Critical Congenital Heart Disease and Infant Cancer

Congenital heart defects (CHDs) affect nearly 1% of births in the United States, and 20% of these are classified as critical congenital heart disease (CCHD).1 Different types of heart defects are included under CCHD, but each affects blood flow into, out of, or through the heart. Children with any CHD may be at an increased risk for cancer2–8 although this literature is extremely limited with respect to isolated CCHD and has primarily focused on the risk of leukemia in children with Trisomy 21. The objective of this descriptive study was to estimate the risk of cancers in the first year of life for infants born with CCHD.Data are from the Study of Mothers and Infants,9 an administrative birth cohort derived from vital statistics files linked to a hospital discharge database maintained by the California Department of Health Care Access. We included singleton, live-birth deliveries between 2007 and 2020. CCHD and cancers, as well as maternal and infant descriptive factors, were identified from International Classification of Diseases (ICD) codes in hospital records or birth certificate data through the first year of life. In addition to any cancer, specific cancers were selected based on prevalence and included leukemia, central nervous system (CNS) tumors, rhabdomyosarcoma, hepatoblastoma, retinoblastoma, Wilms tumor, and lymphoma. We performed generalized log-linear regression with a Poisson distribution and robust SEs, limiting models to those with exposed case counts of at least 5. To document the association between CCHD and cancers in the first year of life, models were purposefully unadjusted (allowing for the interpretation to be descriptive). Subsequent models excluded Trisomy 21 and select congenital malformation syndromes associated with short stature (eg, Noonan syndrome) or otherwise unspecified (eg, Costello syndrome) because of well-documented associations with both CCHD and select cancers.From 6 079 530 births, we identified 24 213 cases of CCHD (398 cases per 100 000 live births). Infants with CCHD were more likely to be born to mothers with diabetes, hypertension, or infection during pregnancy or who had a substance use disorder, be born prematurely, and have Trisomy 21 or select genetic syndromes (Table 1). Infants with CCHD were at an increased risk of any cancer in the first year of life (1107/100 000 vs 94/100 000; RR, 12.0 (95% CI, 10.6–13.5) (Table 2), which was slightly attenuated in children without Trisomy 21 or select genetic syndromes. The risk of leukemia increased with CCHD (RR, 14.9 [95% CI, 10.2–21.9]), which remained elevated although attenuated in children without Trisomy 21 or select genetic syndromes. Other cancers associated with CCHD included CNS tumors (RR, 5.7 [95% CI, 2.4,–13.9]), rhabdomyosarcoma (RR, 14.1 [95% CI, 5.7–34.7]), and hepatoblastoma (12.2 [95% CI, 5.4–27.6]), which were essentially unchanged when removing children with Trisomy 21 or select genetic syndromes. Retinoblastoma, Wilms tumor, and lymphoma could not be evaluated because of cells less than 5.In this descriptive analysis, infants with CCHD were more likely to have cancer, independent of select genetic conditions. Although studies specific to CCHD are lacking, the association between birth defects and cancer has been well described.10 A complex interplay of genetic, epigenetic, and environmental factors may influence the risk of CCHD during the prenatal period, and some of these same factors may also increase the risk of cancer. In a population-based study in Denmark, risk estimates were elevated among cases of CHD requiring surgical repair, but CIs were wide.8 In a study assessing the risk of cancer among children with birth defects, children with pulmonary valve atresia and stenosis were at a 3-fold increased risk of any cancer. When stratified by type of cancer, pulmonary valve atresia and stenosis were associated with greater risk of hepatoblastoma.4 Our work expands this limited literature by limiting our analysis to CCHD and assessing individual cancers. Limitations to this work include the limited timeframe (infancy) of cancer assessment and reliance on birth records and ICD codes for CCHD. Detection bias of cancers in infants with CCHD may inflate associations. Finally, small cell sizes led to unstable estimates and inability to evaluate potential common causes of CCHD and cancer, such as assisted reproductive technology or teratogens. This work highlights the importance of monitoring all children with CCHD for cancer.