Background: 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. Methods: 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. Results: 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). Conclusions: 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.

Background: Exposure to pesticides has been associated with an increased risk of developing childhood leukemia. However, the impact of pesticides on childhood leukemia survival has not been examined. We investigated the associations between residential pesticide use during key developmental periods and 5-year survival in children treated for acute lymphoblastic leukemia (ALL). Methods: Residential use of insecticides, herbicides, rodenticides, and flea control products from preconception up to 12 months prior to diagnosis and sociodemographic characteristics were collected via parental interview among 837 children diagnosed with ALL between 1995 and 2008 in California, USA. Data on clinical features were abstracted from medical records. Vital status was obtained through linkage to the National Death Index (NDI) up to 2020. Cox proportional hazards regression models were used to estimate hazard ratios (HRs), adjusting for sociodemographic factors and clinical risk group. Results: A total of 108 children with ALL (~13%) died within 5 years of diagnosis. Exposure to any pesticides pre- and/or postnatally was slightly higher among deceased compared to alive children (95.4% vs. 91.5%; p = 0.23), while use of rodenticides was significantly higher in children who died (25.0%) vs. those who survived (15.5%; p = 0.02). In fully adjusted models, exposure to rodenticides was associated with an increased risk of mortality (HR 1.70; 95% confidence interval (CI) 1.08–2.64; p = 0.02), especially when the child was exposed during pregnancy (HR 1.90; 95% CI 1.15–3.16; p = 0.01) and possibly 12 months before diagnosis (HR 1.60; 95% CI 0.98–2.61; p = 0.06). Increased hazards of death were also observed with other types of pesticides during pregnancy, but those associations were not statistically significant. Conclusions: This study is the first to report reduced survival among children with ALL previously exposed to rodenticides, particularly during pregnancy, underscoring the need to further evaluate mechanisms by which environmental exposures during key developmental stages may later impact cancer outcomes.

Genome-wide association studies have identified a growing number of single nucleotide polymorphisms (SNPs) associated with childhood acute lymphoblastic leukemia (ALL), yet the functional roles of most SNPs are unclear. Multiple lines of evidence suggest that epigenetic mechanisms may mediate the impact of heritable genetic variation on phenotypes. Here, we investigated whether DNA methylation mediates the effect of genetic risk loci for childhood ALL. We performed an epigenome-wide association study (EWAS) including 808 childhood ALL cases and 919 controls from California-based studies using neonatal blood DNA. For differentially methylated CpG positions (DMPs), we next conducted association analysis with 23 known ALL risk SNPs followed by causal mediation analyses addressing the significant SNP-DMP pairs. DNA methylation at CpG cg01139861, in the promoter region of IKZF1, mediated the effects of the intronic IKZF1 risk SNP rs78396808, with the average causal mediation effect (ACME) explaining ~30% of the total effect (ACME P = 0.0031). In analyses stratified by self-reported race/ethnicity, the mediation effect was only significant in Latinos, explaining ~41% of the total effect of rs78396808 on ALL risk (ACME P = 0.0037). Conditional analyses confirmed the presence of at least three independent genetic risk loci for childhood ALL at IKZF1, with rs78396808 unique to non-European populations. We also demonstrated that the most significant DMP in the EWAS, CpG cg13344587 at gene ARID5B (P = 8.61 × 10⁻¹⁰), was entirely confounded by the ARID5B ALL risk SNP rs7090445. Our findings provide new insights into the functional pathways of ALL risk SNPs and the DNA methylation differences associated with risk of childhood ALL.