Risk Of Infant Leukemia Research Articles

Cesarean Delivery and Risk of Infant Leukemia: A Report from the Children's Oncology Group.

Background: Studies have reported increased risks of pediatric acute lymphoblastic leukemia (ALL) among children born by cesarean delivery (CD). However, no previous study has examined the impact of CD on risk of infant leukemia specifically.Methods: In this study, 443 infants diagnosed with acute leukemia, including both ALL and acute myelogenous leukemia (AML), were identified at Children's Oncology Group institutions between January 1996 and December 2006; 324 controls frequency matched by year of birth were identified though random digit dialing and random selection from U.S. birth registries. Using interview data and, for a subset of participants, medical record data, we analyzed CD overall and by indications that likely resulted in pre-labor CD (PLCD) or emergency CD (ECD). Odds ratios (ORs) and 95% confidence intervals (CIs) for risk of ALL and AML were estimated using multivariable unconditional logistic regression models, adjusted for year of birth, birth weight, and maternal race.Results: We observed an increased point estimate for the association between CD and ALL (OR, 1.52 and 95% CI, 1.02-2.25). We did not observe an association between CD and AML (OR, 1.02 and 95% CI, 0.64-1.62). In analyses of indication for CD, we observed elevated effect estimates for the associations of both PLCD and ECD and infant ALL.Conclusions: Our analysis suggests an increased risk of infant ALL following CD, including both PLCD and ECD. Altered microbiota colonization may be involved in development of leukemia in infants, but clear biological mechanisms have yet to be determined.Impact: This study provides the first in-depth examination of CD and infant leukemia. Cancer Epidemiol Biomarkers Prev; 27(4); 473-8. ©2018 AACR.

Parental Age and Risk of Infant Leukaemia: A Pooled Analysis.

Infant leukaemia (IL) is extremely rare with fewer than 150 cases occurring each year in the United States. Little is known about its causes. However, recent evidence supports a role of de novo mutations in IL aetiology. Parental age has been associated with several adverse outcomes in offspring, including childhood cancers. Given the role of older parental age in de novo mutations in offspring, we carried out an analysis of parental age and IL. We evaluated the relationship between parental age and IL in a case-control study using registry data from New York, Minnesota, California, Texas, and Washington. Records from 402 cases [219 acute lymphoblastic leukaemia (ALL), 131 acute myeloid leukaemia (AML), and 52 other] and 45392 controls born during 1981-2004 were analysed. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by logistic regression. Estimates were adjusted for infant sex, birth year category, maternal race, state, and mutually adjusted for paternal or maternal age, respectively. Infants with mothers' age ≥40years had an increased risk of developing AML (OR 4.80, 95% CI 1.80, 12.76). In contrast, paternal age <20 was associated with increased risk of ALL (OR 3.69, 95% CI 1.62, 8.41). This study demonstrates increased risk of infant ALL in relation to young paternal age. Given record linkage, there is little concern with recall or selection bias, although data are lacking on MLL gene status and other potentially important variables. Parent of origin effects, de novo mutations, and/or carcinogenic exposures may be involved in IL aetiology.

Genetic Susceptibility Loci and Risk of Infant Leukemia by Subtype and MLL status: A Children's Oncology Group Report

Abstract 749 Introduction.Leukemia in infancy is extremely rare and etiologically distinct from leukemia arising in older children. Infant leukemia cases likely arise in utero, typically involve rearrangements of the mixed lineage leukemia (MLL) gene, and have a much poorer survival than older children with leukemia. Since genetic determinants of susceptibility to infant leukemia are likely different from those in older children, we aimed to evaluate genetic variants previously identified by genome wide association studies of childhood acute lymphoblastic leukemia (ALL). Methods.We genotyped candidate susceptibility loci in 171 Caucasian infants less than 12 months of age with acute leukemia (including 102 ALL, 67 acute myeloid leukemia (AML), and 2 biphenotypic cases) diagnosed during the period 1996–2006. Controls consisted of 384 healthy Caucasian blood donors. Associations between genetic polymorphisms in IKZF1, ARID5B, and CEBPE and infant leukemia were evaluated using logistic regression and were further stratified by leukemia subtype and presence or absence of MLL gene rearrangements. Results.We observed a statistically significant association with two copies of the IKZF1 rs11978267 variant allele in infant leukemia overall (Odds Ratio (OR)=2.3, 95% Confidence Interval (CI)=1.3-4.2), but not with the other susceptibility loci. The association with IKZF1 was concentrated in the AML group, with an increased risk associated with two copies of the variant allele (OR=3.9, 95%CI=1.8-8.4), but not one copy. The association was similarly strong in those with and without a MLL gene rearrangement. In contrast, a strong association with the IKZF1 variant was seen in infants with ALL lacking a MLL rearrangement (OR=5.1, 95%CI=1.8-14.5), but not in those with MLL rearrangements (OR=0.7, 95%CI=0.2-2.2). Moreover, infants with ALL and no MLL rearrangement had a strong association with a genetic variant in the gene, ARID5B (rs10821936, OR=7.2, 95%CI=2.5-20.6), which was also not seen in those with ALL and a MLL rearrangement. Discussion.IKZF1 (IKAROS)is expressed in early hematopoiesis, and its role in lymphopoiesis and lymphoid leukemia is well-described. IKAROS is also expressed in precursor myeloid cells, and our report is the first evidence that IKZF1 is important in the etiology of infant myeloid leukemia, irrespective of MLL gene rearrangements. Moreover, our data indicate striking differences in genetic susceptibility to infant ALL with and without rearrangements of the MLL gene. This knowledge could provide important new etiologic insights into this extremely rare but heterogeneous hematopoietic malignancy. Supported by NIH CA079940, T32 CA099936, K05 CA157439 and the Children's Cancer Research Fund, Minneapolis, MN. Disclosures:No relevant conflicts of interest to declare.

Maternal prenatal cigarette, alcohol and illicit drug use and risk of infant leukaemia: a report from the Children's Oncology Group

Several case-control studies have evaluated associations between maternal smoking, alcohol consumption and illicit drug use during pregnancy and risk of childhood leukaemia. Few studies have specifically focused on infants (<1 year) with leukaemia, a group that is biologically and clinically distinct from older children. We present data from a Children's Oncology Group case-control study of 443 infants diagnosed with acute leukaemia [including acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML)] between 1996 and 2006 and 324 population controls. Mothers were queried about their cigarette, alcohol and illicit drug use 1 year before and throughout pregnancy. Odds ratios (ORs) and 95% confidence intervals [CI] were calculated using adjusted unconditional logistic regression models. Maternal smoking (>1 cigarette/day) and illicit drug use (any amount) before and/or during pregnancy were not significantly associated with infant leukaemia. Alcohol use (>1 drink/week) during pregnancy was inversely associated with infant leukaemia overall [OR = 0.64; 95% CI 0.43, 0.94], AML [OR = 0.49; 95% CI 0.28, 0.87], and leukaemia with mixed lineage leukaemia gene rearrangements ('MLL+') [OR = 0.59; 95% CI 0.36, 0.97]. While our results agree with the fairly consistent evidence that maternal cigarette smoking is not associated with childhood leukaemia, the data regarding alcohol and illicit drug use are not consistent with prior reports and are difficult to interpret. It is possible that unhealthy maternal behaviours during pregnancy, some of which carry potential legal consequences, may not be adequately measured using only self-report. Future case-control studies of childhood leukaemia that pursue these exposures may benefit from incorporation of validated instruments and/or biomarkers when feasible.

Maternal exposure to household chemicals and risk of infant leukemia: a report from the Children’s Oncology Group

Utilizing data from the largest study to date, we examined associations between maternal preconception/prenatal exposure to household chemicals and infant acute leukemia. We present data from a Children's Oncology Group case-control study of 443 infants (<1year 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 1month 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). 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. 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.

Analgesic use during pregnancy and risk of infant leukaemia: A Children's Oncology Group study

Background:Infant leukaemia is likely initiated in utero.Methods:We examined whether analgesic use during pregnancy was associated with risk by completing telephone interviews of the mothers of 441 infant leukaemia cases and 323 frequency-matched controls, using unconditional logistic regression.Results:With the exception of a reduced risk for infant acute myeloid leukaemias with non-aspirin non-steroidal anti-inflammatory drugs (NSAID) use early in pregnancy (odds ratios=0.60; confidence intervals: 0.37–0.97), no statistically significant associations were observed for aspirin, non-aspirin NSAIDs, or acetaminophen use in early pregnancy or after knowledge of pregnancy.Conclusion:Overall, analgesic use during pregnancy was not significantly associated with the risk of infant leukaemia.

N -Acetyltransferase 2 Polymorphisms and Susceptibility to Infant Leukemia with Maternal Exposure to Dipyrone during Pregnancy

Maternal exposure to dipyrone during pregnancy has been associated with risk of infant leukemia (IL). N-Acetyltransferase 2 (NAT2) enzyme acetylates dipyrone, resulting in a detoxified metabolite. We performed genotyping to identify the distribution of NAT2 polymorphisms in duo samples from mothers and children previously investigated in a case-controlled study of IL. Samples from 132 IL, 131 age-matched controls, mothers of cases (n = 86), and mothers of controls (n = 36) were analyzed. PCR-RFLP assays were used to determine the NAT2 variants 191G>A, 282C>T, 341T>C, 481C>T, 590G>A, 803A>G, and 857G>A. The test for case-control differences in the distribution of genotypes was based on χ(2) statistics. Unconditional logistic regression was used to examine the association between maternal exposure to dipyrone during the index pregnancy, IL, and NAT2 phenotypes. Crude and adjusted odds ratios (OR) are given with the 95% confidence interval (95% CI). NAT2 slow-acetylation haplotypes were associated with IL (OR, 8.90; 95% CI, 1.71-86.7). An association between IL and NAT2 phenotype was observed in IL whether the mothers reported dipyrone exposures (OR, 4.48; 95% CI, 1.88-10.7) or not (OR, 4.27; 95% CI, 1.75-10.5). The combination of NAT2 slow/slow (mother/child) phenotypes confers a higher risk of IL (OR, 30.0; 95% CI, 5.87-279.7). NAT2 slow-acetylation profiles are associated with IL regardless of maternal exposure to dipyrone during pregnancy. Further recommendations about medicine exposures during pregnancy should take into account that infants with the maternal NAT2 slow-acetylation genotypes might be particularly vulnerable to greater risk.

Maternal vitamin and iron supplementation and risk of infant leukaemia: a report from the Children's Oncology Group

Background:Prenatal supplementation has been inversely associated with childhood, but not with infant, leukaemia.Methods:Mothers of 443 cases of infant leukaemia diagnosed during 1996–2006 and 324 frequency-matched controls completed interviews. Associations were evaluated by unconditional logistic regression.Results:We observed no associations between prenatal vitamin (odds ratio (OR)=0.79, 95% confidence interval (CI): 0.44–1.42) or iron supplementation (OR=1.07, 95% CI: 0.75–1.52) and infant leukaemia after adjustment for race/ethnicity and income. Similar results were observed for leukaemia subtypes analysed separately.ConclusionThe observed null associations may be attributable to high supplementation rates and/or national fortification programmes.

90 NQO1 polymorphism, maternal exposure and the risk of infant leukemia

90 NQO1 polymorphism, maternal exposure and the risk of infant leukemia

Pre-pregnancy weight, rate of gestational weight gain and risk of infant leukemia

Pre-pregnancy weight, rate of gestational weight gain and risk of infant leukemia

Birth Characteristics, Maternal Reproductive History, and the Risk of Infant Leukemia: A Report from the Children's Oncology Group

Leukemias with MLL gene rearrangements predominate in infants (<1 year of age), but not in older children, and may have a distinct etiology. High birth weight, higher birth order, and prior fetal loss have, with varying consistency, been associated with infant leukemia, but no studies have reported results with respect to MLL status. Here, we report for the first time such an analysis. During 1999 to 2003, mothers of 240 incident cases (113 MLL(+), 80 MLL(-), and 47 indeterminate) and 255 random digit dialed controls completed a telephone interview. Odds ratios and 95% confidence intervals for quartile of birth weight, birth order, gestational age, maternal age at delivery, prior fetal loss, pre-pregnancy body mass index, and weight gain during pregnancy were obtained using unconditional logistic regression; P for linear trend was obtained by modeling continuous variables. There was a borderline significant linear trend of increasing birth weight with MLL(+) (P = 0.06), but not MLL(-) (P = 0.93), infant leukemia. Increasing birth order showed a significant inverse linear trend, independent of birth weight, with MLL(+) (P = 0.01), but not MLL(-) (P = 0.18), infant leukemia. Other variables of interest were not notably associated with infant leukemia regardless of MLL status. This investigation further supports the contention that molecularly defined subtypes of infant leukemia have separate etiologies.

Maternal hemoglobin concentration during pregnancy and risk of infant leukaemia: a children's oncology group study

In contrast to the positive association found in three studies between maternal anaemia during pregnancy and childhood leukaemia, no such association was found in infant leukaemia (odds ratio 0.85, 95% confidence interval 0.53–1.37).

Maternal Hemoglobin Concentration during Pregnancy and Risk of Infant Leukemia.

Little is known about the etiology of childhood leukemia. Elevated birth weight (> 4000 g) is gaining acceptance as a risk factor, particularly for children diagnosed < 2 years of age, but the underlying biological or physiological explanation for this association has yet to be defined. At least three recent studies have demonstrated a positive association with childhood leukemia and maternal anemia during pregnancy. Physiologic anemia of pregnancy, which results from normal plasma volume expansion, is thought to produce optimal blood viscosity for the low flow area of the placenta and is associated with the highest average birth weights in the offspring. We therefore hypothesized that maternal physiologic anemia of pregnancy would have a positive association with infant leukemia. To test this hypothesis, we utilized data from a case-control study conducted by the Children's Oncology Group (COG) that consisted of 240 incident cases of acute infant leukemia (< 12 months of age) diagnosed between 1996 and 2002 and 255 controls obtained by random digit dialing. Maternal blood counts were obtained by medical record abstraction. Information regarding the patients' diagnoses and cytogenetic/molecular abnormalities were obtained from COG institutions. Physiologic anemia of pregnancy was defined as a hemoglobin concentration of < 11 g/dL in the second or third trimester of pregnancy (WHO classification). Anemia earlier in pregnancy is more frequently due to nutritional deficiencies and can be associated with poor fetal outcomes and thus was excluded. Maternal hemoglobin values from the second or third trimester were available for 178 case and 180 control mothers. Data were analyzed using unconditional logistic regression. We found no evidence that physiologic anemia of pregnancy was associated with birth weight of > 4000 g (odds ratio (OR) 1.05, 95% confidence interval (CI)=0.55–1.99) Overall, the OR for physiologic anemia of pregnancy and risk of infant leukemia was 0.85 (95%CI=0.53–1.37). The association remained non-significant when cases were divided into acute myeloid leukemia (AML) (n=63) and acute lymphocytic leukemia (ALL) (n=115) with ORs of 0.64 (95%CI=0.32–1.30) and 0.98 (95%CI=0.58–1.66), respectively. The association was also not significant when cases were stratified by MLL gene abnormality status (OR=0.77; 95%CI=0.42–1.40 and OR=0.88; 95%CI=0.45–1.73, for cases with (n=92) and without (n=62) an MLL gene abnormality, respectively). These associations remained non-significant when the data were adjusted for birth weight, maternal race, and birth order. More stringent criteria for anemia also did not modify the results. We found no evidence for an increased risk of infant leukemia in the offspring of mothers with physiologic anemia of pregnancy. This work was supported by NIH R01 CA79940 and the Children's Cancer Research Fund.

404: Pain Reliever use during Pregnancy and Risk of Infant Leukemia: A Children's Oncology Group Study

404: Pain Reliever use during Pregnancy and Risk of Infant Leukemia: A Children's Oncology Group Study

Prescription medication use during pregnancy and risk of infant leukemia (United States).

We explored whether maternal medication use during pregnancy may be an important etiologic area for investigation in studies of infant leukemia. In this case-control study, associations were explored between specific medications as recorded in the medical records of 243 mothers of infants who were diagnosed with leukemia at < 18 months of age and 393 mothers ol infants without leukemia identified through random digit dialing. Cases included 157 acute lymphoblastic (ALL), 77 acute myeloid (AML), and nine other leukemias. A total of 27 different drugs that were prescribed for at least six women were analyzed. Overall, non-statistically significant negative associations (Odds ratios, OR < 0.5) were observed with amoxicillin, nystatin, clomiphene, levothyroxine, cefaclor, and trimethobenzamide HCL. When cases were restricted to either myeloid or lymphoblastic leukemia, cotrimoxazole was prescribed for five ALL case mothers and no matched controls; no association with cotrimoxazole was observed with AML. Given the number of comparisons, chance cannot be ruled out for any of the associations found here. However, a strength of this study is the lack of recall bias. The disparate data observed between AML and ALL in some instances may indicate areas of interest; they will be explored further in a case-control study of infant leukemia that is currently underway.

Family history of cancer and autoimmune disease and risk of leukemia in infancy: a report from the Children's Cancer Group (United States and Canada).

As there are some suggestions that a family history of cancer or autoimmune disease might be associated with an increased risk of leukemia in children, we explored this possibility using data from a matched case-control study conducted by the Children's Cancer Group. We compared the family history of cancer and autoimmune diseases of 302 infant leukemia cases (diagnosed within the first 18 months of life) with that of 668 individually matched controls in the United States and Canada. Although not significant, cancer history in parents was found to be associated with an elevated risk of infant leukemia (odds ratio [OR] = 1.4, 95 percent confidence interval [CI] = 0.6-3.6), predominantly acute myeloid leukemia (AML) (OR = 2.2, CI = 0.6-9.0). Cancer history among second-degree relatives was also related to a nonsignificantly elevated risk of AML. Family history of autoimmune diseases, on the other hand, was generally not found to be related to the risk of infant leukemia. This study provided no strong evidence that family history of cancer or autoimmune disease is a major risk factor for infant leukemia.

Evaluating the relationships among maternal reproductive history, birth characteristics, and infant leukemia: A report from the children's cancer group

PURPOSE: Specific events in the mother's reproductive history and certain birth characteristics have been associated with childhood leukemia. Few studies have explored these associations specifically in infants. METHODS: The Children's Cancer Group (CCG) conducted three separate case-control studies of childhood leukemia that involved similar methodologies and data collection. Data from interviews of the mothers of a total of 303 children diagnosed with leukemia at 1 year of age or younger and their matched controls ( n = 468) were available from the three studies. These data included maternal reproductive history (stillbirths, abortions, and miscarriages) and certain birth characteristics of the index child. RESULTS: Compared with controls, cases were significantly more likely to be female ( P < 0.01) and were more often heavier at birth (particularly cases diagnosed after 6 months of age (odds ratio, 4.18; 95% confidence interval, 1.75–10.02)). Overall, there were no statistically significant differences between cases and controls in regard to maternal report of any type of previous fetal loss. Finally, being a later-born child was associated with an increased risk of acute myeloid leukemia but not of acute lymphoblastic leukemia. CONCLUSIONS: The relationships among birthweight, prior fetal loss, and risk of infant leukemia appear to be complex. Further studies of infant leukemia that incorporate molecular as well as epidemiologic data may help to elucidate these differences.