Reductions in child mortality by preventing spina bifida and anencephaly: Implications in achieving Target 3.2 of the Sustainable Development Goals in developing countries.

BACKGROUND: There is an opportunity to reduce child mortality by preventing folic acid-preventable spina bifida and anencephaly (FAP SBA) in developing countries. We estimated reductions in FAP SBA-associated child mortality in 69 countries with an immediate potential for mandatory fortification of wheat flour. METHODS: Using data from multiple sources, we estimated the percent reductions in neonatal, infant, and under-five mortality that would have occurred by preventing FAP SBA; and the contributions of these reductions toward each country's Sustainable Development Goals (SDG) for child mortality reduction. We used the combined prevalence of spina bifida and anencephaly in selected countries before fortification, and estimated preventable child mortality associated with FAP SBA, assuming 0.5 per 1,000 live births as minimum achievable prevalence from mandatory fortification. RESULTS: Annually, 56,785 live births with FAP SBA occurred in the 69 countries examined. Of these, about 49,680 (87%) would have resulted in deaths under age 5 years, and are preventable through mandatory folic acid fortification. On average, compared to current rates, prevention of FAP SBA would have reduced the neonatal, infant, and under-five mortality by 19% (95% uncertainty interval [UI]: 16-24%), 15% (UI: 13-17%), and 14%, (95% UI: 13-17%), respectively. Prevention of FAP SBA seemed to contribute toward achieving SDG on neonatal and under-five mortality in developing countries. CONCLUSIONS: Prevention of FAP SBA will lead to notable and immediate reductions in child mortality. Many countries have an opportunity to effectively move toward child mortality-related SDG targets with existing milling infrastructure for food fortification.

Folate deficiency in north Indian children undergoing maintenance chemotherapy for acute lymphoblastic leukemia-Implications and outcome.

BACKGROUND: Treatment-related toxicity and mortality are not uncommon during maintenance chemotherapy for childhood acute lymphoblastic leukemia (ALL), especially in the low- and middle-income countries (LMIC). Undernutrition and micronutrient deficiencies are commonly seen in children from LMICs undergoing treatment for ALL. The present study examines the prevalence and clinical implications of folate deficiency in north Indian children with ALL during the maintenance phase of treatment in view of prolonged antifolate treatment and high population prevalence of folate deficiency. PROCEDURES: Pre-cycle folate levels/deficiency as well as weight for age z-score and serum albumin level were determined and correlated with complications of treatment and mortality encountered during the maintenance phase of treatment. RESULTS: Twenty-nine of 52 children enrolled in the study had folate deficiency at some point during maintenance chemotherapy. Neutropenia (18 of 29 vs. 4 of 23; P = 0.002), thrombocytopenia (17 of 29 vs. 4 of 23; P = 0.005), febrile neutropenia (17 of 29 vs. 4 of 23; P = 0.005), and need for chemotherapy dose reduction (20 of 29 vs. 7 of 21; P = 0.01) were more common in folate-deficient children. Maintenance deaths were higher (8 of 29 vs. 1 of 23; P = 0.03) and survival lower (P = 0.02) in deficient children. In multivariate analysis, hypoalbuminemia (P = 0.02) and folate deficiency (P = 0.01) were associated with febrile neutropenia, and folate deficiency with maintenance deaths (P = 0.03). CONCLUSIONS: Folate deficiency was associated with treatment-related complications and adverse outcome in our patients. The risks and benefits of folate supplementation in deficient children during maintenance chemotherapy need to be explored with properly designed randomized studies in similar settings.

Intergenerational impact of paternal lifetime exposures to both folic acid deficiency and supplementation on reproductive outcomes and imprinted gene methylation.

STUDY QUESTION: Do paternal exposures to folic acid deficient (FD), and/or folic acid supplemented (FS) diets, throughout germ cell development adversely affect male germ cells and consequently offspring health outcomes? SUMMARY ANSWER: Male mice exposed over their lifetimes to both FD and FS diets showed decreased sperm counts and altered imprinted gene methylation with evidence of transmission of adverse effects to the offspring, including increased postnatal-preweaning mortality and variability in imprinted gene methylation. WHAT IS KNOWN ALREADY: There is increasing evidence that disruptions in male germ cell epigenetic reprogramming are associated with offspring abnormalities and intergenerational disease. The fetal period is the critical time of DNA methylation pattern acquisition for developing male germ cells and an adequate supply of methyl donors is required. In addition, DNA methylation patterns continue to be remodeled during postnatal spermatogenesis. Previous studies have shown that lifetime (prenatal and postnatal) folic acid deficiency can alter the sperm epigenome and increase the incidence of fetal morphological abnormalities. STUDY DESIGN, SIZE, DURATION: Female BALB/c mice (F0) were placed on one of four amino-acid defined diets for 4 weeks before pregnancy and throughout pregnancy and lactation: folic acid control (Ctrl; 2 mg/kg), 7-fold folic acid deficient (7FD; 0.3 mg/kg), 10-fold high FS (10FS, 20 mg/kg) or 20-fold high FS (20FS, 40 mg/kg) diets. F1 males were weaned to their respective prenatal diets to allow for diet exposure during all windows of germline epigenetic reprogramming: the erasure, re-establishment and maintenance phases. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: F0 females were mated with chow-fed males to produce F1 litters whose germ cells were exposed to the diets throughout embryonic development. F1 males were subsequently mated with chow-fed female mice. Two F2 litters, unexposed to the experimental diets, were generated from each F1 male; one litter was collected at embryonic day (E)18.5 and one delivered and followed postnatally. DNA methylation at a global level and at the differentially methylated regions of imprinted genes (H19, Imprinted Maternally Expressed Transcript (Non-Protein Coding)-H19, Small Nuclear Ribonucleoprotein Polypeptide N-Snrpn, KCNQ1 Opposite Strand/Antisense Transcript 1 (Non-Protein Coding)-Kcnq1ot1, Paternally Expressed Gene 1-Peg1 and Paternally Expressed Gene 3-Peg3) was assessed by luminometric methylation analysis and bisulfite pyrosequencing, respectively, in F1 sperm, F2 E18.5 placenta and F2 E18.5 brain cortex. MAIN RESULTS AND THE ROLE OF CHANCE: F1 males exhibited lower sperm counts following lifetime exposure to both folic acid deficiency and the highest dose of folic acid supplementation (20FS), (both P < 0.05). Post-implantation losses were increased amongst F2 E18.5 day litters from 20FS exposed F1 males (P < 0.05). F2 litters derived from both 7FD and 20FS exposed F1 males had significantly higher postnatal-preweaning pup death (both P < 0.05). Sperm from 10FS exposed males had increased variance in methylation across imprinted gene H19, P < 0.05; increased variance at a few sites within H19 was also found for the 7FD and 20FS groups (P < 0.05). While the 20FS diet resulted in inter-individual alterations in methylation across the imprinted genes Snrpn and Peg3 in F2 E18.5 placenta, ≥50% of individual sites tested in Peg1 and/or Peg3 were affected in the 7FD and 10FS groups. Inter-individual alterations in Peg1 methylation were found in F2 E18.5 day 10FS group brain cortex (P < 0.05). LARGE SCALE DATA: Not applicable. LIMITATIONS REASONS FOR CAUTION: The cause of the increase in postnatal-preweaning mortality was not investigated post-mortem. Further studies are required to understand the mechanisms underlying the adverse effects of folic acid deficiency and supplementation on developing male germ cells. Genome-wide DNA and histone methylome studies as well as gene expression studies are required to better understand the links between folic acid exposures, an altered germ cell epigenome and offspring outcomes. WIDER IMPLICATIONS OF THE FINDINGS: The findings of this study provide further support for paternally transmitted environmental effects. The results indicate that both folic acid deficiency and high dose supplementation can be detrimental to germ cell development and reproductive fitness, in part by altering DNA methylation in sperm. STUDY FUNDING AND COMPETING INTERESTS: This study was supported by a grant to J.M.T. from the Canadian Institutes of Health Research (CIHR #89944). The authors declare they have no conflicts of interest.

The dietary requirement of young rainbow trout (Oncorhynchus mykiss) for folic acid.

We sought to determine the dietary folic acid requirement of young rainbow trout using growth indices supported by measurements of tissue folate concentrations. The investigation was conducted with purified diets that had, by assay, basal folic acid levels of 0.08 and 0.16 mg/kg in the first and second, respectively, of two experiments. Each experiment was started with fry (initial mean weight, 1.4 and 2.8 g/fish in Experiments 1 and 2, respectively) and was conducted at a water temperature of 15 degrees C. Experiment 1 lasted 18 wk and Experiment 2 lasted 16 wk. Recovery tests (of 8 wk duration, performed on fish fed the unsupplemented diet) and pair-feeding showed that the unsupplemented diet led to a folate-specific deficiency condition in which the main hematological abnormality was the appearance of misshapen nuclei in a small proportion (2.3%) of erythrocytes. Dietary requirements were shown not to exceed 0.3 and 0.6 mg folic acid/kg (17 and 33 micrograms/MJ digestible energy) for optimizing survival and growth indices, respectively. We conclude that the dietary folate requirement of the trout is comparable to that of other vertebrates for the purpose of achieving maximal weight gain.