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Original Investigation
June 20, 2019

Association Between Birth Defects and Cancer Risk Among Children and Adolescents in a Population-Based Assessment of 10 Million Live Births

Author Affiliations
  • 1Department of Pediatrics, Baylor College of Medicine, Houston, Texas
  • 2Texas Children’s Cancer Center, Texas Children’s Hospital, Houston
  • 3Department of Medicine, Baylor College of Medicine, Houston, Texas
  • 4Department of Epidemiology, University of North Carolina at Chapel Hill
  • 5Department of Epidemiology, University of Arkansas for Medical Sciences, Little Rock
  • 6Arkansas Children’s Research Institute, Little Rock
  • 7Birth Defects Epidemiology and Surveillance Branch,Texas Department of State Health Services, Austin
  • 8Division for Vital Records and Health Statistics, Michigan Department of Health and Human Services, Lansing, Michigan
  • 9Department of Maternal and Child Health, University of North Carolina at Chapel Hill
  • 10School of Biological and Population Health Sciences, Oregon State University, Corvallis
  • 11Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
  • 12Smith Breast Center, Baylor College of Medicine, Houston, Texas
  • 13Department of Biostatistics and Epidemiology, Hudson College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City
  • 14Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
  • 15Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas
  • 16Division of Hematology and Oncology, Department of Pediatrics, Huntsman Cancer Institute, University of Utah, Salt Lake City
  • 17Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock
  • 18Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 19Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas
  • 20Department of Pediatrics, University of Florida College of Medicine Gainsville
  • 21Department of Epidemiology, University of Florida College of Medicine and College of Public Health and Health Professions, Gainesville
JAMA Oncol. 2019;5(8):1150-1158. doi:10.1001/jamaoncol.2019.1215
Key Points

Question  What are the associations between specific birth defects and specific childhood cancers?

Findings  In a large population-based registry study of more than 10 million children in 4 states, assessment of cancer risk among children with birth defects identified, 40 specific birth defect–childhood cancer associations were identified that were statistically significant, including several novel associations. Cancer risk increased with an increasing number of major nonchromosomal birth defects.

Meaning  Children with nonchromosomal birth defects have an increased relative risk of cancer, although the absolute risk remains low at less than 1%.

Abstract

Importance  Birth defects affect approximately 1 in 33 children. Some birth defects are known to be strongly associated with childhood cancer (eg, trisomy 21 and acute leukemia). However, comprehensive evaluations of childhood cancer risk in those with birth defects have been limited in previous studies by insufficient sample sizes.

Objectives  To identify specific birth defect–childhood cancer (BD-CC) associations and characterize cancer risk in children by increasing number of nonchromosomal birth defects.

Design, Setting, and Participants  This multistate, population-based registry linkage study pooled statewide data on births, birth defects, and cancer from Texas, Arkansas, Michigan, and North Carolina on 10 181 074 children born from January 1, 1992, to December 31, 2013. Children were followed up to 18 years of age for a diagnosis of cancer. Data were retrieved between September 26, 2016, and September 21, 2017, and data analysis was performed from September 2, 2017, to March 21, 2019.

Exposures  Birth defects diagnoses (chromosomal anomalies and nonchromosomal birth defects) recorded by statewide, population-based birth defects registries.

Main Outcomes and Measures  Cancer diagnosis before age 18 years, as recorded in state cancer registries. Cox regression models were used to generate hazard ratios (HRs) and 95% CIs to evaluate BD-CC associations and the association between number of nonchromosomal defects and cancer risk.

Results  Compared with children without any birth defects, children with chromosomal anomalies were 11.6 (95% CI, 10.4-12.9) times more likely to be diagnosed with cancer, whereas children with nonchromosomal birth defects were 2.5 (95% CI, 2.4-2.6) times more likely to be diagnosed with cancer before 18 years of age. An increasing number of nonchromosomal birth defects was associated with a corresponding increase in the risk of cancer. Children with 4 or more major birth defects were 5.9 (95% CI, 5.3-6.4) times more likely to be diagnosed with cancer compared with those without a birth defect. In the analysis of 72 specific BD-CC patterns, 40 HRs were statistically significant (adjusted P < .05) after accounting for multiple comparisons. Cancers most frequently associated with nonchromosomal defects were hepatoblastoma and neuroblastoma.

Conclusions and Relevance  Several significant and novel associations were observed between specific birth defects and cancers. Among children with nonchromosomal birth defects, the number of major birth defects diagnosed was significantly and directly associated with cancer risk. These findings could inform clinical treatment for children with birth defects and may elucidate mechanisms that lead to these complex outcomes.

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