partially explained by birth defect status. Methods We used a population-based birth cohort with linked data from birth certificates, birth defects registries, and cancer registries from Arkansas, Michigan, North Carolina, and Texas. We conducted counterfactual mediation analysis to estimate the natural direct and indirect effects of sex on cancer risk, modeling birth defect status as mediator. State, birth year, plurality, and maternal race/ethnicity, age, and education were considered confounders. We conducted separate analyses limited to cancers diagnosed at age <1 year. Results Our dataset included 10,181,074 children: 15,110 diagnosed with cancer, 539,567 diagnosed with birth defects, and 2,124 co-occurring cases. Birth defect status mediated 38% of the association between sex and cancer overall. The proportion mediated varied by cancer type, including acute myeloid leukemia (93%), neuroblastoma (35%), and non-Hodgkin lymphoma (6%). Among children <1 year of age at cancer diagnosis, the proportion mediated was substantially higher (82%). Conclusions Our results suggest birth defects mediate a statistically significant proportion of the relationship between sex and childhood cancer. The proportion mediated varied by cancer type and diagnosis age. These findings improve our understanding of the causal pathway underlying male sex as risk factor for childhood cancer.

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Paediatric cancer burden in Namibia, A 10 year retrospective, analytical study of patients admitted at Windhoek Central Hospital

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