Two Randomized Trials of Low-Dose Calcium Supplementation in Pregnancy.

BACKGROUND: The World Health Organization recommends 1500 to 2000 mg of calcium daily as supplementation, divided into three doses, for pregnant persons in populations with low dietary calcium intake in order to reduce the risk of preeclampsia. The complexity of the dosing scheme, however, has led to implementation barriers. METHODS: We conducted two independent randomized trials of calcium supplementation, in India and Tanzania, to assess the noninferiority of a 500-mg daily dose to a 1500-mg daily dose of calcium supplementation. In each trial, the two primary outcomes were preeclampsia and preterm birth, and the noninferiority margins for the relative risks were 1.54 and 1.16, respectively. RESULTS: A total of 11,000 nulliparous pregnant women were included in each trial. The cumulative incidence of preeclampsia was 3.0% in the 500-mg group and 3.6% in the 1500-mg group in the India trial (relative risk, 0.84; 95% confidence interval [CI], 0.68 to 1.03) and 3.0% and 2.7%, respectively, in the Tanzania trial (relative risk, 1.10; 95% CI, 0.88 to 1.36) - findings consistent with the noninferiority of the lower dose in both trials. The percentage of live births that were preterm was 11.4% in the 500-mg group and 12.8% in the 1500-mg group in the India trial (relative risk, 0.89; 95% CI, 0.80 to 0.98), which was within the noninferiority margin of 1.16; in the Tanzania trial, the respective percentages were 10.4% and 9.7% (relative risk, 1.07; 95% CI, 0.95 to 1.21), which exceeded the noninferiority margin. CONCLUSIONS: In these two trials, low-dose calcium supplementation was noninferior to high-dose calcium supplementation with respect to the risk of preeclampsia. It was noninferior with respect to the risk of preterm live birth in the trial in India but not in the trial in Tanzania. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT03350516; Clinical Trials Registry-India number, CTRI/2018/02/012119; and Tanzania Medicines and Medical Devices Authority Trials Registry number, TFDA0018/CTR/0010/5).

Predictors of anaemia in mothers and children in Uttar Pradesh, India.

OBJECTIVE: Anaemia affects more than half of Indian women and children, but the contribution of its causes remains unquantified. We examined interrelationships between Hb and nutritional, environmental, infectious and genetic determinants of anaemia in non-pregnant mothers and children in Uttar Pradesh (UP). DESIGN: We conducted a cross-sectional survey of households in twenty-five districts of UP between October and December 2016. We collected socio-demographic data, anthropometry and venous blood in 1238 non-pregnant mothers and their children. We analysed venous blood samples for malaria, Hb, ferritin, retinol, folate, Zn, vitamin B12, C-reactive protein, α1-acid glycoprotein (AGP) and ß-thalassaemia. We used path analysis to examine pathways through which predictors of anaemia were associated with Hb concentration. SETTING: Rural and urban households in twenty-five districts of UP. PARTICIPANTS: Mothers 18-49 years and children 6-59 months in UP. RESULTS: A total of 36·4 % of mothers and 56·0 % of children were anaemic, and 26·7 % of women and 44·6 % of children had Fe deficiency anaemia. Ferritin was the strongest predictor of Hb (ß (95 % CI) = 1·03 (0·80, 1·27) g/dL in women and 0·90 (0·68, 1·12) g/dL in children). In children only, red blood cell folate and AGP were negatively associated with Hb and retinol was positively associated with Hb. CONCLUSIONS: Over 70 % of mothers and children with anaemia had Fe deficiency, needing urgent attention. However, several simultaneous predictors of Hb exist, including nutrient deficiencies and inflammation. The potential of Fe interventions to address anaemia may be constrained unless coexisting determinants are jointly addressed.

The role of dairy consumption in the relationship between wealth and early life physical growth in India: evidence from multiple national surveys.

INTRODUCTION: Prevalence of undernutrition continues to be high in India and low household wealth is consistently associated with undernutrition. This association could be modified through improved dietary intake, including dairy consumption in young children. The beneficial effect of dairy on child growth has not been explored at a national level in India. The present analyses aimed to evaluate the direct and indirect (modifying association of household level per adult female equivalent milk and milk product consumption) associations between household wealth index on height for age (HAZ) and weight for age (WAZ) in 6-59 months old Indian children using data from of nationally representative surveys. METHODS: Two triangulated datasets of two rounds of National Family Health Survey, (NFHS-3 and 4) and food expenditure (National Sample Survey, NSS61 and 68) surveys, were produced by statistical matching of households using Non-Iterative Bayesian Approach to Statistical Matching technique. A Directed Acyclic Graph was constructed to map the pathways in the relationship of household wealth with HAZ and WAZ based on literature. The direct association of wealth index and its indirect association through per adult female equivalent dairy consumption on HAZ and WAZ were estimated using separate path models for each round of the surveys. RESULTS: Wealth index was directly associated with HAZ and WAZ in both the rounds, but the association decreased from NFHS-3 (ßHAZ: 0.145; 95% CI: 0.129, 0.16) to NFHS-4 (ßHAZ: 0.102; 95%CI: 0.093, 0.11). Adult female equivalent milk intake (increase of 10gm/day) was associated with higher HAZ (ß_NFHS-3=0.001;95% CI: 0, 0.002; ß_NFHS-4=0.002;95% CI: 0.002, 0.003) but had no association with WAZ. The indirect association of wealth with HAZ through dairy consumption was 2-fold higher in NFHS-4 compared to NFHS-3. CONCLUSIONS: The analysis of triangulated survey data shows that household level per- adult female equivalent dairy consumption positively modified the association between wealth index and HAZ, suggesting that regular inclusion of milk and milk products in the diets of children from households across all wealth quintiles could improve linear growth in this population.

Untargeted Maternal Plasma Metabolomics in Hirschsprung Disease: A Pilot Study.

Background and Aims: Hirschsprung disease (HSCR) is a congenital disorder of unknown etiology affecting the enteric nervous system (ENS). Since the early gestational development of the ENS is dependent on the prenatal maternal metabolic environment, the objective of this pilot study was to explore the role of specific maternal plasma metabolites in the etiology of HSCR. Methods: In this cross-sectional study, postnatal (as a surrogate for prenatal) plasma samples were obtained from mothers of children diagnosed with HSCR (n = 7) and age-matched mothers of normal children (n = 6). The plasma metabolome was analyzed by ultra-high-pressure liquid chromatography and mass spectrometry. Metabolites were identified by mzCloud using Compound Discoverer software. Using an untargeted metabolomics workflow, metabolites with case versus control group differences were identified. Results: A total of 268 unique plasma metabolites were identified and annotated in maternal plasma. Of these, 57 were significantly different between case and control groups (P < 0.05, t-test). Using a false discovery rate corrected cutoff of 10% to adjust for multiple comparisons, 19 metabolites were significantly different in HSCR cases, including carnitines, medium-chain fatty acids, and glutamic acid. Pathways affected were for amino acid and lipid metabolism. Conclusion: Disordered prenatal metabolic pathways may be involved in the etiopathogenesis of HSCR in the developing fetus. This is the first study to assess maternal plasma metabolomics in HSCR.

The recent WHO guideline on acute malnutrition overestimates therapeutic energy requirement.

The World Health Organization has recently updated the guideline on the prevention and management of wasting and nutritional oedema (acute malnutrition) in infants and children under 5 years. Apart from differences with regard to the nutritional framework that defines the quantity of energy required as Ready-to-Use Therapeutic Food (RUTF) for the outpatient treatment of severe wasting and/or nutritional oedema, there are also important gaps in the practical guidance. Instead of the recommended energy intake of 150-185 kcal/kg/day, our alternative calculations indicate the requirement to be only 105-120 kcal/kg/day. If true, the implementation of such caloric overfeeding can have adverse consequences. Gaps in practical guidance also need to be addressed, including the timing of transition to home-based diets, maximal duration of therapeutic feeding, especially in non-responders (∼50% in South Asia), and the role of augmented home foods as the primary therapeutic food option.

Evidence on Milk Consumption and Production Linkages from Rural Bihar, India.

Background: Milk is an important source of protein for many Indian households. However, milk intake is very low. Hence, it is necessary to examine production-consumption linkages of milk within the paradigm of accessibility, availability, and affordability. Objectives: This study examined linkages between milk consumption and production, accounting for sales and factors associated with production investments in rural Bihar, a major milk-producing state of India with very poor nutritional status. Methods: A panel of households from the Gaya and Nalanda districts of Bihar were surveyed: the first round in July and August 2019 (n = 2026 households) and the second round from December 2019 to January 2020 (n = 2001 households). Data were collected on household consumption, production, and sale of milk, as well as other foods. The study examines the consumption-production linkage of milk and the association of dietary diversity with consumption from own production, with households as the unit of analysis. Ordinary least square regression analysis of average monthly household milk consumption was used to identify factors associated with milk consumption, particularly milk production. Results: The median (Quartile 1, Quartile 3) per capita milk consumption per day was 83.3 (41.6, 166.6) mL in the milk-consuming households. Average monthly household milk consumption in liters was higher in milk-producing households [ß: 7.1; 95% confidence interval (CI): 6.1, 8.1] than households relying on market purchases. Household milk consumption was higher in the third tertile of milk production than the first tertile of production (ß: 14.3 L/wk; 95% CI: 12.1, 17.2) and lower in the highest tertile of household sale quantity (ß: -8.8 L/wk in tertile 3, 95% CI: -12.7, -5) than the first tertile of household sale quantity of milk. Conclusions: The study provides evidence that consumption of milk in rural households is associated with own production such that households with higher production consume more. However, sale preferences restrict the quantity of milk consumed in milk-producing households.

Anthropometric Growth Reference for Indian Children and Adolescents.

OBJECTIVE: We aimed to develop anthropometric growth references for Indian children and adolescents, based on available 'healthy' child data from multiple national surveys. METHODOLOGY: Data on 'healthy' children, defined by comparable WHO's Multicentre Growth Reference Study (MGRS) selection criteria, were extracted from four Indian surveys over the last 2 decades, viz, NFHS-3, 4, and 5 and Comprehensive National Nutrition Survey (CNNS). Reference distributions of height-for-age for children up to 19 years, weight-for-age for children up to 9y, weight-for-height for children less than 5 years and BMI for age for children between 5-19 y were estimated by GAMLSS with Box-Cox Power Exponential (BCPE) family. The national prevalence of growth faltering was also estimated by the NFHS-5 and CNNS data. RESULTS: The distributions of the new proposed Indian growth references are consistently lower than the WHO global standard, except in the first 6 months of age. Based on these references, growth faltering in Indian children and adolescents reduced > 50% in comparison with the WHO standard. CONCLUSION: The study findings revealed that the WHO one-standard-fits-all approach may lead to inflated estimates of under nutrition in India and could be a driver of misdirected policy and public health expenditure in the Indian context. However, these findings need validation through prospective and focussed studies for more robust evidence base.

Effect of calcium supplementation on reversing metformin-based inhibition of vitamin B12 bioavailability in healthy adults using a [13C] cyanocobalamin tracer - A pilot study.

BACKGROUND & AIMS: Metformin is a widely prescribed first line drug for the treatment of type 2 diabetes mellitus (DM). Studies have shown that the use of metformin is often associated with a decrease in vitamin B12 (B12) levels in patients with DM. Few studies have shown that this effect could be mitigated with calcium supplementation. In the present study, we quantified the effect of metformin, and metformin co-administered with calcium on B12 absorption using a novel stable isotope [13C] cyanocobalamin tracer. METHODS: A pilot crossover study was conducted to estimate the bioavailability of B12 in healthy subjects, using [13C] cyanocobalamin as a tracer. In the study, [13C] cyanocobalamin was administered orally to the participants followed by hourly venous sampling to measure the concentration of the tracer and estimate bioavailability. This protocol was followed for three experiment days, each separated by a one month wash out period. As part of the study, all participants received the tracer alone for the control day (C), metformin 850 mg along with the tracer for the metformin day (M) and metformin 850 mg with calcium 500 mg and the tracer for the metformin calcium day (MC). RESULTS: Seven participants completed all three experiment days. The mean B12 bioavailability (±SD, n = 7) was 42.6 ± 10.2% for the control day (C), 30.8 ± 15.3% for the metformin day (M) and 46.4 ± 8.6% for the metformin-calcium day (MC). Repeated measures ANOVA was done and the pairwise comparison showed a significant difference in the B12 bioavailability between control and metformin day (C vs M p = 0.010), and between the metformin and metformin with calcium day (M vs MC p = 0.003). CONCLUSION: B12 bioavailability reduced significantly from baseline (C) when metformin (M) was administered and this reduction was reversed when calcium was co-administered (MC) in healthy participants. In patients using metformin, calcium supplementation as a strategy to prevent B12 deficiency needs to be further studied.

Mandatory fortification of rice in the public distribution system in India: An ethics perspective.

In response to the continuing high prevalence of anaemia recorded in the National Family Health Survey-5, the Indian government launched a policy for mandatory iron fortification of the rice provided through public nutrition programmes in India. This was done even though a rigorous evidence analysis had already concluded that rice fortification was not effective in preventing anaemia or iron deficiency at the population level. Fortification also poses a potential risk of iron toxicity over time, but there is no stated time period for the policy's implementation. The risk is particularly high in segments of the population who already have a high habitual iron intake, and who could be exposed to simultaneous fortification in different staples and food commodities along with the ongoing weekly Iron and Folic Acid tablets supplementation programme. Finally, this fortification policy also requires significant additional funding and resources to implement. It is crucial to examine such mandatory health actions, and to weigh the benefits and risks of harm, using the principles of public health ethics.

Landscape of pharmacogenetic variants associated with non-insulin antidiabetic drugs in the Indian population.

INTRODUCTION: Genetic variants contribute to differential responses to non-insulin antidiabetic drugs (NIADs), and consequently to variable plasma glucose control. Optimal control of plasma glucose is paramount to minimizing type 2 diabetes-related long-term complications. India's distinct genetic architecture and its exploding burden of type 2 diabetes warrants a population-specific survey of NIAD-associated pharmacogenetic (PGx) variants. The recent availability of large-scale whole genomes from the Indian population provides a unique opportunity to generate a population-specific map of NIAD-associated PGx variants. RESEARCH DESIGN AND METHODS: We mined 1029 Indian whole genomes for PGx variants, drug-drug interaction (DDI) and drug-drug-gene interactions (DDGI) associated with 44 NIADs. Population-wise allele frequencies were estimated and compared using Fisher's exact test. RESULTS: Overall, we found 76 known and 52 predicted deleterious common PGx variants associated with response to type 2 diabetes therapy among Indians. We report remarkable interethnic differences in the relative cumulative counts of decreased and increased response-associated alleles across NIAD classes. Indians and South Asians showed a significant excess of decreased metformin response-associated alleles compared with other global populations. Network analysis of shared PGx genes predicts high DDI risk during coadministration of NIADs with other metabolic disease drugs. We also predict an increased CYP2C19-mediated DDGI risk for CYP3A4/3A5-metabolized NIADs, saxagliptin, linagliptin and glyburide when coadministered with proton-pump inhibitors (PPIs). CONCLUSIONS: Indians and South Asians have a distinct PGx profile for antidiabetes drugs, marked by an excess of poor treatment response-associated alleles for various NIAD classes. This suggests the possibility of a population-specific reduced drug response in atleast some NIADs. In addition, our findings provide an actionable resource for accelerating future diabetes PGx studies in Indians and South Asians and reconsidering NIAD dosing guidelines to ensure maximum efficacy and safety in the population.

Infant growth and body composition from birth to 24 months: are infants developing the same?

BACKGROUND: Given the importance of infancy for establishing growth trajectories, with later-life health consequences, we investigated longitudinal body composition among infants from six economically and ethnically diverse countries. METHODS: We recruited mother-infant dyads using the WHO Multicenter Growth Reference Study criteria. We measured fat-free mass (FFM) in 1393 (49% female) infants from birth to 6 months of age (Australia, India, and South Africa; n = 468), 3-24 months of age (Brazil, Pakistan, South Africa, and Sri Lanka; n = 925), and derived fat mass (FM), fat mass index (FMI), and fat-free mass index (FFMI). Height-for-age (HAZ), weight-for-age (WAZ), and weight-for-length (WHZ) Z-scores were computed. Sex differences were assessed using a t-test, and country differences using a one-way analysis of covariance. We further compared subsamples of children with average (-0.25 > HAZ < +0.25), below-average (≤-0.25) and above-average (≥+0.25) HAZ. RESULTS: HAZ performed well between 0 and 6 months, but less so between 3 and 24 months. The stunting prevalence peaked at 10.3% for boys and 7.8% for girls, at 24 months. By 24 months, girls had greater FMI (10%) than boys. There were significant differences in FFM (both sexes in all countries) and FM (Brazilian boys, Pakistani and South African girls) by 24 months of age between infants with average, above-average, and below-average HAZ. CONCLUSION: In a multi-country sample representing more ideal maternal conditions, body composition was heterogeneous even among infants who exhibited ideal length. Having a mean HAZ close to the median of the WHO standard for length reduced FFM between-country heterogeneity but not FM, suggesting that other factors may influence adiposity.

An Optimization Tool to Formulate Diets within a Supplementary Nutrition Program for Children.

Background: In large supplementary feeding programs for children, it is challenging to create and sustain contextual, acceptable, nutritionally complete, and diverse supplemental foods. For example, the Indian Supplementary Nutrition Program (SNP) supplements the dietary intake of children, pregnant and lactating women, and severely acutely malnourished (SAM) children by offering dry take home rations (THRs) or hot cooked meals (HCMs) across India, but an optimization tool is necessary to create local contextual recipes for acceptable and nutritionally adequate products. Objectives: This study aimed to create a linear programming (LP) model to optimize diverse food provisions for a SNP to meet its program guidelines, using locally available foods, within budgetary allocations. Methods: A LP algorithm with appropriate constraints was used to generate an optimal THR based on raw foods, or an optimal weekly HCM menu comprised of a lunch meal with mid-morning snacks, based on user choices of foods and recipes. The database of foods used was created by a prospective survey conducted across all states of India for this purpose, such that the recipe and food optimization was diverse and specific to the guidelines for each beneficiary group. Results: An interactive web-based app, which can optimize feeding programs at any population level, was developed for use by program implementers and is hosted at https://www.datatools.sjri.res.in/SNP/. In the Indian example analyzed here, the recommended optimized diets met the guidelines for diversified and nutritionally complete SNP provision but at a cost that was almost 25% higher than the present Indian budget allocation. Conclusions: The optimization model developed demonstrates that contextual SNP diets can be created to meet macronutrient and most essential micronutrient needs of large-scale feeding programs, but appropriate diversification entails additional costs.