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Background: There is a well-recognized male excess in childhood cancer incidence; however, it is unclear whether there is etiologic heterogeneity by sex when defined by epidemiologic risk factors., Methods: Using a 5-state registry-linkage study (cases n = 16,411; controls n = 69,816), we estimated sex-stratified odds ratios (OR) and 95% confidence intervals (95% CI) between birth and demographic characteristics for 16 pediatric cancers. Evidence of statistical interaction (p-interaction < 0.01) by sex was evaluated for each characteristic in each cancer., Results: Males comprised > 50% of cases for all cancers, except Wilms tumor (49.6%). Sex interacted with a number of risk factors (all p-interaction < 0.01) including gestational age for ALL (female, 40 vs. 37-39 weeks OR: 0.84, 95% CI 0.73-0.97) and ependymoma (female, 40 vs. 37-39 OR: 1.78, 95% CI 1.14-2.79; female, ≥ 41 OR: 2.01. 95% CI 1.29-3.14), birth order for AML (female,  ≥ 3rd vs. 1st OR: 1.39, 95% CI 1.01-1.92), maternal education for Hodgkin lymphoma (male, any college vs. < high school[HS] OR: 1.47, 95% CI 1.03-2.09) and Wilms tumor (female, any college vs. HS OR: 0.74, 95% CI 0.59-0.93), maternal race/ethnicity for neuroblastoma (male, black vs. white OR: 2.21, 95% CI 1.21-4.03; male, Hispanic vs. white OR: 1.86, 95% CI 1.26-2.75; female, Asian/Pacific Islander vs. white OR: 0.28, 95% CI 0.12-0.69), and paternal age (years) for hepatoblastoma in males (< 24 vs. 25-29 OR: 2.17, 95% CI 1.13-4.19; ≥ 35 vs. 25-29 OR: 2.44, 95% CI 1.28-4.64)., Conclusions: These findings suggest etiologic heterogeneity by sex for childhood cancers for gestational age, maternal education, and race/ethnicity and paternal age., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: History of fetal loss including miscarriage and stillbirth has been inconsistently associated with childhood (0-14 years) leukemia in subsequent offspring. A quantitative synthesis of the inconclusive literature by leukemia subtype was therefore conducted., Methods: Eligible studies (N = 32) were identified through the screening of over 3500 publications. Random-effects meta-analyses were conducted on the association of miscarriage/stillbirth history with overall (AL; 18,868 cases/35,685 controls), acute lymphoblastic (ALL; 16,150 cases/38,655 controls), and myeloid (AML; 3042 cases/32,997 controls) leukemia. Sensitivity and subgroup analyses by age and ALL subtype, as well as meta-regression were undertaken., Results: Fetal loss history was associated with increased AL risk [Odds Ratio (OR) 1.10, 95% Confidence Intervals (CI) 1.04-1.18]. The positive association was seen for ALL (OR 1.12, 95%CI 1.05-1.19) and for AML (OR 1.13, 95%CI 0.91-1.41); for the latter the OR increased in sensitivity analyses. Notably, stillbirth history was significantly linked to ALL risk (OR 1.33, 95%CI 1.02-1.74), but not AML. By contrast, the association of ALL and AML with previous miscarriage reached marginal significance. The association of miscarriage history was strongest in infant ALL (OR 2.34, 95%CI 1.19-4.60)., Conclusions: In this meta-analysis involving >50,000 children, we found noteworthy associations by indices of fetal loss, age at diagnosis, and leukemia type; namely, of stillbirth with ALL and miscarriage history with infant ALL. Elucidation of plausible underlying mechanisms may provide insight into leukemia pathogenesis and indicate monitoring interventions prior to and during pregnancy.

Purpose: It has been suggested that home paint exposure increases the risk of childhood acute lymphoblastic leukemia (ALL)., Methods: We obtained individual level data from eight case-control studies participating in the Childhood Leukemia International Consortium. All studies had home paint exposure data (sometimes including lacquers and varnishes) for the pregnancy period with additional data for the 1-3-month period before conception in five, the year before conception in two, and the period after birth in four studies, respectively. Cytogenetic subtype data were available for some studies. Data were harmonized to a compatible format. Pooled analyses of individual data were undertaken using unconditional logistic regression., Results: Based on 3,002 cases and 3,836 controls, the pooled odds ratio (OR) for home paint exposure in the 1-3 months before conception and risk of ALL was 1.54 [95% confidence interval (CI) 1.28, 1.85], while based on 1,160 cases and 1,641 controls for exposure in the year before conception, it was 1.00 (95% CI 0.86, 1.17). For exposure during pregnancy, using 4,382 cases and 5,747 controls, the pooled OR was 1.14 (95% CI 1.04, 1.25), and for exposure after birth, the OR was 1.22 (95% CI 1.07, 1.39), based on data from 1,962 cases and 2,973 controls. The risk was greater for certain cytogenetic subtypes and if someone other than the parents did the painting., Conclusions: Home paint exposure shortly before conception, during pregnancy, and/or after birth appeared to increase the risk of childhood ALL. It may be prudent to limit exposure during these periods., Competing Interests: The authors declare that they have no conflict of interest.

Purpose: It has been suggested that parental occupational paint exposure around the time of conception or pregnancy increases the risk of childhood leukemia in the offspring., Methods: We obtained individual level data from 13 case-control studies participating in the Childhood Leukemia International Consortium. Occupational data were harmonized to a compatible format. Meta-analyses of study-specific odds ratios (ORs) were undertaken, as well as pooled analyses of individual data using unconditional logistic regression., Results: Using individual data from fathers of 8,185 cases and 14,210 controls, the pooled OR for paternal exposure around conception and risk of acute lymphoblastic leukemia (ALL) was 0.93 [95% confidence interval (CI) 0.76, 1.14]. Analysis of data from 8,156 ALL case mothers and 14,568 control mothers produced a pooled OR of 0.81 (95% CI 0.39, 1.68) for exposure during pregnancy. For acute myeloid leukemia (AML), the pooled ORs for paternal and maternal exposure were 0.96 (95% CI 0.65, 1.41) and 1.31 (95% CI 0.38, 4.47), respectively, based on data from 1,231 case and 11,392 control fathers and 1,329 case and 12,141 control mothers. Heterogeneity among the individual studies ranged from low to modest., Conclusions: Null findings for paternal exposure for both ALL and AML are consistent with previous reports. Despite the large sample size, results for maternal exposure to paints in pregnancy were based on small numbers of exposed. Overall, we found no evidence that parental occupational exposure to paints increases the risk of leukemia in the offspring, but further data on home exposure are needed.

Purpose: Previous assessments of childhood rhabdomyosarcoma have indicated maternal and birth characteristics may be associated with tumor development; however, much work remains to identify novel and confirm suspected risk factors. Our objective was to evaluate the associations between maternal and birth characteristics and childhood rhabdomyosarcoma., Methods: This case-control study included 322 cases and 322 pair-matched controls. Cases were enrolled in a trial run by the Intergroup Rhabdomyosarcoma Study Group. Population-based controls were identified using random digit dialing and were individually matched to cases on race, sex, and age. Families of the case and control subjects participated in a telephone interview, which captured information on maternal characteristics (birth control use, number of prenatal visits, anemia, and abnormal bleeding during pregnancy) and birth characteristics [birth weight, preterm birth, and type of delivery (vaginal vs. cesarean)]. Conditional logistic regression models were used to calculate an odds ratio (OR) and 95% confidence interval (CI) for each exposure, adjusted for age, race, sex, household income, and parental education. As the two most common histologic types of rhabdomyosarcoma are embryonal (n = 215) and alveolar (n = 66), we evaluated effect heterogeneity of these exposures., Results: The only characteristic that was associated with childhood rhabdomyosarcoma, and statistically significant, was abnormal vaginal bleeding during pregnancy (OR 1.75, 95% CI 1.12-2.74). Birth control use (OR 1.45, 95% CI 0.96-2.18), anemia during pregnancy (OR 1.27, 95% CI 0.81-1.99), and preterm birth (OR 2.51, 95% CI 0.74-8.49) were positively associated with childhood rhabdomyosarcoma, but were not statistically significant. Low birth weight [adjusted odds ratios (aOR) 4.46, 95% CI 1.41-14.1] and high birth weight (aOR 2.41, 95% CI 1.09-5.35) were strongly associated with alveolar rhabdomyosarcoma. However, these factors did not display significant effect heterogeneity between histologic types (p > 0.15 for all characteristics)., Conclusions: Overall, we found little evidence that these maternal and birth characteristics are strongly associated with childhood rhabdomyosarcoma.

Objective: Utilizing data from the largest study to date, we examined associations between maternal preconception/prenatal exposure to household chemicals and infant acute leukemia., Methods: We present data from a Children's Oncology Group case-control study of 443 infants (<1 year of age) diagnosed with acute leukemia [including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML)] between 1996 and 2006 and 324 population controls. Mothers recalled household chemical use 1 month before and throughout pregnancy. We used unconditional logistic regression adjusted for birth year, maternal age, and race/ethnicity to calculate odds ratios (ORs) and 95% confidence intervals (CIs)., Results: We did not find evidence for an association between infant leukemia and eight of nine chemical categories. However, exposure to petroleum products during pregnancy was associated with AML (OR = 2.54; 95% CI:1.40-4.62) and leukemia without mixed lineage leukemia (MLL) gene rearrangements ("MLL-") (OR = 2.69; 95% CI: 1.47-4.93). No associations were observed for exposure in the month before pregnancy., Conclusions: Gestational exposure to petroleum products was associated with infant leukemia, particularly AML, and MLL- cases. Benzene is implicated as a potential carcinogen within this exposure category, but a clear biological mechanism has yet to be elucidated.

Family history of testicular cancer is an established risk factor for adult testicular germ cell tumors (GCT). We evaluated the association between family history of cancer and pediatric GCT in a Children's Oncology Group case-control study that included 274 GCT cases (195 female and 79 male) diagnosed < age 15 years and 418 controls frequency matched to cases on sex and age. Family history data were collected through telephone interviews with biological mothers and fathers and unconditional logistic regression was used to evaluate associations with GCT adjusting for potential confounders. A family history of cancer with onset < age 40 years was associated with a reduced risk of GCT among female cases (Odds Ratio (OR) = 0.50, 95% Confidence Interval (CI) 0.28-0.89) and an increased risk among male cases (OR = 2.56, 95% CI 1.02-6.44). Male cases were more likely to report family history of melanoma compared with male controls (OR = 4.65, 95% CI 1.40-15.4). There was an inverse association between family history of ovarian or uterine cancers and GCT in girls (OR = 0.46, 95% CI 0.22-0.96). These sex and cancer site specific associations should be confirmed in additional studies as they may provide clues to the etiology of pediatric GCT.

Objective: A comprehensive case-control study was conducted to evaluate parental risk factors for medulloblastoma (MB) and primitive neuroectodermal tumor (PNET). This analysis was conducted to evaluate associations between fathers' hobbies and risk of their children developing MB/PNET. The hobbies chosen for study were those with similar exposures as occupations associated with childhood cancers., Methods: Cases were 318 subjects under six years of age at diagnosis between 1991 and 1997 and registered with the Children's Cancer Group. An equal number of controls were selected through random digit dialing and individually matched to cases., Results: In multivariate analyses, a significant association was seen for lawn care with pesticides [during pregnancy: odds ratio (OR) = 1.6, 95% confidence interval (CI): 1.0, 2.5; after birth: OR = 1.8, 95% CI: 1.2, 2.8] and a weak association was seen for stripping paint [during pregnancy: OR = 1.4, 95% CI: 0.8, 2.6; after birth: OR = 1.4, 95% CI: 0.7, 2.6]., Conclusions: This study suggests that household exposures from hobbies, particularly pesticides, may increase risk of MB/PNET in children; previous research has been mostly limited to occupational exposures.