Association Between Nonsyndromic Congenital Heart Disease and Childhood Cancer in a Population‐Based, Retrospective Cohort of 11 Million Children

BACKGROUND: Epidemiologic studies have demonstrated associations between congenital heart disease (CHD) and childhood cancer. However, these assessments have not fully accounted for the pathogenetic and clinical heterogeneity of CHD, limiting their capacity to inform pathogenetic studies and the clinical management of children with CHD. METHODS: To achieve a more detailed understanding of cancer risk in children with nonsyndromic CHD, we evaluated 60 cardiac lesions in 7 categories in a cohort of 11 million children from Massachusetts, North Carolina, Oklahoma, and Texas. We used Cox proportional hazards regression to estimate the hazard ratios (HRs) and 95% CIs of cancer in children with each lesion relative to children without congenital anomalies when there were ≥3 co-occurring cases. RESULTS: We identified 74 755 children with CHD and observed increased hazards for several malignancies. Notable associations included aortic arch obstruction-lymphoma (HR, 12.7 [95% CI, 4.9-31.0]); single-ventricle disease-lymphoma (HR, 9.7 [95% CI, 3.8-24.4]); complex atrioventricular septal defect-leukemia (HR, 8.05 [95% CI, 2.8-23.0]); ventricular septal defect-hepatoblastoma (HR, 11.2 [95% CI, 5.9-21.1]); and conotruncal defects-neuroblastoma (HR, 6.4 [95% CI, 1.9-22.2]). The cumulative incidence of cancer was <1% for all CHD groups evaluated. CONCLUSIONS: Cancer incidence in children with nonsyndromic CHD was generally low. However, we identified >5-fold increases in the hazard of hepatoblastoma, neuroblastoma, leukemia, and lymphoma in children with certain lesions. Our findings may assist in generating hypotheses about the causes of cancer in children with CHD.