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

Johnson, Kimberly; Lee, Jong Min; Ahsan, Kazi; Padda, Hannah; Feng, Qianxi; Partap, Sonia; Fowler, Susan A.; Druley, Todd E.

doi:10.1371/journal.pone.0181246

Cited by 45 publications

(62 citation statements)

References 92 publications

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“…More than 80 studies have reported an association between birth defects and cancer, based on a variety of study designs, sample sizes, and data sources. 10 The 2.07-fold increase in cancer risk among children with major nonchromosomal birth defects in the fertile group that we report is consistent with the other US population-based cohort studies that linked to state birth defect and cancer registries, with increases ranging from 1.58-fold 11 to 2.0-fold 12 , 2.5-fold, 13 , 14 to 2.86-fold. 15 The finding of a 15.45-fold cancer risk among children with chromosomal birth defects in the fertile group is also consistent with the point estimates and 95% CIs of previous reports, ranging from 11.6 (95% CI, 10.4-12.9) to 15.52 (95% CI, 11.66-20.27).…”

Section: Discussionsupporting

confidence: 90%

Assessment of Birth Defects and Cancer Risk in Children Conceived via In Vitro Fertilization in the US

et al. 2020

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Key Points Question Is the incidence of birth defects and childhood cancer among children conceived via in vitro fertilization different from that among children conceived naturally? Findings In this population-based cohort study of 1 053 415 children in 4 states, the presence of a birth defect and the number of birth defects were associated with an increased risk of childhood cancer. The increased risk was 2-fold higher for children conceived via in vitro fertilization than for children conceived naturally. Meaning In this study, cancer risk increased in the presence of birth defects at a higher rate in children conceived via in vitro fertilization than in children conceived naturally; further study is warranted.

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Section: Discussionsupporting

confidence: 90%

Assessment of Birth Defects and Cancer Risk in Children Conceived via In Vitro Fertilization in the US

et al. 2020

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“…The present findings of a consistent, increased incidence among males for all ages combined and by single year of age for cancer overall and most tumor types suggest that sex, and the associated biologic properties, may underlie the male excess in childhood cancer incidence. Some sex disparities in childhood cancer incidence may be due to the male excess in birth defects (overall male:female ratio 1.18; 95% CI, 1.13–1.24) and chromosomal abnormalities such as Down syndrome, which are associated with an increased risk of childhood cancer and leukemia, respectively. Other biologic mechanisms for the increased risk of childhood cancer among males may depend on sex differences in (1) germline variation and gene expression on the X and autosomal chromosomes; (2) immune responses; and (3) pubertal hormone profiles and the corresponding growth rates …”

Section: Discussionmentioning

confidence: 99%

Sex ratio among childhood cancers by single year of age

Williams

Richardson

Marcotte

et al. 2019

Pediatric Blood & Cancer

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Background The male excess in childhood cancer incidence is well‐established; however, the underlying biologic mechanisms remain unknown. Examining the association between male sex and childhood cancer by single year of age and tumor type may highlight important periods of risk such as variation in growth and hormonal changes, which will inform etiologic hypotheses. Methods Using data from the Surveillance, Epidemiology, and End Results (SEER) 18 registries (2000–2015), incidence rate ratios (IRR) and 95% confidence intervals (95% CI) were estimated as the measure of association between male sex and childhood cancer by single year of age (0–19). Results The IRR for male cancer overall was 1.19 (95% CI, 1.18–1.20) and was similar in magnitude at nearly every year of age. Burkitt lymphoma was strongly associated with male sex (IRRs ≥2 at each year of age). Increased incidence was observed among males for acute lymphoblastic leukemia, Hodgkin and non‐Hodgkin lymphomas for nearly all years of age. Medulloblastoma was the only central nervous system tumor with a significant male predominance at nearly every age. Male sex displayed a consistent inverse association with nephroblastoma and thyroid carcinoma over the ages studied. Conclusions Male sex was positively associated with most cancers. The higher incidence rates observed in males remained consistent over the childhood and adolescent periods, suggesting that childhood and adolescent hormonal fluctuations may not be the primary driving factor for the sex disparities in childhood cancer. The observed incidence disparities may be due to sex differences in exposures, genetics, or immune responses.

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“…We conducted analyses for only those cancers with at least 5 cases diagnosed among each age group. Because of the documented association between certain childhood cancers and chromosomal anomalies or single gene disorders, which are generally independent of sex ( 9 , 22–24 ), we conducted subgroup analyses excluding children with chromosomal anomalies (n = 22 420), or single gene disorders (neurofibromatosis type I and tuberous sclerosis) (n = 2972). This was done to quantify the mediation effect of nonsyndromic birth defects alone.…”

Section: Methodsmentioning

confidence: 99%

Male Sex and the Risk of Childhood Cancer: The Mediating Effect of Birth Defects

Marcotte

Schraw

Desrosiers

et al. 2020

JNCI Cancer Spectrum

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Background There is a persistent, unexplained disparity in sex ratio among childhood cancer cases, whereby males are more likely to develop most cancers. This male predominance is also seen for most birth defects, which are strongly associated with risk of childhood cancer. We conducted mediation analysis to estimate whether the increased risk of cancer among males is partially explained by birth defect status. Methods We used a population-based birth cohort with linked data from birth certificates, birth defects registries, and cancer registries from Arkansas, Michigan, North Carolina, and Texas. We conducted counterfactual mediation analysis to estimate the natural direct and indirect effects of sex on cancer risk, modeling birth defect status as mediator. State, birth year, plurality, and maternal race/ethnicity, age, and education were considered confounders. We conducted separate analyses limited to cancers diagnosed at age <1 year. Results Our dataset included 10,181,074 children: 15,110 diagnosed with cancer, 539,567 diagnosed with birth defects, and 2,124 co-occurring cases. Birth defect status mediated 38% of the association between sex and cancer overall. The proportion mediated varied by cancer type, including acute myeloid leukemia (93%), neuroblastoma (35%), and non-Hodgkin lymphoma (6%). Among children <1 year of age at cancer diagnosis, the proportion mediated was substantially higher (82%). Conclusions Our results suggest birth defects mediate a statistically significant proportion of the relationship between sex and childhood cancer. The proportion mediated varied by cancer type and diagnosis age. These findings improve our understanding of the causal pathway underlying male sex as risk factor for childhood cancer.

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

Cited by 45 publications

References 92 publications

Assessment of Birth Defects and Cancer Risk in Children Conceived via In Vitro Fertilization in the US

Assessment of Birth Defects and Cancer Risk in Children Conceived via In Vitro Fertilization in the US

Sex ratio among childhood cancers by single year of age

Male Sex and the Risk of Childhood Cancer: The Mediating Effect of Birth Defects

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