Sex differences in childhood cancer risk among children with major birth defects: a Nordic population-based nested case-control study

BACKGROUND: Childhood cancer is more common among children with birth defects, suggesting a common aetiology. Whether this association differs by sex is unclear. METHODS: We performed a population-based nested case-control study using nationwide health registries in four Nordic countries. We included 21 898 cancer cases (0–19 years) and 218 980 matched population controls, born 1967–2014. Associations between childhood cancer and major birth defects were calculated as odds ratios (ORs) with 95% confidence intervals (CIs) using logistic regression models. Effect modification was evaluated using a counterfactual framework to estimate confidence intervals and P-values for the natural indirect effects. RESULTS: Birth defects were present for 5.1% (1117/21 898) of childhood cancer cases and 2.2% (4873/218 980) of controls; OR of cancer was higher for chromosomal (OR = 10, 95% CI = 8.6–12) than for non-chromosomal defects (OR = 1.9, 95% CI = 1.8–2.1), strongest between genetic syndromes/microdeletion and renal tumours, Down syndrome and leukaemia, and nervous system defects and central nervous system tumours. The association between birth defects and cancer was stronger among females (OR = 2.8, 95% CI = 2.6–3.1) than males (OR = 2.1, 95% CI = 1.9–2.2, P(interaction) <0.001). Male sex was an independent risk factor for childhood cancer, but very little of the overall association between sex and childhood cancer was mediated through birth defects (4.8%, P(NIE) <0.001), although more at younger ages (10% below years and 28% below 1 year). CONCLUSIONS: The birth defect–cancer associations were generally stronger among females than males. Birth defects did not act as a strong mediator for the modest differences in childhood cancer risk by sex, suggesting that other biological pathways are involved.