Parental tobacco smoking and risk of childhood leukemia in Costa Rica: A population-based case-control study

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.

Cigarette smoke has been linked to adult myeloid leukemia; however, the association between parental smoking and childhood leukemia remains unclear. Parental smoking and the risk of childhood leukemia were examined in the Northern California Childhood Leukemia Study, a case-control study, between 1995 and 2002. The present analysis included 327 acute childhood leukemia cases (281 acute lymphoblastic leukemia (ALL) and 46 acute myeloid leukemia (AML)) and 416 controls matched on age, sex, maternal race, and Hispanic ethnicity. Maternal smoking was not associated with an increased risk of either ALL or AML. Paternal preconception smoking was significantly associated with an increased risk of AML (odds ratio = 3.84, 95% confidence interval: 1.04, 14.17); an increased risk for ALL was suggestive for paternal preconception smoking (odds ratio = 1.32, 95% confidence interval: 0.86, 2.04). Greater risks of ALL were observed compared with the risk associated with paternal preconception smoking alone, when paternal preconception smoking was combined with maternal postnatal smoking (p(interaction) = 0.004) or postnatal passive smoking exposure (p(interaction) = 0.004). These results strongly suggest that exposure to paternal preconception smoking alone or in combination with postnatal passive smoking may be important in the risk of childhood leukemia.

Studies of the relation between parental smoking and childhood leukemia have produced inconsistent results. In the largest case-control studies of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) conducted to date, the authors evaluated leukemia risk relative to parental self-report of cigarette smoking. In telephone interviews in which a structured questionnaire was used, parents of 1842 ALL patients, 517 AML patients, and their matched controls were asked about their cigarette smoking habits before, during, and after the pregnancy with the index child. Risk of leukemia was examined by histologic type, age of the child at diagnosis, immunophenotype (for ALL), and French-American-British morphology group (for AML). The risk of ALL was not associated with the father's ever having smoked (odds ratio [OR] = 1.04, 95% confidence interval [CI] 0.90-1.20) or the mother's ever having smoked (OR = 1.04, 95% CI 0.91-1.19). Similarly, no significant risk of AML was observed for paternal (OR = 0.88, 95% CI 0.67-1.16) or maternal smoking (OR = 0.95, 95% CI 0.74-1.22). The relative risk of leukemia was not significantly different from the null for parental smoking in any time period during or around the index pregnancy, nor was it related to the number of cigarettes, the number of years of smoking, or the number of pack-years. A small number of sporadic, statistically significant associations were found, but overall there appeared to be no association between parental cigarette smoking and ALL or AML, or any subgroup of leukemia. Parental smoking while pregnant or exposure to cigarette smoke shortly after birth is unlikely to contribute substantially to the risk of childhood leukemia in North America.

Whether parental drinking and smoking during pregnancy are associated with an increased risk of cancer in offspring is controversial. There are some indications that maternal alcohol consumption is associated with an elevated risk of acute myeloid leukemia (AML) appearing in very young children. Evidence for an association between maternal smoking during pregnancy and risk of leukemia in offspring has been inconsistent. Using data from a Children's Cancer Group case-control study, we evaluated relationships between infant leukemia risk and parental alcohol consumption and/or cigarette smoking during pregnancy or during the month prior to it. Three hundred two leukemia cases (203 acute lymphoid leukemias [ALLs], 88 AMLs, and 11 other leukemia types) diagnosed in children at 18 months of age or younger and 558 individually matched, regional (i.e., same telephone area code and exchange number) controls were included in the analysis. Information concerning parental alcohol consumption and smoking behavior during the index pregnancy and during the month prior to it was collected by telephone interviews with the mothers of all case and control subjects and the fathers of 250 case and 361 control subjects. Odds ratios (ORs) were used to measure the risk of infant leukemia associated with parental smoking and drinking; tests for trend were used to assess dose-response relationships. The data were analyzed further after stratifying the leukemia cases according to histologic and morphologic types. Reported P values are from two-sided tests of statistical significance. Maternal drinking during pregnancy (compared with not drinking) was associated with ORs of 1.43 (95%) confidence interval [CI] = 1.00-2.04) for ALL and 2.64 (95% CI = 1.36-5.06) for AML. A dose-response relationship was observed for total maternal alcohol consumption during pregnancy and risk of AML (P < .01). Alcohol-related risk appeared to be most pronounced for children who developed AML with a morphology of M1 (myeloblastic with minimal maturation) or M2 (myeloblastic with maturation (OR = 7.62; 95% CI = 2.03-28.64). Paternal alcohol consumption did not confer an increased risk of infant leukemia. Maternal smoking during pregnancy (compared with not smoking) was negatively associated with infant leukemia risk (OR = 0.66 and 95% CI = 0.46-0.94 for total leukemia; OR = 0.45 and 95% CI = 0.21-0.96 for AML), whereas paternal smoking 1 month prior to pregnancy (compared with not smoking during the same period) was related to an elevated risk of ALL (OR = 1.56; 95% CI = 1.03-2.36). Maternal alcohol consumption during pregnancy increases the risk of infant leukemia, especially AML. Maternal smoking, however, does not elevate risk for either AML or ALL. The data suggest that in utero exposure to alcohol may contribute to leukemogenesis involving myeloid cells.

The occurrence of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) during childhood may be influenced by factors operating in fetal life. Furthermore, childhood ALL has been suggested to be linked to patterns of infection during infancy. To explore these hypotheses and other associations, we studied the impact of sibling patterns (e.g., birth order) and birth characteristics (e.g., birth weight) on the risk of childhood ALL and AML. By linkage of records of population-based registries, a cohort of all children whose mothers were born in Denmark from April 1935 through March 1978 was established. Children who developed ALL or AML during the period from April 1968 through December 1992 were identified by linkage with the Danish Cancer Registry. Birth weights were obtained for children born during the period from January 1973 through December 1992 by linkage with the Medical Birth Registry. The cohort of approximately 2.0 million children was followed for the diagnosis of ALL or AML for 20.9 million person-years. A total of 704 cases of childhood ALL were identified. Among 0-4 year olds, the relative risks (RRs) of ALL for birth order positions 1, 2, 3, and 4+ were 1.00 (reference), 0.85 (95% confidence interval [CI] = 0.68-1.07), 0.91 (95% CI = 0.66-1.25), and 0.57 (95% CI = 0.30-1.06), respectively (P for trend = .09). A decreasing trend was not observed among 5-14 year olds. A significant log-linear association between birth weight and the risk of ALL was observed for both age groups. Overall, the RR of ALL increased by a factor of 1.46 (95% CI = 1.18-1.81) (P = .0005) for each kilogram of increase in birth weight. A total of 114 cases of childhood AML were identified. Children born second or later in the birth order had an increased risk of AML (RR = 1.53; 95% CI = 1.01-2.32) compared with firstborns. A particularly high risk of AML at ages 2 (RR = 2.53; 95% CI = 1.46-4.40) and 3 years was associated with having siblings compared with being an only child at those ages. Similar to the findings for ALL risk, there was a significant association between birth weight and AML risk. The relative increase in AML risk per 1-kg increase in birth weight was 2.14 (95% CI = 1.19-3.85; P = .009). The association between birth weight and childhood leukemia suggests the importance of intrauterine factors. A plausible explanation may be that increasing birth weight is associated with a higher rate of cell proliferation and/or a larger number of precursor cells being at risk of malignant transformation. The inverse association between birth order and ALL risk among 0-4 year olds was weak, but it was compatible with the hypothesis that delayed exposure to infection may increase the risk of ALL in this age group. The association of childhood AML with birth order and sibship size at young ages deserves further attention in the search for environmental factors that affect childhood AML risk.

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

The association between tobacco smoke and acute myeloid leukemia (AML) is well established in adults but not in children. Individual-level data on parental cigarette smoking were obtained from 12 case-control studies from the Childhood Leukemia International Consortium (CLIC, 1974-2012), including 1,330 AML cases diagnosed at age <15 years and 13,169 controls. We conducted pooled analyses of CLIC studies, as well as meta-analyses of CLIC and non-CLIC studies. Overall, maternal smoking before, during, or after pregnancy was not associated with childhood AML; there was a suggestion, however, that smoking during pregnancy was associated with an increased risk in Hispanics (odds ratio = 2.08, 95% confidence interval (CI): 1.20, 3.61) but not in other ethnic groups. By contrast, the odds ratios for paternal lifetime smoking were 1.34 (95% CI: 1.11, 1.62) and 1.18 (95% CI: 0.92, 1.51) in pooled and meta-analyses, respectively. Overall, increased risks from 1.2- to 1.3-fold were observed for pre- and postnatal smoking (P < 0.05), with higher risks reported for heavy smokers. Associations with paternal smoking varied by histological type. Our analyses suggest an association between paternal smoking and childhood AML. The association with maternal smoking appears limited to Hispanic children, raising questions about ethnic differences in tobacco-related exposures and biological mechanisms, as well as study-specific biases.

Birth weight and other perinatal characteristics and childhood leukemia in California

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.

Background: Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in folate metabolism, DNA methylation and synthesis. Two MTHFR polymorphisms, C677T and A1298C, have been associated with reduced enzyme activity. Rapidly replicating cell types, such as hematopoietic cells, may be especially sensitive to changes in the availability of intracellular folate. The aim of this case-control study was to evaluate whether the mentioned polymorphisms in MTHFR gene plays a role in altering susceptibility to acute myeloid leukemia and acute lymphoblastic leukemia. Material and methods: 281 patients comprising 101 patients with acute lymphoblastic leukemia and 180 patients with acute myeloid leukemia as well as 490 normal individuals as control group were studied for the C677T and the A1298C MTHFR gene polymorphisms using PCR. The PCR products were digested with HinfI and Mbo‌‌‌‌‌II restriction enzymes respectively (RFLP). The results were electrophoresed on agaros gel and analyzed using SPSS software. Results: The number of patients with acute lymphoblastic leukemia who had C677T polymorphism was less than the control group, but this difference was not significant. Also, combination of C677T/A1298C genotypes in both case and control groups, showed no increase of susceptibility to acute myeloid leukemia and/or acute lymphoblastic leukemia risk. There was no significant relationship between common MTHFR variants and the risk of acute myeloid leukemia and acute lymphoblastic leukemia in controls and the cases. Conclusion: Our findings showed that the MTHFR C677T and A1298C gene variants do not have a major influence on the susceptibility to acute lymphoblastic leukemia and acute myeloid leukemia in Iranian individuals. However, the C677T polymorphism has a protection role in acute lymphoblastic leukemia group, but this difference was not statistically significant.

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

Objective: To investigate the association between individual- and community-level socio-economic status (SES) and childhood leukemia, particularly its subtypes: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Study design: We conducted a large case-control registry-based study in California. Methods: Information on 5788 cases and 5788 controls was obtained by linking California cancer and birth registries. We evaluated relative risk of childhood leukemia by community- (census-based) and individual-level SES measures (parental education and source of payment for delivery) using conditional logistic regression. Results: Children in higher census-based SES categories had a tendency toward slightly decreased risk of total childhood leukemia and ALL compared to children of the lowest SES. Compared to < 12 years of school, 13 and more years of parental education were associated with slightly decreased risk of total childhood leukemia, ALL and AML; however, confidence intervals were imprecise. Source of payment for delivery was not associated with either childhood leukemia nor with its subtypes. Conclusion: We found little evidence to support the suggestion that SES is associated with risk of childhood leukemia or either major subtype. It is likely that results of many previous studies that found an association between childhood leukemia and SES were influenced by selection or ecological bias.

Exposure to tobacco smoke during pregnancy and the risk of multiple sclerosis in offspring: A systematic review and meta-analysis.

Bone Marrow Microbiome: Metagenomic Comparsion of Childhood Acute Lymphoblastic and Acute Myeloid Leukamias

Treatment of cancer with the epipodophyllotoxins (etoposide and teniposide) has been linked to the development of acute myeloid leukemia (AML) in children and adults, but the factors that might influence the risk of this complication of therapy are poorly defined. We therefore assessed the importance of potential risk factors for secondary AML in 734 consecutive children with acute lymphoblastic leukemia who attained complete remission and received continuation (maintenance) treatment according to different schedules of epipodophyllotoxin administration. Secondary AML was diagnosed in 21 of the 734 patients, in 17 of whom this complication was the initial adverse event. Prolonged administration of epipodophyllotoxin (teniposide with or without etoposide) twice weekly or weekly was independently associated with the development of secondary AML (P less than 0.01 by Cox regression analysis). The overall cumulative risk of AML at six years was 3.8 percent (95 percent confidence interval, 2.3 percent to 6.1 percent); but within the subgroups treated twice weekly or weekly, the risks were 12.3 percent (95 percent confidence interval, 5.7 percent to 25.4 percent) and 12.4 percent (95 percent confidence interval, 6.1 percent to 24.4 percent), respectively. In the subgroups not treated with epipodophyllotoxins or treated with them only during remission induction or every two weeks during continuation treatment, the highest cumulative risk was 1.6 percent (95 percent confidence interval, 0.4 percent to 6.1 percent). After adjustment for treatment frequency, there was no apparent relation between the total dose of epipodophyllotoxins and the development of secondary AML. The relative hazard of etoposide as compared with teniposide could not be determined. The risk of epipodophyllotoxin-related AML depends largely on the schedule of drug administration. Other factors, including the cumulative dose of epipodophyllotoxin, radiotherapy, and the initial biologic features of the leukemic blast cells, do not appear to have critical roles.