Research Article: Pediatric cancer risk in association with birth defects: A systematic review

Date Published: July 27, 2017

Publisher: Public Library of Science

Author(s): Kimberly J. Johnson, Jong Min Lee, Kazi Ahsan, Hannah Padda, Qianxi Feng, Sonia Partap, Susan A. Fowler, Todd E. Druley, Jeffrey S Chang.


Many epidemiological studies have examined associations between birth defects (BDs) and pediatric malignancy over the past several decades. Our objective was to conduct a systematic literature review of studies reporting on this association.

We used librarian-designed searches of the PubMed Medline and Embase databases to identify primary research articles on pediatric neoplasms and BDs. English language articles from PubMed and Embase up to 10/12/2015, and in PubMed up to 5/12/2017 following an updated search, were eligible for inclusion if they reported primary epidemiological research results on associations between BDs and pediatric malignancies. Two reviewers coded each article based on the title and abstract to identify eligible articles that were abstracted using a structured form. Additional articles were identified through reference lists and other sources. Results were synthesized for pediatric cancers overall and for nine major pediatric cancer subtypes.

A total of 14,778 article citations were identified, of which 80 met inclusion criteria. Pediatric cancer risk was increased in most studies in association with BDs overall with some notable specific findings, including increased risks for CNS tumors in association with CNS abnormalities and positive associations between rib anomalies and several pediatric cancer types.

Some children born with BDs may be at increased risk for specific pediatric malignancy types. This work provides a foundation for future investigations that are needed to clarify specific BD types predisposing toward malignancy and possible underlying causes of both BDs and malignancy.

Partial Text

Pediatric cancer is diagnosed in >14,000 U.S. children per year from the ages of 0–19 years and is the leading cause of disease-related death among children aged 1–14 years [1, 2]. Although a few risk factors have been conclusively identified, including exposure to high dose radiation and certain genetic syndromes, the etiology underlying most cases remains unknown.

Abbreviations used in this review are provided in Table 1. Our review followed the 2009 Preferred Reporting Method for Systematic Reviews (PRISMA) guidelines [8] (See S1 Checklist). A summary of the review protocol is provided below.

A total of 14,407 article citations, 9,672 from Embase and 4,735 from PubMed, were initially identified. After removing 851 non-unique citations (844 in both PubMed and Embase and 7 contained in Embase twice), 13,556 citations remained. With the addition of 371 articles identified through the reference lists of selected articles, the IARC publication [11], additional PubMed searches, and the updated systematic search in PubMed, 13,927 records were screened for eligibility of which 13,789 were excluded. One hundred thirty-eight full-text articles were abstracted and 80 were included (Fig 1).

Associations between BDs and pediatric cancer have been extensively studied. Overall conclusions on pediatric cancer risk in children with BDs are limited by heterogeneity in study design, subject selection (including inclusion/exclusion criteria), measurement, definitions, and length of follow-up for ascertaining BDs, as well as covariate adjustment in models. For example, in studies ascertaining individuals with BDs from BD surveillance systems, standardized definitions using published classification schemes were used to group individuals with BDs according to BD type (e.g. major, minor, and specific BD types), while for studies ascertaining BDs through parental questionnaire, coding schemes were often elusive. We strongly emphasize that future studies on this topic should employ and clearly report in their methods a standardized classification system such as that reported by Rasmussen et al. for the National Birth Defects Prevention Study [93], which will facilitate pooling and meta-analysis studies that are needed to more precisely quantify pediatric cancer risk in children with BDs. In spite of the differences in methodology used by studies on this topic that limit overall conclusions, several noteworthy findings emerged from this review.




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