Home paint exposures and risk of childhood acute lymphoblastic leukemia: findings from the Childhood Leukemia International Consortium.

Introduction: Recent meta-analyses have reported modest but significant associations between birth by cesarean delivery (CD) and subsequent risk of immune-related disorders. An association of CD with childhood leukemia has not been established, although two recent case-control studies showed an increased risk of acute lymphoblastic leukemia (ALL) among young children born by CD, and elective CD (E-CD) in particular. Methods: We pooled data from 12 case-control studies in the Childhood Leukemia International Consortium. We analyzed CD overall and according to indications that likely resulted in E-CD (multiple birth and previous CD). Odds ratios (OR) and 95% confidence intervals (CIs) for risk of ALL and acute myeloid leukemia (AML) were estimated using multivariable logistic regression, adjusting for child's birth weight, sex, age, ethnicity, parental education, maternal age, and study center. Results: Delivery method was known for 8017 ALL cases, 659 AML cases, and 21273 controls. Among three studies with information on indication for CD, data were available for 3677 ALL cases, 114 AML cases, and 3929 controls. The association between CD and ALL (pooled OR: 1.06 [95% CI: 0.99, 1.14]) was not statistically significant, whereas birth by E-CD was associated with an increased risk of ALL (pooled OR: 1.27 [95% CI: 1.06, 1.52]). Subgroup analysis by immunophenotype revealed an association between E-CD and B-ALL (pooled OR: 1.28 [95% CI: 1.04, 1.57]), but not T-ALL. Pooled ORs for AML were 1.02 (95% CI: 0.82, 1.27) for overall CD and 1.39 (95% CI: 0.76, 2.53) for E-CD. Conclusions: Findings derived from a pooled analysis of data from several countries suggest a higher risk of childhood ALL following E-CD. More comprehensive assessment of the indications for E-CD in consortia studies will allow investigators to further explore the potential for confounding by indication. If this association is causal, maladaptive immune activation due to lack of stress response before birth and differential colonization of the microbiome in children born by E-CD should be considered as potential mechanisms. Risk of childhood leukemia associated with cesarean delivery overall and elective cesarean deliveryCesarean delivery (all indications)Pre-labor elective cesarean deliveryNumber of studiesExposed controlsExposed casesOR (95% CI)Number of studiesExposed controlsExposed casesOR (95% CI)Overall12340419241.06 (0.99, 1.14)32513081.27 (1.06, 1.52)ALL12340417491.06 (0.99, 1.14)32512901.27 (1.06, 1.52)AML824781221.02 (0.82, 1.27)1126161.39 (0.76, 2.53)ImmunophenotypeB-cell9313212201.07 (0.99, 1.16)22241961.28 (1.04, 1.57)T-cell931321300.95 (0.77, 1.18)2224241.18 (0.75, 1.88)Age012251561.08 (0.73, 1.60)36102.89 (0.93, 8.89)1-512221212261.05 (0.96, 1.15)31711921.22 (0.98, 1.53)6-10126693481.09 (0.93, 1.28)350591.34 (0.90, 2.01)11-14112721190.97 (0.74, 1.26)324291.25 (0.70, 2.24)Year of birth1970-1979464551.06 (0.70, 1.60)29111.13 (0.46, 2.80)1980-198997235351.01 (0.88, 1.15)31021221.30 (0.99, 1.72)1990-19991215296671.06 (0.95, 1.19)362741.32 (0.92, 1.90)2000-2009810524741.14 (0.98, 1.33)173781.14 (0.78, 1.65)2010-2013336181.93 (0.57, 6.51)1551.81 (0.16, 20.4)Gestational ageEarly preterm11126451.19 (0.67, 2.11)3650.58 (0.10, 3.24)Late preterm112581281.13 (0.84, 1.52)313151.56 (0.61, 3.98)Early term116943481.11 (0.93, 1.32)364851.27 (0.87, 1.86)Full term1113196331.01 (0.90, 1.14)31001311.31 (0.99, 1.72)Late term105482571.02 (0.86, 1.22)3760.95 (0.31, 2.90) Citation Format: Erin Marcotte, Thomas Thomopoulos, Jacqueline Clavel, John Dockerty, Sameera Ezzat, Stephen S. Francis, Claire Infante-Rivard, Corrado Magnani, Catherine Metayer, Ana Maria Mora, Beth A. Mueller, Wafaa M. Rashed, Michael E. Scheurer, Joachim Schuz, Catharina Wesseling, Alkistis Skalkidou, Eleni Petridou, Logan Spector. Cesarean delivery and risk of childhood leukemia: findings from the Childhood Leukemia International Consortium (CLIC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-194. doi:10.1158/1538-7445.AM2015-LB-194

Caesarean delivery and risk of childhood leukaemia: a pooled analysis from the Childhood Leukemia International Consortium (CLIC)

Objective:Tobacco smoke contains carcinogens known to damage somatic and germ cells. In this study, we investigated the effect of tobacco smoking on the risk of childhood acute lymphoblastic leukemia (ALL) and myeloid leukemia (AML).Methods:Information about tobacco smoking exposures of the mother before, during, and after pregnancy was collected via PubMed, Embase, and Web of Science databases through November 5, 2018. We performed to evaluate the association between smoking exposure and the risk of childhood ALL and AML. Study selection, data abstraction, and quality assessment were performed by 2 independent reviewers. Random effects models were used to obtain summary odds ratios (ORs) and 95% confidence intervals (CIs).Results:Nineteen case–control studies of childhood leukemia (age < 15 years) conducted in 9 countries from 1974 to 2018. Maternal smoking exposures did not a significant association with childhood ALL (OR = 1.004, 95% CI 0.953–1.058, P = .881) and AML (OR = 0.92, 95% CI 0.815–1.038, P = .177) during exposure time windows. However, there was an association with paternal smoking and ALL (OR = 1.15, 95% CI 1.038–1.275, P = .007). Paternal smoking in AML showed there was no association with smoking exposures and childhood AML (OR = 1.133, 95% CI 0.943–1.362, P = .181). Next, maternal daily cigarettes consumption showed no associations with ALL (OR = 1.08, 95% CI 1.000–1.168, P = .051) during pregnancy. No association with maternal daily smoking and AML (OR = 0.909, 95% CI 0.682–1.211, P = .514). Paternal daily cigarettes consumption was associated with increased risks of childhood ALL (OR = 1.200, 95% CI 1.112–1.302, P = .000). The higher consumption of paternal smoking (more than 10 per day) was significantly related to childhood ALL. Paternal daily smoking consumption also was related to AML (OR = 1.242, 95% CI 1.031–1.496, P = .022).Conclusion:Maternal smoking before, during, or after pregnancy was not associated with childhood ALL or AML. However, paternal smoking was related to a significantly elevated risk of childhood ALL during pregnancy, but not for AML. Maternal daily smoking consumption was not associated with ALL or AML during pregnancy. The higher consumption of paternal smoking were, the higher the risk of childhood ALL or AML.

Surrogate measures of infectious exposures have been consistently associated with lower childhood acute lymphoblastic leukemia (ALL) risk. However, recent reports have suggested that physician-diagnosed early-life infections increase ALL risk, thereby raising the possibility that stronger responses to infections might promote risk. We examined whether medically diagnosed infections were related to childhood ALL risk in an integrated health-care system in the United States. Cases of ALL (n=435) diagnosed between 1994-2014 among children aged 0-14 years, along with matched controls (n=2,170), were identified at Kaiser Permanente Northern California. Conditional logistic regression was used to estimate risk of ALL associated with history of infections during first year of life and across the lifetime (up to diagnosis). History of infection during first year of life was not associated with ALL risk (odds ratio (OR)=0.85, 95% confidence interval (CI): 0.60, 1.21). However, infections with at least 1 medication prescribed (i.e., more "severe" infections) were inversely associated with risk (OR=0.42, 95% CI: 0.20, 0.88). Similar associations were observed when the exposure window was expanded to include medication-prescribed infections throughout the subjects' lifetime (OR=0.52, 95% CI: 0.32, 0.85).

Maternal prenatal supplementation with folic acid and other vitamins has been inconsistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Little is known regarding the association with acute myeloid leukemia (AML), a rarer subtype. We obtained original data on prenatal use of folic acid and vitamins from 12 case-control studies participating in the Childhood Leukemia International Consortium (enrollment period: 1980-2012), including 6,963 cases of ALL, 585 cases of AML, and 11,635 controls. Logistic regression was used to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for child's age, sex, ethnicity, parental education, and study center. Maternal supplements taken any time before conception or during pregnancy were associated with a reduced risk of childhood ALL; odds ratios were 0.85 (95% CI = 0.78-0.92) for vitamin use and 0.80 (0.71-0.89) for folic acid use. The reduced risk was more pronounced in children whose parents' education was below the highest category. The analyses for AML led to somewhat unstable estimates; ORs were 0.92 (0.75-1.14) and 0.68 (0.48-0.96) for prenatal vitamins and folic acid, respectively. There was no strong evidence that risks of either types of leukemia varied by period of supplementation (preconception, pregnancy, or trimester). Our results, based on the largest number of childhood leukemia cases to date, suggest that maternal prenatal use of vitamins and folic acid reduces the risk of both ALL and AML and that the observed association with ALL varied by parental education, a surrogate for lifestyle and sociodemographic characteristics.

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. 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. 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. 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.

Positive associations have been reported between the measures of accelerated fetal growth and risk of childhood acute lymphoblastic leukemia (ALL). We investigated this association by pooling individual-level data from 12 case-control studies participating in the Childhood Leukemia International Consortium. Two measures of fetal growth-weight-for-gestational-age and proportion of optimal birth weight (POBW)-were analysed. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, and combined in fixed effects meta-analyses. Pooled analyses of all data were also undertaken using multivariable logistic regression. Subgroup analyses were undertaken when possible. Data on weight for gestational age were available for 7,348 cases and 12,489 controls from all 12 studies and POBW data were available for 1,680 cases and 3,139 controls from three studies. The summary ORs from the meta-analyses were 1.24 (95% CI: 1.13, 1.36) for children who were large for gestational age relative to appropriate for gestational age, and 1.16 (95% CI: 1.09, 1.24) for a one-standard deviation increase in POBW. The pooled analyses produced similar results. The summary and pooled ORs for small-for-gestational-age children were 0.83 (95% CI: 0.75, 0.92) and 0.86 (95% CI: 0.77, 0.95), respectively. Results were consistent across subgroups defined by sex, ethnicity and immunophenotype, and when the analysis was restricted to children who did not have high birth weight. The evidence that accelerated fetal growth is associated with a modest increased risk of childhood ALL is strong and consistent with known biological mechanisms involving insulin-like growth factors. © 2013 UICC.

The association between CCAAT/enhancer binding protein-ε (CEBPE) rs2239633 polymorphism and acute lymphoblastic leukemia (ALL) risk has been reported, but results of previous studies remain controversial and ambiguous. To assess the association between CEBPE rs2239633 polymorphism and childhood ALL risk, a meta-analysis was performed. Based on comprehensive searches of the PubMed, Embase, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biomedical Literature Database (CBM), we identified outcome data from all articles estimating the association between CEBPE rs2239633 polymorphism and childhood ALL risk. The pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated. A significant association between CEBPE rs2239633 polymorphism with childhood ALL was found (OR = 1.19, 95% CI 1.11-1.28, P < 0.01). Subgroup analysis stratified by ethnicity also suggested a significant association between this polymorphism and childhood ALL in the Caucasian subgroup (OR = 1.19, 95% CI 1.09-1.30, P < 0.01) and Hispanic subgroup (OR = 1.39, 95% CI 1.18-1.63, P < 0.01). No significant association was observed in the Asian subgroup (OR = 1.05, 95% CI 0.90-1.22, P = 0.53). The CEBPE rs2239633 polymorphism increased B cell ALL risk (OR = 1.29, 95% CI 1.15-1.44, P < 0.01) and B hyperdiploid ALL risk (OR = 1.84, 95% CI 1.40-2.43, P < 0.01). This meta-analysis demonstrated that the CEBPE rs2239633 polymorphism was significantly associated with childhood ALL risk.

BackgroundRecently, there have been a number of studies on the association between XRCC1 polymorphisms and childhood acute lymphoblastic leukemia (ALL) risk. However, the results of previous reports are inconsistent. Thus, we performed a meta-analysis to clarify the effects of XRCC1 variants on childhood ALL risk.MethodsA meta-analysis was performed to examine the association between XRCC1 polymorphisms (Arg399Gln, Arg194Trp, and Arg280His) and childhood ALL risk. We critically reviewed 7 studies with a total of 880 cases and 1311 controls for Arg399Gln polymorphism, 3 studies with a total of 345 cases and 554 controls for Arg280His polymorphism, and 6 studies with a total of 783 cases and 1180 controls for Arg194Trp polymorphism, respectively. Odds ratio (OR) and its 95% confidence interval (CI) were used.ResultsSignificant association between XRCC1 Arg399Gln polymorphism and childhood ALL risk was observed in total population analyses (ORadditive model = 1.501, 95% CI 1.112–2.026, POR = 0.008; ORdominant model = 1.316, 95% CI = 1.104–1.569, POR = 0.002) and Asian subgroup analyses (ORadditive model = 2.338, 95%CI = 1.254–4.359, POR = 0.008; ORdominant model = 2.108, 95%CI = 1.498–2.967, POR = 0.000). No association was detected in Caucasians, Metizo and mixed populations. Ethnicity was considered as a significant source of heterogeneity in the meta-regression model. For the other two XRCC1 polymorphisms, no association with childhood ALL risk was found.ConclusionsThe meta-analysis results suggested that XRCC1 Arg399Gln polymorphism might be associated with elevated childhood ALL risk among Asian population.

The association between parental smoking and risk of childhood acute lymphoblastic leukemia (ALL) was investigated in an Australian population-based case-control study that included 388 cases and 868 controls aged <15 years, recruited from 2003 to 2006. Both of the child's parents provided information about their smoking habits for each year from age 15 years to the child's birth. Data were analyzed by logistic regression. Maternal smoking was not associated with risk of childhood ALL, but the odds ratio for paternal smoking of ≥15 cigarettes per day around the time of the child's conception was 1.35 (95% confidence interval: 0.98, 1.86). The associations between parental smoking risk of childhood ALL did not differ substantially by immunophenotypic or cytogenetic subtype. Meta-analyses of paternal smoking, including results from the Australian Study of Causes of Acute Lymphoblastic Leukemia in Children and those of previous studies, produced summary odds ratios of 1.15 (95% confidence interval: 1.06, 1.24) for any paternal smoking around the time of the child's conception and 1.44 (95% confidence interval: 1.24, 1.68) for smoking ≥20 cigarettes per day at that time. Study results suggest that heavier paternal smoking around the time of conception is a risk factor for childhood ALL. Men should be strongly encouraged to cease smoking, particularly when planning to start a family.

The mammalian target of rapamycin (mTOR) is an important protein kinase regulating cell survival and apoptosis. To determine whether genetic variations in mTOR are associated with risk of acute lymphoblastic leukemia (ALL) in Chinese children, we genotyped two tag single nucleotide poymorphisms (SNPs) in mTOR (rs2536 and rs2295080) in a case–control study. We observed that the variant genotype TC of mTOR rs2536 was associated with a significantly decreased risk of childhood ALL (adjusted odds ratio [OR] = 0.67, 95% confidence interval [CI] = 0.46–0.96), and the association was more pronounced in high-risk ALL and T-phenotype ALL groups. Additionally, we found that the combined genotypes TC/CC decreased the risk of ALL only in the high-risk ALL group (adjusted OR = 0.54, 95% CI = 0.32–0.91) and T-phenotype ALL group (adjusted OR = 0.29, 95% CI = 0.10–0.84). These results suggest that the mTOR rs2536 polymorphism is involved in the susceptibility to childhood ALL in a Chinese population.

The Australian Study of Causes of Acute Lymphoblastic Leukemia in Children (Aus-ALL) was designed to test the hypothesis, raised by a previous Western Australian study, that maternal folic acid supplementation during pregnancy might reduce the risk of childhood acute lymphoblastic leukemia (ALL). Aus-ALL was a national, population-based, multicenter case-control study that prospectively recruited 416 cases and 1,361 controls between 2003 and 2007. Detailed information was collected about maternal use of folic acid and other vitamin supplements before and during the index pregnancy. Data were analyzed using logistic regression, adjusting for matching factors and potential confounders. A meta-analysis with the results of previous studies of folic acid supplementation was also conducted. We found weak evidence of a protective effect of maternal folate supplementation before pregnancy against risk of childhood ALL, but no evidence for a protective effect of its use during pregnancy. A meta-analysis including this and 2 other studies, but not the study that raised the hypothesis, also found little evidence that folate supplementation during pregnancy protects against ALL: the summary odds ratios (ORs) for folate supplementation were 1.06 [95% confidence interval (CI): 0.77-1.48] with reference to no folate supplementation and 1.02 (95% CI: 0.86-1.20) with reference to no vitamin supplementation. For vitamin supplementation in general, the summary OR from a meta-analysis of 5 studies-including Aus-ALL-was 0.83 (95% CI: 0.73-0.94). Vitamin supplementation in pregnancy may protect against childhood ALL, but this effect is unlikely to be large or, if real, specifically due to folate.

Genetic polymorphisms in the promoter regions of FAS, FASL and CASP8 involved in the apoptotic signaling pathway are thought to be associated with susceptibility to cancer. We hypothesized that these functional genetic variants might be associated with the risk of childhood acute lymphoblastic leukemia (ALL). A case–control study in a Chinese population with 361 cases of ALL and 519 controls was performed to evaluate the association between FAS, FASL and CASP8 variants and risk of childhood ALL. Individuals with FAS − 1377AG had an odds ratio (OR) of 0.72 for the risk of ALL compared to − 1377GG and the variant FASL − 844CC was associated with a statistically significantly decreased risk of childhood ALL (OR = 0.38). Furthermore, combined genotypes with 5–8 protective alleles were associated with a significantly decreased risk of childhood ALL compared with those with 0–4 variants, and this decreased risk was more pronounced among the subgroups of age < 6 years, female, parental never-drinking status and never house-painting. Our results provide evidence that FAS–FASL–CASP8 polymorphisms contributed to a reduced risk of childhood ALL in our population. Larger studies are warranted to validate our findings.

It is plausible that exposure of the parents before birth or of the child to sources of benzene increases the risk of childhood acute lymphoblastic leukaemia (ALL). The aim of this analysis was to investigate whether refuelling a vehicle with petrol before birth or burning wood to heat the home before or after the child's birth increased the risk of childhood ALL. Data from 389 cases and 876 frequency-matched controls were analysed using unconditional logistic regression, adjusting for study matching factors and potential confounders. The odds ratio (OR) for the mother ever refuelling a vehicle with petrol for non-occupational purposes before or during the pregnancy was 0.97 [95% confidence interval (CI) 0.69, 1.38]. The OR for the father for this exposure in the year before conception was 0.88 [95% CI 0.52, 1.48]. The OR for use of a closed wood burner to heat the home in the year before or during pregnancy was 1.41 [95% CI 1.02, 1.94] and 1.25 [95% CI 0.92, 1.70] after birth. We found no evidence that non-occupational refuelling a vehicle with petrol in the year before or during pregnancy increased the risk of ALL in the offspring. There was weak evidence that burning wood in a closed burner to heat the home increased the risk, but there was no dose-response relationship and chance could explain the finding.

The early onset of childhood acute lymphoblastic leukemia (ALL) suggests that critical exposures occurring during pregnancy may increase risk. We investigated the effects of maternal coffee and tea consumption during pregnancy on ALL risk by pooling data from eight case-control studies participating in the Childhood Leukemia International Consortium. Data on maternal coffee intake were available for 2,552 cases and 4,876 controls, and data on tea intake were available for 2,982 cases and 5,367 controls. Coffee and tea intake was categorized into 0, > 0-1, > 1-2, and > 2 cups/day, and covariates were combined and harmonized. Data on genetic variants in NAT2, CYP1A1, and NQO1 were also available in a subset. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression, and linear trends across categories were assessed. No association was seen with 'any' maternal coffee consumption during pregnancy, but there was evidence of a positive exposure-response; the pooled OR for > 2 cups/day versus none was 1.27 (95% CI 1.09-1.43), p trend = 0.005. No associations were observed with tea consumption. No interactions were seen between coffee or tea intake and age, maternal smoking or genotype, and there was little or no evidence that associations with coffee or tea differed among cases with and without chromosomal translocations. Despite some limitations, our findings suggest that high coffee intake during pregnancy may increase risk of childhood ALL. Thus, current advice to limit caffeine intake during pregnancy to reduce risk of preterm birth may have additional benefits.