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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.In 2001, a case-control study from Western Australia reported a strong protective effect of maternal folate supplementation (with or without iron) during pregnancy on risk of common acute lymphoblastic leukemia (ALL): odds ratio (OR) ¼ 0.40, 95% CI: 0.21-0.73. 1 Iron supplementation alone was only weakly protective: OR ¼ 0.75, 95% CI: 0.37-1.51, suggesting that if there was a protective effect it lay with folate or the combination of folate and iron. A protective effect of folate is biologically plausible because of its dual roles in methylation and the synthesis and repair of DNA. 2 Folate provides 5-methyltetrahydrofolate for the methylation of homocysteine to methionine, which is converted to S-adenosylmethionine, the principal methyl donor in DNA methylation. DNA methylation affects gene expression, and specific

Acute lymphoblastic leukaemia (ALL) is the commonest childhood cancer in developed countries. Little is known about its causes, although its early age at diagnosis has focused interest on maternal and perinatal factors. We have previously observed a protective effect of maternal folate supplementation during pregnancy against ALL, and a number of studies have reported protective effects of some common polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene. One study has suggested that the effect of MTHFR polymorphisms on risk of ALL may depend on folate status. This study aimed to look for evidence of an interaction between maternal folate supplementation and child's genotype among the cases from our previous study. Bone marrow specimens from 82 of 83 case children were available. DNA was extracted and genotyped for MTHFR C677T and A1298C using standard techniques. We used a case-only analysis to estimate the case-only odds ratio (COR) for MTHFR genotype and folate supplementation in association with ALL. None of the CORs indicated a significant departure from a multiplicative model. Adjustment for sex, age or genotype at the other locus had little effect on the results. Other studies of this gene and environment interaction in ALL and other cancers have produced contradictory results, perhaps because of varying definitions of folate exposure. Further research into the interaction of folate intake and genotype in causing ALL and other cancers is needed. We are specifically studying it in an Australian national case-control study of genetic and environmental causes of ALL. ' 2006 Wiley-Liss, Inc.Key words: folate; leukaemia; gene; child; interaction Acute lymphoblastic leukaemia (ALL) is the commonest childhood cancer in developed countries. It is more common in males and 60% of cases are diagnosed in the first 5 years of life. 1 The only environmental cause of ALL that is known with any certainty is prenatal exposure to ionizing radiation. Risk is also increased with a few specific constitutional chromosomal disorders. The early age at diagnosis of most childhood ALL has focused interest on maternal and perinatal factors, and parental environmental exposures prior to conception. 2 In our case-control study of childhood ALL, we found that maternal folate supplementation in pregnancy was associated with a significantly reduced risk of ALL in the offspring (OR 5 0.4, 95% confidence interval (CI) 0.21-0.73). 3 Further evidence that folate-related mechanisms may be associated with risk of ALL comes from studies that have shown a protective effect of the common polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene-C677T and A1298C-in children 4-6 and in adults. 7 Krajinovic et al. found a protective effect of MTHFR polymorphisms in children born before 1996 (about the time that Health Canada recommended folate supplementation during pregnancy) but not in children born later. 5 We aimed to determine whether there was evidence of this interaction in cases of childhood ALL from our previous...

Increases in the incidence of childhood acute lymphoblastic leukemia (ALL) have been reported in some countries, while other reports from similar geographical regions have indicated stable rates. The reasons for the discrepancies have been debated in the literature, with the focus on whether the observed increases are “real” or an artifact resulting from improvements in diagnosis, case ascertainment and population coverage over time. We used population‐based data from Western Australia to investigate trends in the incidence of childhood ALL between 1960 and 2006. Age‐standardized incidence rates (ASRs) and rate ratios (indicating annual percent change) were estimated using Poisson regression. Between 1960 and 2006, the ASR was 3.7 per 100,000 person‐years, with an annual percent increase of 0.40% (95% CI: −0.20, 1.00). Between 1982 and 2006, the ASR was 3.8, with an annual percent increase of 0.80% (95% CI = −0.70 to 2.30). This increased to 1.42% (95% CI: −0.30, 3.0) when a sensitivity analysis was undertaken to assess the effect of excluding the final 2 years of data. Annual increases of 3.7% (95% CI: −0.50, 8.00) among children aged 5–14 years, and of 3.10% (95% CI: 0.50, 5.70) in girls, were observed for this latter period. These results were supported by national Australian incidence data available for 1982–2003. There may have been a small increase in the incidence of ALL since 1982 among girls and older children, but an overall increase appears unlikely. No impact of folate supplementation or fortification is apparent. © 2007 Wiley‐Liss, Inc.