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.].

Body Composition and Cardiometabolic Risk Markers in Children of Women who Took Part in a Randomized Controlled Trial of a Preconceptional Nutritional Intervention in Mumbai, India.

BACKGROUND: Maternal nutrition influences fetal development and may permanently alter ("program") offspring body composition and metabolism, thereby influencing later risk of diabetes and cardiovascular (cardiometabolic) disease. The prevalence of cardiometabolic disease is rising rapidly in India. OBJECTIVES: To test the hypothesis that supplementing low-income Indian women with micronutrient-rich foods preconceptionally and during pregnancy has a beneficial impact on the children's body composition and cardiometabolic risk marker profiles. METHODS: Follow-up of 1255 children aged 5-10 y whose mothers took part in the Mumbai Maternal Nutrition Project [Project "SARAS"; International Standard Randomised Controlled Trial Number (ISRCTN)62811278]. Mothers were randomly assigned to receive a daily micronutrient-rich snack or a control snack of lower micronutrient content, both made from local foods, in addition to normal diet, from before pregnancy until delivery. Children's body composition was assessed using anthropometry and DXA. Their blood pressure, plasma glucose, insulin, and lipid concentrations were measured. Outcomes were compared between allocation groups with and without adjustment for confounding factors. RESULTS: Overall, 15% of children were stunted, 34% were wasted, and 3% were overweight. In the intention-to-treat analysis, there were no differences in body composition or risk markers between children in the intervention and control groups. Among children whose mothers started supplementation ≥3 mo before conception (the "per protocol" sample) the intervention increased adiposity among girls, but not boys. BMI in girls was increased relative to controls by 2% (95% CI: 1, 4; P = 0.01); fat mass index by 10% (95% CI: 3, 18; P = 0.004); and percent fat by 7% (95% CI: 1, 13; P = 0.01) unadjusted, with similar results in adjusted models. CONCLUSIONS: Overall, supplementing women with micronutrient-rich foods from before pregnancy until delivery did not alter body composition or cardiometabolic risk markers in the children. Subgroup analyses showed that, if started ≥3 mo before conception, supplementation may increase adiposity among female children.

Body Composition and Cardiometabolic Risk Markers in Children of Women who Took Part in a Randomized Controlled Trial of a Preconceptional Nutritional Intervention in Mumbai, India.

BACKGROUND: Maternal nutrition influences fetal development and may permanently alter ("program") offspring body composition and metabolism, thereby influencing later risk of diabetes and cardiovascular (cardiometabolic) disease. The prevalence of cardiometabolic disease is rising rapidly in India. OBJECTIVES: To test the hypothesis that supplementing low-income Indian women with micronutrient-rich foods preconceptionally and during pregnancy has a beneficial impact on the children's body composition and cardiometabolic risk marker profiles. METHODS: Follow-up of 1255 children aged 5-10 y whose mothers took part in the Mumbai Maternal Nutrition Project [Project "SARAS"; International Standard Randomised Controlled Trial Number (ISRCTN)62811278]. Mothers were randomly assigned to receive a daily micronutrient-rich snack or a control snack of lower micronutrient content, both made from local foods, in addition to normal diet, from before pregnancy until delivery. Children's body composition was assessed using anthropometry and DXA. Their blood pressure, plasma glucose, insulin, and lipid concentrations were measured. Outcomes were compared between allocation groups with and without adjustment for confounding factors. RESULTS: Overall, 15% of children were stunted, 34% were wasted, and 3% were overweight. In the intention-to-treat analysis, there were no differences in body composition or risk markers between children in the intervention and control groups. Among children whose mothers started supplementation ≥3 mo before conception (the "per protocol" sample) the intervention increased adiposity among girls, but not boys. BMI in girls was increased relative to controls by 2% (95% CI: 1, 4; P = 0.01); fat mass index by 10% (95% CI: 3, 18; P = 0.004); and percent fat by 7% (95% CI: 1, 13; P = 0.01) unadjusted, with similar results in adjusted models. CONCLUSIONS: Overall, supplementing women with micronutrient-rich foods from before pregnancy until delivery did not alter body composition or cardiometabolic risk markers in the children. Subgroup analyses showed that, if started ≥3 mo before conception, supplementation may increase adiposity among female children.

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 D deficiency and GDM risk: evidence for the case of investing more attention in antenatal clinics.

Gestational diabetes mellitus (GDM) is a global public health problem, and in India, it affects about 20% of pregnancies. India, despite being a tropical country with abundant sunshine has a high prevalence (80%) of vitamin D deficiency (VDD) among reproductive-aged women. Global and Indian evidence links VDD with a higher risk of hyperglycaemia in pregnancy and GDM. VDD has also been implicated in gestational hypertension, preterm birth and poorer offspring health. Global scientific consensus acknowledges the need for maternal vitamin D screening and supplementation, but knowledge gaps exist about optimal blood levels (50-100 nmol/l), and the required vitamin D dosage (400-4000 IU). Diet can provide <10% of the vitamin D requirements, food fortification can deliver limited amounts, and hence optimal antenatal supplementation is key. Prenatal calcium supplements containing 400 IU of vitamin D may be sufficient for calcium absorption and bone health, but may not provide immunomodulatory benefits, including GDM prevention. Increasing evidence calls for higher maternal vitamin D requirements (2000-4000 IU) for skeletal, metabolic and immune health benefits. Current screening and supplementation for maternal VDD in India is low. We need to invest in future studies to determine optimal maternal vitamin D requirements and formulate policies for vitamin D supplementation to prevent GDM. Improving the maternal vitamin D status is an important nutritional priority for policymakers to reduce the large economic burden of non-communicable diseases (10% of India's gross domestic product), and eventually achieve the 2030 UN sustainable development goals.

Social, economic and cultural influences on adolescent nutrition and physical activity in Jimma, Ethiopia: perspectives from adolescents and their caregivers.

OBJECTIVE: To explore influences on adolescent diet and physical activity, from the perspectives of adolescents and their caregivers, in Jimma, Ethiopia. DESIGN: Qualitative design, using focus group discussions (FGD). SETTING: A low-income setting in Jimma, Ethiopia. PARTICIPANTS: Five FGD with adolescents aged 10-12 years and 15-17 years (n 41) and three FGD with parents (n 22) were conducted. RESULTS: Adolescents displayed a holistic understanding of health comprising physical, social and psychological well-being. Social and cultural factors were perceived to be the main drivers of adolescent diet and physical activity. All participants indicated that caregivers dictated adolescents' diet, as families shared food from the same plate. Meals were primarily determined by caregivers, whose choices were driven by food affordability and accessibility. Older adolescents, particularly boys, had opportunities to make independent food choices outside of the home which were driven by taste and appearance, rather than nutritional value. Many felt that adolescent physical activity was heavily influenced by gender. Girls' activities included domestic work and family responsibilities, whereas boys had more free time to participate in outdoor games. Girls' safety was reported to be a concern to caregivers, who were fearful of permitting their daughters to share overcrowded outdoor spaces with strangers. CONCLUSIONS: Adolescents and caregivers spoke a range of social, economic and cultural influences on adolescent diet and physical activity. Adolescents, parents and the wider community need to be involved in the development and delivery of effective interventions that will take into consideration these social, economic and cultural factors.

A scoping review of literature describing the nutritional status and diets of adolescents in Côte d'Ivoire.

OBJECTIVE: Adolescents living in resource-limited settings remain a neglected population regarding their nutritional health. We reviewed what studies on nutrition have been conducted for adolescents living in Côte d'Ivoire. DESIGN: A scoping literature review, searching for any quantitative studies published from 1 January 2000 to 1 May 2019, referenced in PubMed and grey literature, related to adolescent nutritional status and diet, written in English or French. SETTING: Côte d'Ivoire, West Africa. SUBJECTS: Adolescent girls and boys (aged 10-19 years). RESULTS: We used three search strategies to explore studies related to (1) diet and nutritional practices, (2) anthropometry and (3) micronutrient intakes/status. Each identified 285, 108 and 84 titles and abstracts, respectively, resulting in 384 full-text articles to review. Finally, after adding five relevant studies from the grey literature, thirty articles were included. Two-thirds were cross-sectional observation studies. The main topics were anaemia and parasitic diseases. Among seven intervention studies, most focused on micronutrient supplementation or deworming. No studies on macronutrients or food supplementation were found. Overall, studies showed a high prevalence of undernutrition, along with emerging overweight and obesity. Anaemia and Fe deficiency were highly prevalent, with Fe supplementation showing modest improvements. Malaria and gut parasite infections remain a major burden, affecting adolescents' nutritional status. CONCLUSIONS: Few specific relevant studies have been published regarding adolescent nutrition in Côte d'Ivoire, and most studies being focused on younger children. There are knowledge gaps about many nutritional aspects in this population, which urgently need to be addressed.

Effect of maternal preconceptional and pregnancy micronutrient interventions on children's DNA methylation: Findings from the EMPHASIS study.

BACKGROUND: Maternal nutrition in pregnancy has been linked to offspring health in early and later life, with changes to DNA methylation (DNAm) proposed as a mediating mechanism. OBJECTIVE: We investigated intervention-associated DNAm changes in children whose mothers participated in 2 randomized controlled trials of micronutrient supplementation before and during pregnancy, as part of the EMPHASIS (Epigenetic Mechanisms linking Preconceptional nutrition and Health Assessed in India and sub-Saharan Africa) study (ISRCTN14266771). DESIGN: We conducted epigenome-wide association studies with blood samples from Indian (n = 698) and Gambian (n = 293) children using the Illumina EPIC array and a targeted study of selected loci not on the array. The Indian micronutrient intervention was food based, whereas the Gambian intervention was a micronutrient tablet. RESULTS: We identified 6 differentially methylated CpGs in Gambians [2.5-5.0% reduction in intervention group, all false discovery rate (FDR) <5%], the majority mapping to ESM1, which also represented a strong signal in regional analysis. One CpG passed FDR <5% in the Indian cohort, but overall effect sizes were small (<1%) and did not have the characteristics of a robust signature. We also found strong evidence for enrichment of metastable epialleles among subthreshold signals in the Gambian analysis. This supports the notion that multiple methylation loci are influenced by micronutrient supplementation in the early embryo. CONCLUSIONS: Maternal preconceptional and pregnancy micronutrient supplementation may alter DNAm in children measured at 7-9 y. Multiple factors, including differences between the nature of the intervention, participants, and settings, are likely to have contributed to the lack of replication in the Indian cohort. Potential links to phenotypic outcomes will be explored in the next stage of the EMPHASIS study.

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.

What are the public health implications of the life course perspective?

During the past decades innovative research has shown that exposure to harmful events during pregnancy and early infancy ('the first 1000 days') has an impact on health at subsequent stages of the life course and even across generations. Recently it has been shown that even the pre-conception period is of outmost importance, and other scholars have made the case that the 1000 days should be extended to a period of 8000 days post-conception. The present contribution aims to bridge further the gap between research evidence and public health policy by applying a holistic 'full-cycle' perspective. Thus, a conceptual framework is suggested for guiding public health prioritization, including the variables of 'impact on the next generation', 'plasticity' and 'available interventions with documented impact'. This framework could guide decision makers in selecting at which stages of the life course to invest (and not), and furthermore it points to some pertinent research priorities.

Effect of a daily snack containing green leafy vegetables on women's fatty acid status: a randomized controlled trial in Mumbai, India.

BACKGROUND AND OBJECTIVES: There are few data on the fatty acid status of non-pregnant Indian women. Our objective was to investigate the effect of a snack containing green leafy vegetables (GLVs) on women's erythrocyte long chain polyunsaturated fatty acid status (LCPUFA). METHODS AND STUDY DESIGN: Non-pregnant women (n=222) aged 14-35 years from Mumbai slums were randomized to consume a snack containing GLVs, fruit and milk (treatment) or a control snack containing foods of low micronutrient content such as potato and onion, daily under observation. One treatment snack contained a mean (SD) of 54.1 (33.7) mg alpha-linolenic acid (ALA) and one control snack contained 4.1 (3.4) mg ALA. Blood was collected at baseline (0 weeks) and after 12 weeks of supplementation. Erythrocyte fatty acids were analyzed using gas chromatography and expressed as g/100g fatty acids. Plasma malondialdehyde, homocysteine, and erythrocyte superoxide dismutase and glutathione peroxidase were measured. The effect of the treatment on 12 week LCPUFA was assessed using ANCOVA models. RESULTS: Median (IQR) erythrocyte DHA in the treatment group increased from 1.50 (1.11, 2.03) at baseline to 1.86 (1.50, 2.43) (p<0.001) at 12 weeks, and fell in controls from 1.78 (1.37, 2.32) to 1.60 (1.32, 2.04) (p<0.001). The total n-3 fatty acids increased in the treatment group. There was no effect on malondialdehyde and antioxidant enzyme levels. Plasma homocysteine at 0 and 12 weeks was inversely associated with erythrocyte DHA at 12 weeks. CONCLUSION: Daily consumption of a snack containing GLV improved women's erythrocyte DHA levels without increasing oxidative stress.

Effect of a micronutrient-rich snack taken preconceptionally and throughout pregnancy on ultrasound measures of fetal growth: The Mumbai Maternal Nutrition Project (MMNP).

Improving micronutrient intakes of under-nourished mothers in low- and middle-income countries increases birth weight, but there is little data on the nature and timing during gestation of any effects on fetal growth. Ultrasound measures of fetal size were used to determine whether and when a food-based supplement affected fetal growth. Non-pregnant women living in Mumbai slums, India (N = 6,513), were randomly assigned to receive either a daily micronutrient-rich snack containing green leafy vegetables, fruit, and milk (treatment) or a snack made from lower-micronutrient vegetables (control) in addition to their usual diet from before pregnancy until delivery. From 2,291 pregnancies, the analysis sample comprised 1,677 fetuses (1,335 fetuses of women supplemented for ≥3 months before conception). First-trimester (median: 10 weeks, interquartile range: 9-12 weeks) fetal crown-rump length was measured. Fetal head circumference, biparietal diameter, femur length, and abdominal circumference were measured during the second (19, 19-20 weeks) and third trimesters (29, 28-30 weeks). The intervention had no effect on fetal size or growth at any stage of pregnancy. In the second trimester, there were interactions between parity and allocation group for biparietal diameter (p = .02) and femur length (p = .04) with both being smaller among fetuses of primiparous women and larger among those of multiparous women, in the treatment group compared with the controls. Overall, a micronutrient-rich supplement did not increase standard ultrasound measures of fetal size and growth at any stage of pregnancy. Additional ultrasound measures of fetal soft tissues (fat and muscle) may be informative.

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.

Protocol for the EMPHASIS study; epigenetic mechanisms linking maternal pre-conceptional nutrition and children's health in India and Sub-Saharan Africa.

BACKGROUND: Animal studies have shown that nutritional exposures during pregnancy can modify epigenetic marks regulating fetal development and susceptibility to later disease, providing a plausible mechanism to explain the developmental origins of health and disease. Human observational studies have shown that maternal peri-conceptional diet predicts DNA methylation in offspring. However, a causal pathway from maternal diet, through changes in DNA methylation, to later health outcomes has yet to be established. The EMPHASIS study (Epigenetic Mechanisms linking Pre-conceptional nutrition and Health Assessed in India and Sub-Saharan Africa, ISRCTN14266771) will investigate epigenetically mediated links between peri-conceptional nutrition and health-related outcomes in children whose mothers participated in two randomized controlled trials of micronutrient supplementation before and during pregnancy. METHODS: The original trials were the Mumbai Maternal Nutrition Project (MMNP, ISRCTN62811278) in which Indian women were offered a daily snack made from micronutrient-rich foods or low-micronutrient foods (controls), and the Peri-conceptional Multiple Micronutrient Supplementation Trial (PMMST, ISRCTN13687662) in rural Gambia, in which women were offered a daily multiple micronutrient (UNIMMAP) tablet or placebo. In the EMPHASIS study, DNA methylation will be analysed in the children of these women (~1,100 children aged 5-7 y in MMNP and 298 children aged 7-9 y in PMMST). Cohort-specific and cross-cohort effects will be explored. Differences in DNA methylation between allocation groups will be identified using the Illumina Infinium MethylationEPIC array, and by pyrosequencing top hits and selected candidate loci. Associations will be analysed between DNA methylation and health-related phenotypic outcomes, including size at birth, and children's post-natal growth, body composition, skeletal development, cardio-metabolic risk markers (blood pressure, serum lipids, plasma glucose and insulin) and cognitive function. Pathways analysis will be used to test for enrichment of nutrition-sensitive loci in biological pathways. Causal mechanisms for nutrition-methylation-phenotype associations will be explored using Mendelian Randomization. Associations between methylation unrelated to supplementation and phenotypes will also be analysed. CONCLUSION: The study will increase understanding of the epigenetic mechanisms underpinning the long-term impact of maternal nutrition on offspring health. It will potentially lead to better nutritional interventions for mothers preparing for pregnancy, and to identification of early life biomarkers of later disease risk.

The Pune Rural Intervention in Young Adolescents (PRIYA) study: design and methods of a randomised controlled trial.

BACKGROUND: The Pune Maternal Nutrition Study (PMNS) was established to prospectively study the relationship of maternal nutrition to fetal growth and later cardiometabolic risk in the offspring. High homocysteine and low vitamin B12 levels in pregnancy predicted lower birthweight and higher insulin resistance at 6 years in the offspring. B12 deficiency was widespread in this population, due to low dietary intake. We therefore commenced a community-based intervention study with the underlying hypothesis that vitamin B12 supplementation of adolescent members of the PMNS cohort will improve birth weight, B12 status, and reduce future diabetes risk, in their offspring. METHODS: The individually randomised controlled trial commenced in September 2012, with boys and girls randomized into 3 groups, to receive daily for at least 3 years or until the birth of their first child: 1) vitamin B12 2 µg; or 2) vitamin B12 2 µg plus multiple micronutrients (MMN) plus 20 g of milk powder or 3) placebo. Iron and folic acid is given to all participants. Compliance is assessed by monthly supplement counts. Adverse events are recorded using a standardised questionnaire. The primary outcome is cord blood B12 concentration; based on 180-200 pregnancies in the girls, the study has ~80% power to detect a 0.5 SD change in newborn B12, in the B12 supplementation groups compared with controls, at the 5% significance level. Primary analysis will be by intention to treat. DISCUSSION: Our study tests a primordial prevention strategy through an intergenerational intervention started pre-conceptionally in both boys and girls using physiological doses of micronutrients to improve immediate pregnancy-related and long-term cardio metabolic outcomes. The results will have significant public health implications in a setting with widespread B12 deficiency but relative folate sufficiency. The randomised controlled trial design allows us to be confident that our findings will be causally relevant. TRIAL REGISTRATION: ISRCTN 32921044, applied on 14/09/2012. CTRI 2012/12/003212, registered on 02/12/2012. Retrospectively registered.

Association between maternal nutritional status in pregnancy and offspring cognitive function during childhood and adolescence; a systematic review.

BACKGROUND: The mother is the only source of nutrition for fetal growth including brain development. Maternal nutritional status (anthropometry, macro- and micro-nutrients) before and/or during pregnancy is therefore a potential predictor of offspring cognitive function. The relationship of maternal nutrition to offspring cognitive function is unclear. This review aims to assess existing evidence linking maternal nutritional status with offspring cognitive function. METHODS: Exposures considered were maternal BMI, height and weight, micronutrient status (vitamins D, B12, folate and iron) and macronutrient intakes (carbohydrate, protein and fat). The outcome was any measure of cognitive function in children aged <18 years. We considered observational studies and trials with allocation groups that differed by single nutrients. We searched Medline/PubMed and the Cochrane Library databases and reference lists of retrieved literature. Two reviewers independently extracted data from relevant articles. We used methods recommended by the Centre for Reviews and Dissemination, University of York and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: Of 16,143 articles identified, 38 met inclusion criteria. Most studies were observational, and from high-income settings. There were few randomized controlled trials. There was consistent evidence linking maternal obesity with lower cognitive function in children; low maternal BMI has been inadequately studied. Among three studies of maternal vitamin D status, two showed lower cognitive function in children of deficient mothers. One trial of folic acid supplementation showed no effects on the children's cognitive function and evidence from 13 observational studies was mixed. Among seven studies of maternal vitamin B12 status, most showed no association, though two studies in highly deficient populations suggested a possible effect. Four out of six observational studies and two trials (including one in an Iron deficient population) found no association of maternal iron status with offspring cognitive function. One trial of maternal carbohydrate/protein supplementation showed no effects on offspring cognitive function. CONCLUSIONS: Current evidence that maternal nutritional status during pregnancy as defined by BMI, single micronutrient studies, or macronutrient intakes influences offspring cognitive function is inconclusive. There is a need for more trials especially in populations with high rates of maternal undernutrition. SYSTEMATIC REVIEW REGISTRATION: Registered in PROSPERO CRD42013005702 .

A Daily Snack Containing Leafy Green Vegetables, Fruit, and Milk before and during Pregnancy Prevents Gestational Diabetes in a Randomized, Controlled Trial in Mumbai, India.

BACKGROUND: Prospective observational studies suggest that maternal diets rich in leafy green vegetables and fruit may help prevent gestational diabetes mellitus (GDM). OBJECTIVE: Our objective was to test whether increasing women's dietary intake of leafy green vegetables, fruit, and milk before conception and throughout pregnancy reduced their risk of GDM. METHODS: Project SARAS ("excellent") (2006-2012) was a nonblinded, individually randomized, controlled trial in women living in slums in the city of Mumbai, India. The interventions included a daily snack made from leafy green vegetables, fruit, and milk for the treatment group or low-micronutrient vegetables (e.g., potato and onion) for the control group, in addition to the usual diet. Results for the primary outcome, birth weight, have been reported. Women were invited to take an oral-glucose-tolerance test (OGTT) at 28-32 wk gestation to screen for GDM (WHO 1999 criteria). The prevalence of GDM was compared between the intervention and control groups, and Kernel density analysis was used to compare distributions of 120-min plasma glucose concentrations between groups. RESULTS: Of 6513 women randomly assigned, 2291 became pregnant; of these, 2028 reached a gestation of 28 wk, 1008 (50%) attended for an OGTT, and 100 (9.9%) had GDM. In an intention-to-treat analysis, the prevalence of GDM was reduced in the treatment group (7.3% compared with 12.4% in controls; OR: 0.56; 95% CI: 0.36, 0.86; P = 0.008). The reduction in GDM remained significant after adjusting for prepregnancy adiposity and fat or weight gain during pregnancy. Kernel density analysis showed that this was explained by the fact that fewer women in the treatment group had a 2-h glucose concentration in the range 7.5-10.0 mmol/L. CONCLUSIONS: In low-income settings, in which women have a low intake of micronutrient-rich foods, improving dietary micronutrient quality by increasing intake of leafy green vegetables, fruit, and/or milk may have an important protective effect against the development of GDM. This trial was registered at www.controlled-trials.com as ISRCTN62811278.

Maternal antenatal multiple micronutrient supplementation for long-term health benefits in children: a systematic review and meta-analysis.

BACKGROUND: Multiple micronutrient supplementation for pregnant women reduces low birth weight and has been recommended in low- and middle-income countries (LMICs) to improve child survival, growth and health. We aimed to review the evidence from long-term follow-up studies of multiple micronutrient supplementation beginning in the later first or second trimester. METHODS: We searched systematically for follow-up reports from all trials in a 2015 Cochrane review of multiple micronutrient supplementation in pregnancy. The intervention comprised three or more micronutrients and the comparison group received iron (60 mg) and folic acid (400 µg), where possible. Median gestation of commencement varied from 9 to 23 weeks. Primary outcomes were offspring mortality, height, weight and head circumference, presented as unadjusted differences in means or proportions (intervention minus control). Secondary outcomes included other anthropometry, body composition, blood pressure, and cognitive and lung function. RESULTS: We found 20 follow-up reports from nine trials (including 88,057 women recruited), six of which used the UNIMMAP supplement designed to provide recommended daily allowances. The age of follow-up ranged from 0 to 9 years. Data for mortality estimates were available from all trials. Meta-analysis showed no difference in mortality (risk difference -0.05 per 1000 livebirths; 95 % CI, -5.25 to 5.15). Six trials investigated anthropometry and found no difference at follow-up in weight-for-age z score (0.02; 95 % CI, -0.03 to 0.07), height-for-age z score (0.01; 95 % CI, -0.04 to 0.06), or head circumference (0.11 cm; 95 % CI, -0.03 to 0.26). No differences were seen in body composition, blood pressure, or respiratory outcomes. No consistent differences were seen in cognitive function scores. CONCLUSIONS: There is currently no evidence that, compared with iron and folic acid supplementation, routine maternal antenatal multiple micronutrient supplementation improves childhood survival, growth, body composition, blood pressure, respiratory or cognitive outcomes.

Effects of a food-based intervention on markers of micronutrient status among Indian women of low socio-economic status.

Intakes of micronutrient-rich foods are low among Indian women of reproductive age. We investigated whether consumption of a food-based micronutrient-rich snack increased markers of blood micronutrient concentrations when compared with a control snack. Non-pregnant women (n 222) aged 14-35 years living in a Mumbai slum were randomised to receive a treatment snack (containing green leafy vegetables, dried fruit and whole milk powder), or a control snack containing foods of low micronutrient content such as wheat flour, potato and tapioca. The snacks were consumed under observation 6 d per week for 12 weeks, compliance was recorded, and blood was collected at 0 and 12 weeks. Food-frequency data were collected at both time points. Compliance (defined as the proportion of women who consumed ≥ 3 snacks/week) was >85 % in both groups. We assessed the effects of group allocation on 12-week nutrient concentrations using ANCOVA models with respective 0-week concentrations, BMI, compliance, standard of living, fruit and green leafy vegetable consumption and use of synthetic nutrients as covariates. The treatment snack significantly increased ß-carotene concentrations (treatment effect: 47·1 nmol/l, 95 % CI 6·5, 87·7). There was no effect of group allocation on concentrations of ferritin, retinol, ascorbate, folate or vitamin B12. The present study shows that locally sourced foods can be made into acceptable snacks that may increase serum ß-carotene concentrations among women of reproductive age. However, no increase in circulating concentrations of the other nutrients measured was observed.

Contribution of food sources to the vitamin B12 status of South Indian children from a birth cohort recruited in the city of Mysore.

OBJECTIVE: There is evidence that subclinical vitamin B12 (B12) deficiency is common in India. Vegetarianism is prevalent and therefore meat consumption is low. Our objective was to explore the contribution of B12-source foods and maternal B12 status during pregnancy to plasma B12 concentrations. DESIGN: Maternal plasma B12 concentrations were measured during pregnancy. Children's dietary intakes and plasma B12 concentrations were measured at age 9.5 years; B12 and total energy intakes were calculated using food composition databases. We used linear regression to examine associations between maternal B12 status and children's intakes of B12 and B12-source foods, and children's plasma B12 concentrations. SETTING: South Indian city of Mysore and surrounding rural areas. SUBJECTS: Children from the Mysore Parthenon Birth Cohort (n 512, 47.1 % male). RESULTS: Three per cent of children were B12 deficient (<150 pmol/l). A further 14 % had 'marginal' B12 concentrations (150-221 pmol/l). Children's total daily B12 intake and consumption frequencies of meat and fish, and micronutrient-enriched beverages were positively associated with plasma B12 concentrations (P=0.006, P=0.01 and P=0.04, respectively, adjusted for socio-economic indicators and maternal B12 status). Maternal pregnancy plasma B12 was associated with children's plasma B12 concentrations, independent of current B12 intakes (P<0.001). Milk and curd (yoghurt) intakes were unrelated to B12 status. CONCLUSIONS: Meat and fish are important B12 sources in this population. Micronutrient-enriched beverages appear to be important sources in our cohort, but their high sugar content necessitates care in their recommendation. Improving maternal B12 status in pregnancy may improve Indian children's status.