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Birth defects may put children at increased risk for childhood cancers, with a new study estimating that just under 10% of childhood cancers could be attributed to chromosomal or nonchromosomal birth defects.

"However, the overall absolute risk of cancer in children with any birth defect is less than 1%," reported Philip J. Lupo, PhD, of Baylor College of Medicine in Houston, and colleagues in .

The study of more than 10 million births from four ethnically and racially diverse states showed that children born with chromosomal anomalies were at more than 11 times greater risk (odds ratio 11.6; 95% CI 10.4-12.9) and those born with nonchromosomal birth defects were at 2.5 times greater risk (95% CI 2.4-2.6) for being diagnosed with cancer before age 18 compared with children born without any birth defects.

The risk for cancer increased with an increasing number of such birth defects, with children with four or more major birth defects about six times more likely to be diagnosed versus those with none (OR 5.9; 95% CI 5.4-6.5).

In all, Lupo and colleagues identified 40 specific birth-defect childhood cancer associations that were statistically significant even after adjustment for maternal age, child sex, state, and birth weight.

"For example, children with several forms of nonchromosomal congenital heart disease had an increased risk of hepatoblastoma and neuroblastoma," the researchers wrote. "These associations remained consistent and statistically significant when also adjusting for gestational age in models that included congenital heart disease phenotypes associated with preterm birth."

In an , Logan G. Spector, PhD, of the University of Minnesota Medical School in Minneapolis, and Andrew F. Olshan, PhD, of the University of North Carolina at Chapel Hill, praised the study for the "unprecedented" size of its patient sample, but said that the clinical implications for children based on this data remain limited. "Surveillance for cancer cannot be recommended for most children with birth defects because the absolute risk was far below 1%," the editorialists stated. "It may be worth exploring surveillance for children with four or more nonchromosomal birth defects, in whom cumulative risk of cancer was 0.725%."

Moving forward, if research into causative genes is "fruitful, the detection of a birth defect could trigger genetic testing and surveillance in the presence of high-penetrance variants," Spector and Olshan explained.

The clinical implications for pediatric oncologists, however, are greater, the editorial added: Just as data are collected in patients with family histories of cancer, "it would be similarly useful to systematically collect high-quality birth defect data in pediatric oncology practice ... Birth defects, particularly multiple birth defects, may trigger genetic testing, but they also may be examined in association with both survival and survivorship," Spector and Olshan wrote.

Study Details

The study used data on 10,181,074 children born from 1992 to 2013 pooled from Texas, Arkansas, Michigan, and North Carolina. Lupo and co-authors performed data linkages in each state for three areas: birth defects registry to birth certificates, cancer registry to birth certificates, and birth defects registry to corresponding cancer registry. The children were followed for up to 18 years for a diagnosis of cancer.

Of the total population, 539,567 children were born with a birth defect and 15,110 were diagnosed with cancer. Median follow-up was 8.5 years in children with birth defects and 8.1 years among those with birth defects.

The increased risk for cancer seen in patients with chromosomal and nonchromosomal birth defects was similar across all racial subgroups, the team reported. The nonchromosomal defects with the highest risk for cancer were biliary atresia and spina bifida.

Among children with chromosomal anomalies, the research confirmed some associations seen in previous studies. For example, here there were five associations between chromosomal anomalies or single-gene disorders and childhood cancers seen: hepatoblastoma among children with trisomy 18; acute lymphocytic leukemia and acute myeloid leukemia among children with trisomy 21; and astrocytoma and non-rhabdomyosarcoma soft-tissue sarcoma among children with neurofibromatosis.

Cancers most commonly associated in children with nonchromosomal defects were hepatoblastoma and neuroblastoma -- a finding "consistent with previous hypotheses that embryonal tumors could be associated with developmental disruptions rather than with carcinogenic exposures," Lupo, et al. wrote.

Increased cancer risk was also observed in children with craniosynostosis, which has not been previously reported, likely due to its low birth prevalence.

Although children with four or more nonchromosomal birth defects were found to be at six times the risk for cancer, the risk began to markedly increase with only two or more major birth defects (adjusted HR 3.51; 95% CI 3.19-3.56), the researchers found. In addition, this increasing risk occurred independent of the cancer category (hematologic cancers, central nervous system (CNS) tumors, and non-CNS tumors), a finding that Spector and Olshan called "remarkable."

Lupo and co-authors concluded: "If further validated, our results may inform cancer surveillance protocols for early tumor detection in children with specific birth defects. Future studies should evaluate the molecular features of children with co-occurring birth defects and cancers to further elucidate the mechanisms that lead to these complex outcomes."