Daily Folic Acid and/or Vitamin B12 Supplementation Between 6 and 30 Months of Age and Cardiometabolic Risk Markers After 6-7 Years: A Follow-Up of a Randomized Controlled Trial.

BACKGROUND: Deficiencies of vitamin B12 and folate are associated with elevated concentrations of metabolic markers related to CVDs. OBJECTIVES: We investigated the effect of supplementation of vitamin B12 with or without folic acid for 6 mo in early childhood on cardiometabolic risk markers after 6-7 y. METHODS: This is a follow-up study of a 2 × 2 factorial, double-blind, randomized controlled trial of vitamin B12 and/or folic acid supplementation in 6-30-mo-old children. The supplement contained 1.8 µg of vitamin B12, 150 µg of folic acid, or both, constituting >1 AI or recommended daily allowances for a period of 6 mo. Enrolled children were contacted again after 6 y (September 2016-November 2017), and plasma concentrations of tHcy, leptin, high molecular weight adiponectin, and total adiponectin were measured (N = 791). RESULTS: At baseline, 32% of children had a deficiency of either vitamin B12 (<200 pmol/L) or folate (<7.5 nmol/L). Combined supplementation of vitamin B12 and folic acid resulted in 1.19 µmol/L (95% CI: 0.09; 2.30 µmol/L) lower tHcy concentration 6 y later compared to placebo. We also found that vitamin B12 supplementation was associated with a lower leptin-adiponectin ratio in subgroups based on their nutritional status. CONCLUSIONS: Supplementation with vitamin B12 and folic acid in early childhood was associated with a decrease in plasma tHcy concentrations after 6 y. The results of our study provide some evidence of persistent beneficial metabolic effects of vitamin B12 and folic acid supplementation in impoverished populations. The original trial was registered at www. CLINICALTRIALS: gov as NCT00717730, and the follow-up study at www.ctri.nic.in as CTRI/2016/11/007494.

Corrigendum: Pre-conceptional Maternal Vitamin B12 Supplementation Improves Offspring Neurodevelopment at 2 Years of Age: PRIYA Trial.

[This corrects the article DOI: 10.3389/fped.2021.755977.].

Pre-conceptional Maternal Vitamin B12 Supplementation Improves Offspring Neurodevelopment at 2 Years of Age: PRIYA Trial.

Background: The first thousand days window does not include the pre-conceptional period. Maternal pre-conceptional health has a profound influence on early embryonic development (implantation, gastrulation, placentation etc). Nutrition provided by B-complex vitamins is important for fetal growth, especially neural development. We report effects of a maternal pre-conceptional vitamin B12 and multi micronutrient (MMN) supplementation on offspring neurodevelopmental performance. Methods: In the Pune Rural Intervention in Young Adolescents trial (PRIYA), adolescents (N = 557, 226 females) were provided with vitamin B12 (2 µg/day) with or without multiple micronutrients, or a placebo, from preconception until delivery. All groups received mandatory iron and folic acid. We used the Bayley's Scale of Infant Development (BSID-III) at 24-42 months of age to investigate effects on offspring neurodevelopment. Results: Participants had similar baseline B12 levels. The levels improved in the B12 supplemented groups during pre-conception and pregnancy (28 weeks gestation), and were reflected in higher cord blood holotranscobalamin (holo-TC) levels compared to the placebo group. Neurodevelopmental outcomes in the B12 alone group (n = 21) were better than the placebo (n = 27) in cognition (p = 0.044) and language (p = 0.020) domains (adjusted for maternal baseline B12 levels). There was no difference in neurodevelopmental outcomes between the B12 + MMN (n = 26) and placebo group. Cord blood Brain Derived Neurotrophic Factor (BDNF) levels were highest in the B12 alone group, though not significant. Conclusion: Pre-conceptional vitamin B12 supplementation improved maternal B12 status and offspring neurodevelopment at 2 years of age. The usefulness of cord BDNF as a marker of brain development needs further investigation. Our results highlight the importance of intervening during pre-conception.

Maternal Vitamin B12 Status During Pregnancy and Its Association With Outcomes of Pregnancy and Health of the Offspring: A Systematic Review and Implications for Policy in India.

Background: Vitamins B12 and folate participate in the one-carbon metabolism cycle and hence regulate fetal growth. Though vitamin B12 deficiency is widely prevalent, the current public health policy in India is to supplement only iron and folic acid for the prevention of anaemia. Prompted by our research findings of the importance of maternal vitamin B12 status for a healthy pregnancy, birth and offspring health outcomes, we evaluated available literature evidence using a systematic review approach, to inform policy. Methods: A systematic search was performed for relevant Indian studies in the MEDLINE/PubMed and IndMed databases. We selected studies reporting maternal vitamin B12 status (dietary intake or blood concentrations), and/or metabolic markers of vitamin B12 deficiency (homocysteine, methylmalonic acid) or haematological indices during pregnancy and their associations with outcomes of pregnancy, infancy or in later life. Intervention trials of vitamin B12 during pregnancy were also included. Quality of evidence was assessed on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Results: Of the 635 articles identified, 46 studies met the inclusion criteria (cohort studies-26, case-control studies-13, RCT's -7). There is a high prevalence of vitamin B12 deficiency in Indian women during pregnancy (40-70%) (3 studies). Observational studies support associations (adjusted for potential sociodemographic confounders, maternal body size, postnatal factors) of lower maternal B12, higher homocysteine or an imbalance between vitamin B12-folate status with a higher risk of NTDs (6 studies), pregnancy complications (recurrent pregnancy losses, gestational diabetes, pre-eclampsia) (9 studies), lower birth weight (10 studies) and adverse longer-term health outcomes in the offspring (cognitive functions, adiposity, insulin resistance) (11 studies). Vitamin B12 supplementation (7 RCT's) in pregnancy showed a beneficial effect on offspring neurocognitive development and an effect on birth weight was inconclusive. There is a high quality evidence to support the role of low maternal vitamin B12 in higher risk for NTD and low birth weight and moderate-quality evidence for higher risk of gestational diabetes and later life adverse health outcomes (cognitive functions, risk for diabetes) in offspring. Conclusion: In the Indian population low maternal vitaminB12 status, is associated with adverse maternal and child health outcomes. The level of evidence supports adding vitamin B12 to existing nutritional programs in India for extended benefits on outcomes in pregnancy and offspring health besides control of anaemia. Systematic Review Registration: [website], identifier [registration number].

A physiological dose of oral vitamin B-12 improves hematological, biochemical-metabolic indices and peripheral nerve function in B-12 deficient Indian adolescent women.

BACKGROUND: Vitamin B-12 deficiency is often considered synonymous with pernicious anemia, a rare condition in which severe malabsorption of the vitamin requires high-dose parenteral treatment. In developing countries such as India, inadequate dietary intake of B-12 due to socio-cultural factors leads to widely prevalent asymptomatic low B-12 status. In this scenario, lower doses of oral B-12 may be effective, safer and more affordable. OBJECTIVE: To examine the effects of oral B-12 treatment at physiological doses on hematological and biochemical indices and peripheral nerve function in B-12 deficient rural Indian adolescent women. METHODS: Thirty-nine women with B-12 deficiency who were excluded from a community based B-12 supplementation trial (Pune Rural Intervention in Young Adolescents (PRIYA)) received oral B-12 2µg/day, either alone (n = 19) or with multiple micronutrients (UNIMAPP formula + 20gm milk powder, n = 20) for 11 months. Hematological indices, nutrients (B-12, folate), metabolites (homocysteine) and peripheral nerve function (SUDOSCAN, Impetomedical, Paris and sensory nerve conduction velocity (NCV) of median and sural nerves) were assessed at baseline and after 11 months of B-12 treatment. RESULTS: Results were similar in the two treatment allocation groups, which were therefore combined. At baseline, all women had B-12 concentration <100pmol/L, 79% were anemic and 33% had macrocytosis, but none had neuropathy. After 11 months of treatment, B-12 levels increased, while folate did not change. The prevalence of anemia fell to 59% and mean corpuscular volume (MCV) and plasma homocysteine concentrations decreased. Sudomotor nerve function in the feet improved by an average of 14.7%, and sensory conduction velocity in median and sural nerves increased by 16.2% and 29.4% respectively. CONCLUSION: We document clinically beneficial effects of supplementation with a physiological dose of oral B-12 in asymptomatic rural Indian adolescent women with very low B-12 status. These findings support a public health approach to tackle the widely prevalent low B-12 status in young Indians.

Evaluation of tracer labelled methionine load test in vitamin B-12 deficient adolescent women.

BACKGROUND: Methionine loading test (MLT) has been used primarily to identify defects in transsulfuration of homocysteine in cystathionine beta synthase deficiency. It may not be as useful to evaluate remethylation pathway, in vitamin B-12 and folate deficiencies. OBJECTIVE: We used tracer isotope labelled MLT to interrogate transsulfuration and remethylation independently in vitamin B-12 deficiency. DESIGN: We studied vitamin B-12 deficient women with a tracer labelled MLT before and eleven months after treatment with vitamin B-12. The fractional contribution of [13C]homocysteine to breath CO2 was used as a measure of transsulfuration, and difference in the intracellular enrichment of [13C]methionine and that of [C2H3]methionine as a measure of remethylation of homocysteine. Combined pre- and post-treatment results were analyzed to investigate the association between plasma vitamin B-12 concentrations and measures of homocysteine metabolism. RESULTS: The subjects were 17 years old, with a BMI of 19.4 kg/m2. Treatment with vitamin B-12, 2µg/day increased plasma B-12 from 93 (78.7, 106.2) [median (25th, 75th centiles)] to 161.5 (125.5, 226.2) pmol/L; 44% were below <150pmol/L after treatment. Fasting homocysteine concentration was significantly lower and that of cysteine higher in subjects with B-12 levels >150pmol/L. The tracer estimated transsulfuration of homocysteine was lower and remethylation higher with B-12 levels >150pmol/L when compared with those <150pmol/L. CONCLUSIONS: The tracer labelled MLT in combination with fasting parameters is a robust way to estimate parameters of methionine metabolism and can be used in the field where prime-constant rate infusion studies cannot be done efficiently.

Before the beginning: nutrition and lifestyle in the preconception period and its importance for future health.

A woman who is healthy at the time of conception is more likely to have a successful pregnancy and a healthy child. We reviewed published evidence and present new data from low-income, middle-income, and high-income countries on the timing and importance of preconception health for subsequent maternal and child health. We describe the extent to which pregnancy is planned, and whether planning is linked to preconception health behaviours. Observational studies show strong links between health before pregnancy and maternal and child health outcomes, with consequences that can extend across generations, but awareness of these links is not widespread. Poor nutrition and obesity are rife among women of reproductive age, and differences between high-income and low-income countries have become less distinct, with typical diets falling far short of nutritional recommendations in both settings and especially among adolescents. Several studies show that micronutrient supplementation starting in pregnancy can correct important maternal nutrient deficiencies, but effects on child health outcomes are disappointing. Other interventions to improve diet during pregnancy have had little effect on maternal and newborn health outcomes. Comparatively few interventions have been made for preconception diet and lifestyle. Improvements in the measurement of pregnancy planning have quantified the degree of pregnancy planning and suggest that it is more common than previously recognised. Planning for pregnancy is associated with a mixed pattern of health behaviours before conception. We propose novel definitions of the preconception period relating to embryo development and actions at individual or population level. A sharper focus on intervention before conception is needed to improve maternal and child health and reduce the growing burden of non-communicable diseases. Alongside continued efforts to reduce smoking, alcohol consumption, and obesity in the population, we call for heightened awareness of preconception health, particularly regarding diet and nutrition. Importantly, health professionals should be alerted to ways of identifying women who are planning a pregnancy.

Vitamin B12 supplementation influences methylation of genes associated with Type 2 diabetes and its intermediate traits.

AIM: To investigate the effect of B12 and/or folic acid supplementation on genome-wide DNA methylation. METHODS: We performed Infinium HumanMethylation450 BeadChip (Zymo Research, CA, USA) assay in children supplemented with B12 and/or folic acid (n = 12 in each group) and investigated the functional mechanism of selected differentially methylated loci. RESULTS: We noted significant methylation changes postsupplementation in B12 (589 differentially methylated CpGs and 2892 regions) and B12 + folic acid (169 differentially methylated CpGs and 3241 regions) groups. Type 2 diabetes-associated genes TCF7L2 and FTO; and a miRNA, miR21 were further investigated in another B12-supplementation cohort. We also demonstrate that methylation influences miR21 expression and FTO, TCF7L2, CREBBP/CBP and SIRT1 are direct targets of miR21-3p. CONCLUSION: B12 supplementation influences regulation of several metabolically important Type 2 diabetes-associated genes through methylation of miR21. Hence, our study provides novel epigenetic explanation for the association between disordered one carbon metabolism and risk of adiposity, insulin resistance and diabetes and has translational potential.

Associations of Maternal Vitamin B12 Concentration in Pregnancy With the Risks of Preterm Birth and Low Birth Weight: A Systematic Review and Meta-Analysis of Individual Participant Data.

Vitamin B12 (hereafter referred to as B12) deficiency in pregnancy is prevalent and has been associated with both lower birth weight (birth weight <2,500 g) and preterm birth (length of gestation <37 weeks). Nevertheless, current evidence is contradictory. We performed a systematic review and a meta-analysis of individual participant data to evaluate the associations of maternal serum or plasma B12 concentrations in pregnancy with offspring birth weight and length of gestation. Twenty-two eligible studies were identified (11,993 observations). Eighteen studies were included in the meta-analysis (11,216 observations). No linear association was observed between maternal B12 levels in pregnancy and birth weight, but B12 deficiency (<148 pmol/L) was associated with a higher risk of low birth weight in newborns (adjusted risk ratio = 1.15, 95% confidence interval (CI): 1.01, 1.31). There was a linear association between maternal levels of B12 and preterm birth (per each 1-standard-deviation increase in B12, adjusted risk ratio = 0.89, 95% CI: 0.82, 0.97). Accordingly, B12 deficiency was associated with a higher risk of preterm birth (adjusted risk ratio = 1.21, 95% CI: 0.99, 1.49). This finding supports the need for randomized controlled trials of vitamin B12 supplementation in pregnancy.

Supplementation of vitamin B12 or folic acid on hemoglobin concentration in children 6-36 months of age: A randomized placebo controlled trial.

BACKGROUND & AIMS: The main objective of this report is to measure to what extent folate or vitamin B12 given daily for 6 months to young North Indian Children improves hemoglobin (Hb) concentration. METHODS: In a randomized placebo controlled trial in low-to-middle income neighborhoods in New Delhi, India, children were randomized into four groups in a 1:1:1:1 ratio and supplemented daily for 6 months with 2 RDAs of vitamin B12, folic acid, both, or placebo. All children with anemia at baseline were given iron supplementation daily for 2 months. We measured the plasma concentrations of soluble transferrin receptor (sTfR), folate, vitamin B12, total homocysteine (tHcy) and Hb in 262 children. RESULTS: Mean Hb concentration decreased in all four study groups during the six months of follow up and supplementation of either or both of the vitamins did not improve the Hb concentration. Iron supplements for the initial 2 mo had limited effect on anemia at 6 mo as almost 90% were still anemic at study end. CONCLUSION: Supplementation of folic acid and/or vitamin B12 for 6 months does not improve Hb concentration in young children. Our findings do not argue for widespread vitamin B12 or folic acid supplementation to combat anemia. Our results also call for alternative strategies to improve iron status and treat iron deficiency anemia. CLINICAL TRIAL REGISTRY: NCT00717730 at www.clinicaltrials.gov, CTRI No.: CTRI/2010/091/001090 at www.ctri.nic.in.

Lower Circulating B12 Is Associated with Higher Obesity and Insulin Resistance during Pregnancy in a Non-Diabetic White British Population.

OBJECTIVE: Vitamin B12 and folate are critical micronutrients needed to support the increased metabolic demands of pregnancy. Recent studies from India have suggested that low vitamin B12 and folate concentrations in pregnancy are associated with increased obesity; however differences in diet, antenatal vitamin supplementation, and socioeconomic status may limit the generalisability of these findings. We aimed to explore the cross-sectional relationship of circulating serum vitamin B12 and folate at 28 weeks' gestation with maternal adiposity and related biochemical markers in a white non diabetic UK obstetric cohort. METHODS: Anthropometry and biochemistry data was available on 995 women recruited at 28 weeks gestation to the Exeter Family Study of Childhood Health. Associations between B12 and folate with maternal BMI and other obesity-related biochemical factors (HOMA-R, fasting glucose, triglycerides, HDL and AST) were explored using regression analysis, adjusting for potential confounders (socioeconomic status, vegetarian diet, vitamin supplementation, parity, haemodilution (haematocrit)). RESULTS: Higher 28 week BMI was associated with lower circulating vitamin B12 (r = -0.25; P<0.001) and folate (r = -0.15; P<0.001). In multiple regression analysis higher 28 week BMI remained an independent predictor of lower circulating B12 (ß (95% CI) = -0.59 (-0.74, -0.44) i.e. for every 1% increase in BMI there was a 0.6% decrease in circulating B12). Other markers of adiposity/body fat metabolism (HOMA-R, triglycerides and AST) were also independently associated with circulating B12. In a similar multiple regression AST was the only independent obesity-related marker associated with serum folate (ß (95% CI) = 0.16 (0.21, 0.51)). CONCLUSION: In conclusion, our study has replicated the previous Indian findings of associations between lower serum B12 and higher obesity and insulin resistance during pregnancy in a non-diabetic White British population. These findings may have important implications for fetal and maternal health in obese pregnancies.

Vitamin B12 and Folic Acid Improve Gross Motor and Problem-Solving Skills in Young North Indian Children: A Randomized Placebo-Controlled Trial.

OBJECTIVES: Deficiencies of vitamin B12 and folate are associated with delayed development and neurological manifestations. The objective of this study was to measure the effect of daily supplementation of vitamin B12 and/or folic acid on development in young North Indian children. METHODS: In a randomized, double blind trial, children aged six to 30 months, received supplement with placebo or vitamin B12 and/or folic acid for six months. Children were allocated in a 1:1:1:1 ratio in a factorial design and in blocks of 16. We measured development in 422 children by the Ages and Stages Questionnaire 3rd ed. at the end of the intervention. RESULTS: Compared to placebo, children who received both vitamin B12 and folic acid had 0.45 (95% CI 0.19, 0.73) and 0.28 (95% CI 0.02, 0.54) higher SD-units in the domains of gross motor and problem solving functioning, respectively. The effect was highest in susceptible subgroups consisting of stunted children, those with high plasma homocysteine (> 10 µmol/L) or in those who were younger than 24 at end study. With the exception of a significant improvement on gross motor scores by vitamin B12 alone, supplementation of either vitamin alone had no effect on any of the outcomes. CONCLUSION: Our findings suggest that supplementation of vitamin B12 and folic acid benefit development in North Indian Children. TRIAL REGISTRATION: ClinicalTrials.gov NCT00717730.

Vitamin B-12, folic acid, and growth in 6- to 30-month-old children: a randomized controlled trial.

BACKGROUND: Folate and vitamin B-12 are important for growth. Many children in low- and middle-income countries have inadequate intakes of these nutrients. METHODS: We undertook a randomized, placebo controlled double-blind trial in 1000 North Indian children, 6 to 35 months of age, providing twice the recommended daily allowance of folic acid and/or vitamin B-12, or placebo, daily for 6 months. By using a factorial design, we allocated children in a 1:1:1:1 ratio in blocks of 16. We measured the effect of giving vitamin B-12, folic acid, or the combination of both on linear and ponderal growth. We also identified predictors for growth in multiple linear regression models and effect modifiers for the effect of folic acid or vitamin B-12 supplementation on growth. RESULTS: The overall effect of either of the vitamins was significant only for weight; children who received vitamin B-12 increased their mean weight-for-age z scores by 0.07 (95% confidence interval: 0.01 to 0.13). Weight-for-age z scores and height-for-age z scores increased significantly after vitamin B-12 supplementation in wasted, underweight, and stunted children. These subgrouping variables significantly modified the effect of vitamin B-12 on growth. Vitamin B-12 status at baseline predicted linear and ponderal growth in children not receiving vitamin B-12 supplements but not in those who did (P-interaction < .001). CONCLUSIONS: We provide evidence that poor vitamin B-12 status contributes to poor growth. We recommend studies with larger doses and longer follow-up to confirm our findings.

Anguli Parimana in Ayurveda and its association with adiposity and diabetes.

BACKGROUND: Recent studies have shown the association of disproportionate body size measurements with noncommunicable diseases like diabetes. This concept is described in Ayurveda (1500 BC), which uses Anguli Parimana (the breadth of one's own finger as 1 unit) to measure the body proportions. Excessive tallness or shortness (deviation from the reference value of Anguli Parimana) indicated deranged meda dhaatu (mainly adipose tissue). Deranged meda dhatu was associated with Prameha (diabetes). OBJECTIVES: To find association of Anguli Parimana with modern parameters of adiposity and diabetes. MATERIALS AND METHODS: We studied 192 village residents representing the whole population (94 men and 98 women) to measure height, arm span, facial structures and limbs and expressed them in Anguli pariman (ratio of each measure as: Length or height of the body part [cm]/anguli, i.e. average finger breadth [cm]). The Anguli measurements were associated with body mass index, body fat percentage by DEXA, glucose and fasting insulin levels. RESULTS: The volunteers were adults between 20 and 40 years age. Their mean fasting and 2 h plasma glucose concentrations were 91.6 mg% and 102.8 mg%, respectively. Of all, only 6 subjects had impaired glucose tolerance, while 3 were diabetic (WHO 1999). When compared with reference Anguli measurements mentioned by Charaka Samhita and Sushruta Samhita, the participants had smaller height, facial structures, and lower limbs. Those, who had proportionately smaller facial, neck and limb structures, had higher obesity, adiposity, plasma glucose, insulin and insulin resistance (homeostatic model assessment [HOMA]-R) indicating higher metabolic risk. In contrast, those who had proportionately larger forehead and face had higher beta cell function measured as HOMA-B indicating lower risk for diabetes (r = 0.20 both P < 0.05 all, adjusted for age and gender). CONCLUSION: Compared with ancient Indian Anguli reference, our subjects were proportionately smaller in most of the measurements except fingers and upper arm. Relative smallness of body parts was predictive of increased risk of type 2 diabetes.

Folic acid and vitamin B-12 supplementation and common infections in 6-30-mo-old children in India: a randomized placebo-controlled trial.

BACKGROUND: Young children in low- and middle-income countries frequently have inadequate vitamin B-12 (cobalamin) status. Poor folate status is also common and is associated with increased diarrheal and respiratory morbidity. OBJECTIVE: The objective was to measure the effect of folic acid and/or vitamin B-12 administration on the incidence of diarrhea and acute lower respiratory tract infections. DESIGN: One thousand North Indian children (6-30 mo of age) were enrolled in a randomized, double-blind, placebo-controlled trial to receive 2 times the Recommended Dietary Allowance of folic acid and/or vitamin B-12 or placebo daily for 6 mo. Children were individually randomly assigned in a 1:1:1:1 ratio in blocks of 16. Primary outcomes were the number of episodes of acute lower respiratory infections, diarrhea, and prolonged diarrhea. RESULTS: Folic acid and vitamin B-12 supplementation significantly improved vitamin B-12 and folate status, respectively. Neither folic acid nor vitamin B-12 administration reduced the incidence of diarrhea or lower respiratory infections. In comparison with placebo, children treated with folic acid alone or in combination with vitamin B-12 had a significantly higher risk of persistent diarrhea (OR: 2.1; 95% CI: 1.1, 3.8). CONCLUSIONS: Folic acid or vitamin B-12 supplementation did not reduce the burden of common childhood infections. In view of the increased risk of diarrhea, the safety of folic acid supplements in young children should be further assessed. This trial was registered at www.clinicaltrials.gov as NCT00717730 and at www.ctri.nic.in as CTRI/2010/091/001090.

Iron fortification of whole wheat flour reduces iron deficiency and iron deficiency anemia and increases body iron stores in Indian school-aged children.

Wheat is the primary staple food for nearly one-third of the world's population. NaFeEDTA is the only iron (Fe) compound suitable for fortifying high extraction flours. We tested the hypothesis that NaFeEDTA-fortified, whole wheat flour reduces Fe deficiency (ID) and improves body Fe stores (BIS) and cognitive performance in Indian children. In a randomized, double-blind, controlled, school feeding trial, 6- to 15-y-old, Fe-depleted children (n = 401) were randomly assigned to either a daily wheat-based lunch meal fortified with 6 mg of Fe as NaFeEDTA or an otherwise identical unfortified control meal. Hemoglobin (Hb) and Fe status were measured at baseline, 3.5 mo, and 7 mo. Cognitive performance was evaluated at baseline and 7 mo in children (n = 170) at one of the study sites. After 7 mo, the prevalence of ID and ID anemia in the treatment group significantly decreased from 62 to 21% and 18 to 9%, respectively. There was a time x treatment interaction for Hb, serum ferritin, transferrin receptor, zinc protoporphyrin, and BIS (all P < 0.0001). Changes in BIS differed between the groups; it increased in the treatment group (0.04 ± 0.04 mmol/kg body weight) and decreased in the control group (-0.02 ± 0.04 mmol/kg body weight) (P < 0.0001). In sensory tests, NaFeEDTA-fortified flour could not be differentiated from unfortified flour. There were no significant differences in cognitive performance tests between the groups. NaFeEDTA-fortified wheat flour markedly improved BIS and reduced ID in Fe-depleted children. It may be recommended for wider use in national school feeding programs.

Is a low blood level of vitamin B12 a cardiovascular and diabetes risk factor? A systematic review of cohort studies.

PURPOSE: To assess the prior hypothesis that low blood vitamin B12, partly through hyperhomocysteinemia and partly through direct effects, increases the risk of cardiovascular diseases and diabetes. As background, we also extracted all-cause mortality from the studies that met our criteria. METHODS: A systematic review of prospective cohort studies identified through searching six electronic databases, screening of reference lists, and citation search. Included studies reported data on the association between vitamin B12 blood levels, or other appropriate surrogate biological markers e.g. holotranscobalamin or serum/urine methylmalonic acid, and fatal or non-fatal incident diabetes and cardiovascular events. RESULTS: Seven studies were included. Studies differed regarding the population studied, length of follow-up, study outcomes, and data analysis--a narrative synthesis approach was performed to examine the results. Most studies met few of the quality assessment criteria which were adapted from the Scottish Intercollegiate Guidelines Network (SIGN). Only one high-quality study reported that low B12 increased the risk of incident cerebral ischaemia (RR = 1.76; 95% CI = 1.16-2.68). After controlling for homocysteine, the association persisted although weakened (RR = 1.57; 95% CI = 1.02-2.43), suggesting that the effects of low B12 were only partly mediated by homocysteine. In two studies, higher B12 levels were associated with a greater risk of total mortality (RR = 1.00; 95% CI = 1.00-1.00 and HR = 1.15; 95% CI = 1.08-1.22, respectively) and combined fatal and non-fatal coronary events (RR = 1.00; 95% CI = 1.00-1.00). No association between study outcomes and vitamin B12 levels was found in four other studies. CONCLUSIONS: Surprisingly, there is only very limited evidence that vitamin B12 deficiency predisposes to the risk of mortality and morbidity from either cardiovascular diseases or diabetes in adults. Current data do not support vitamin B12 supplementation to reduce the risk of cardiovascular diseases or diabetes.

Oral vitamin B12 supplementation reduces plasma total homocysteine concentration in women in India.

People in India have a high prevalence of low vitamin B12 status and high plasma total homocysteine (tHcy) concentrations. In a proof of principle trial, we studied the effect of oral vitamin B12 (500 microg) and/or 100 g cooked green leafy vegetables (GLV) every alternate day in a 2x2 factorial design over a 6-week period. Forty-two non-pregnant vegetarian women (age 20-50 years) were randomly allocated to four study groups. Clinical measurements were made at the beginning and at the end of the study, and blood samples were collected before, and 2 and 6 weeks after commencement of intervention. Forty women completed the trial. Twenty-six women had low vitamin B12 status (<150 pmol/L) and 24 had hyperhomocysteinemia (>15 micromol/L). GLV supplementation did not alter plasma folate or tHcy. Vitamin B12 supplementation increased plasma vitamin B12 concentration (125 to 215 pmol/L, p <0.05) and reduced tHcy concentration (18.0 to 13.0 micromol/L, p <0.05) within first 2 weeks, both of which remained stable for the next 4 weeks. Plasma vitamin B12 and tHcy concentrations did not change in those who did not receive vitamin B12, and there was no change in plasma folate concentration in any of the groups. Blood haemoglobin concentration increased marginally within first two weeks in those women who received vitamin B12 (by 3 g/L, p <0.05) and the number of women with macrocytosis decreased from 2 to zero. There was no change in vibration sensory threshold during the period of the study. High-dose per oral vitamin B12 supplementation significantly reduced plasma tHcy within 2 weeks but did not achieve normal plasma tHcy concentration even after 6 weeks. People in India have a high prevalence of low vitamin B12 status and high plasma total homocysteine (tHcy) concentrations.

Micronutrients and fetal growth.

Fetal undernutrition affects large numbers of infants in developing countries, with adverse consequences for their immediate survival and lifelong health. It manifests as intrauterine growth retardation (IUGR), defined as birth weight <10th percentile, which probably underestimates the number failing to achieve full growth potential. Birth weight is a crude measure of the dynamic process of fetal growth and does not capture effects of fetal undernutrition on body composition and the development of specific tissues. The link between maternal nutrition and fetal nutrition is indirect. The fetus is nourished by a complex supply line that includes the mother's diet and absorption, endocrine status and metabolism, cardiovascular adaptations to pregnancy and placental function. Micronutrients are essential for growth, and maternal micronutrient deficiency, frequently multiple in developing countries, may be an important cause of IUGR. Supplementation of undernourished mothers with micronutrients has several benefits but there is little hard evidence of improved fetal growth. However, this has been inadequately tested. Most trials have only used single micronutrients and many were inconclusive because of methodological problems. Several food-based studies (some uncontrolled) suggest benefits from improving maternal dietary quality with micronutrient-dense foods. One trial of a multivitamin supplement (HIV-positive mothers, Tanzania) showed increased birth weight and fewer fetal deaths. Well-conducted randomized controlled trials of adequate sample size and including measures of effectiveness are needed in populations at high risk of micronutrient deficiency and IUGR and should include food-based interventions and better measurements of fetal growth, maternal metabolism, and long-term outcomes in the offspring.