Effect of preconception multiple micronutrients vs. iron-folic acid supplementation on maternal and birth outcomes among women from developing countries: a systematic review and meta-analysis.

Background: Maternal malnutrition affects the somatic growth of the fetus and subsequent adverse events during infancy and childhood period. Though trials have been conducted on multiple micronutrient (MMN) supplements initiated during the preconception period, there is no collated evidence on this. Materials and methods: We performed a systematic review of published trials with the application of Grading of Recommendations Assessment, Development, and Evaluation (GRADE). The searches were conducted until 30 September 2023. Meta-analysis was performed using Review Manager 5 software. The primary objective was to compare the effect of preconception MMN vs. iron-folic acid (IFA) supplementation on newborn anthropometric parameters at birth. Results: Of the 11,832 total citations retrieved, 12 studies with data from 11,391 participants [Intervention = 5,767; Control = 5,624] were included. For the primary outcome, there was no significant difference in the birth weight [MD, 35.61 (95% CI, -7.83 to 79.06), p = 0.11], birth length [MD, 0.19 (95% CI, -0.03 to 0.42), p = 0.09], and head circumference [MD, -0.25 (95% CI, -0.64 to -0.14), p = 0.22] between the MMN and control groups. For all the secondary outcomes [except for small for gestational age (SGA) and low birth weight (LBW)], the difference between the MMN and control groups was not significant. The GRADE evidence generated for all the outcomes varied from "very low to moderate certainty." Conclusion: A "very low certainty" of evidence suggests that MMN supplementation may not be better than routine IFA supplementation in improving newborn anthropometric parameters (weight, length, and head circumference). The adverse events resulting from the supplementation were not significant. We need better quality uniformly designed RCTs before any firm recommendation can be made.Systematic review registration: identifier (CRD42019144878: https://www.crd.york.ac.uk/prospero/#searchadvanced).

Adherence and acceptability of multiple micronutrient supplementation during pregnancy: Study protocol for a cluster-randomized non-inferiority trial in Cambodia.

BACKGROUND: Iron and folic acid (IFA) supplements are currently provided to Cambodian women during pregnancy. However, recent research has found benefits of a multiple micronutrient supplement (MMS) over just IFA alone on several outcomes of perinatal and infant health. The Ministry of Health in Cambodia has proposed a transition from IFA to MMS but to effectively guide this transition requires implementation research on the acceptability and adherence to MMS (over IFA). METHODS: This non-inferiority trial aims to assess the adherence and acceptability of IFA (60 mg elemental iron and 400 µg folic acid) compared to MMS (standard UNIMMAP formulation including 15 micronutrients) during antenatal care in Cambodia. A prospective cohort of 1545 pregnant women will be assigned to one of three trial arms: (1) IFA for 90 days [IFA-90]; (2) MMS for 180 days with two distributions of 90-count tablet bottles [MMS-90]; or (3) MMS for 180 days with one 180-count tablet bottle [MMS-180]. Each arm will enroll 515 women across 48 health centers (clusters) in Kampong Thom Province in Cambodia. The primary outcome is the non-inferiority of adherence rates of MMS-180 compared to IFA-90, as assessed by tablet counts. Mixed-effects logistic and linear regression models will be used to estimate the difference in the adherence rate between the two groups, with an 'a priori' determined non-inferiority margin of 15%. Acceptability of MMS and IFA will be measured using a quantitative survey conducted with enrolled pregnant women at 30-day, 90-day, and 180-day time-points. DISCUSSION: Findings from this study will guide an effective and feasible MMS scale-up strategy for Cambodia. Additionally, the findings will be shared globally with other stakeholders planning to scale up MMS in other countries. TRIAL REGISTRATION: NCT05867836 ( ClinicalTrials.gov , registered May 18, 2023).

Maternal Iron and Vitamin D Status during the Second Trimester Is Associated with Third Trimester Depression Symptoms among Pregnant Participants in the APrON Cohort.

BACKGROUND: The maternal status of multiple micronutrients during pregnancy and postpartum and their potential associations with maternal health outcomes are largely undescribed. OBJECTIVES: This study aimed to examine associations between maternal iron and vitamin D status, individually and in combination, on depression symptoms in pregnant individuals. METHODS: The Alberta Pregnancy Outcomes and Nutrition cohort study included pregnant participants and their children from Calgary and Edmonton, Canada. Iron biomarkers (serum ferritin [SF], soluble transferrin receptor, and hepcidin) were measured via immunoassays and vitamin D [25-hydroxyvitamin D3 (25(OH)D3) and 3-epi-25-hydoxyvitamin D3 (3-epi-25(OH)D3)] metabolites were quantifed using liquid chromatography with tandem mass spectroscopy. Four categories of maternal iron and vitamin D status during the second trimester were conceptualized using concentrations of SF and total 25-hydoxyvitamin D [25(OH)D], respectively. Maternal Edinburgh Postnatal Depression Scale (EPDS) scores during the third trimester (n = 1920) and 3 mo postpartum (n = 1822) were obtained. RESULTS: Concentrations of maternal 25(OH)D3, 3-epi-25(OH)D3, and the ratio of both metabolites were significantly higher during the second trimester compared with their status at 3 mo postpartum. Higher second trimester maternal concentrations of SF (ß: -0.8; 95% confidence interval [CI]: -1.5, -0.01), hepcidin (ß: -0.5; 95% CI: -0.9, -0.2), and 25(OH)D3 (ß: -0.01; 95% CI: -0.02, -0.004) predicted lower maternal EPDS scores during the third trimester. Pregnant individuals with a low iron (SF <15 µg/L) and replete vitamin D (25(OH)D ≥75 nmol/L) (ß: 1.1; 95% CI: 0.03, 2.1) or low iron (SF <15 µg/L) and vitamin D (25(OH)D <75 nmol/L) (ß: 2.2; 95% CI: 0.3, 4.2) status during midpregnancy had higher third trimester EPDS scores compared with those that were replete in both micronutrients. CONCLUSIONS: A higher midpregnancy maternal iron and vitamin D status, independently or in combination, predicted fewer maternal depression symptoms in the third trimester. Concentrations of maternal 25(OH)D3 and 3-epi-25(OH)D3 may be lower in the postpartum period compared with midpregnancy.

Factors associated with anemia among school-going adolescents aged 10-17 years in Zanzibar, Tanzania: a cross sectional study.

BACKGROUND: Anemia among adolescents (ages 10-19 years) is a leading cause of morbidity and mortality in low- and middle-income countries and carries long-term health and economic consequences. To address the issue, policymakers and programmers require evidence of the burden of anemia among adolescents in specific contexts, as well as an understanding of the factors associated with anemia in this population. METHODS: We conducted a cross-sectional survey as a baseline assessment to determine the prevalence and factors associated with anemia in secondary school students, as part of a cluster-randomized effectiveness trial testing different micronutrient supplementation strategies in addressing anemia among adolescents in Zanzibar. Between March 7th to 25th, 2022 the survey was conducted on 2,479 school-going adolescents aged 10-17 years from 42 schools on the island of Zanzibar, Tanzania. Hemoglobin concentration was measured along with the collection of socio-demographics, health, food frequency, and water, sanitation and hygiene data. RESULTS: Based on the World Health Organization cutoffs for anemia, 53.3% of the sample had anemia (mild, moderate, or severe). Using chi-square tests and logistic regressions, we determined that females had higher odds of anemia than males (Adjusted OR = 1.47; 95% CI: 1.24, 1.74), those in the highest wealth quintile had lower odds of anemia than those in the lowest wealth quintile (Adjusted OR = 0.7; CI: 0.54, 0.91), stunted adolescents had higher odds of anemia than non-stunted students (Adjusted OR = 1.38; 95% CI: 1.06,1.81), and those who used shared toilets had higher odds of moderate or severe anemia than those with private toilet access (Adjusted OR = 1.68; CI: 1.07, 2.64). CONCLUSIONS: The high prevalence of anemia in this sample indicates an urgent need to address anemia among adolescents in Zanzibar, and the factors associated with anemia point to the importance of water, sanitation, and hygiene interventions in addition to dietary and nutritional support. TRIAL REGISTRATION: NCT05104554, registered 03/11/2021.

Periconceptional Folic Acid Only Versus Multiple Micronutrients Containing Folic Acid and Association with Gestational Diabetes Mellitus - Beijing Municipality, China, 2017-2021.

What is already known about this topic?: Inconsistent results have been reported on the association between periconceptional folic acid only (FAO) or multiple micronutrients containing folic acid (MMFA) supplementation and the risk of gestational diabetes mellitus (GDM) in previous research. What is added by this report?: In a prospective cohort study conducted among pregnant women in Haidian District, Beijing Municipality, it was observed that those who took MMFA demonstrated a higher likelihood of developing GDM in comparison to those who consumed FAO periconceptionally. Interestingly, the increased risk for GDM in pregnant women supplemented with MMFA compared to FAO was primarily due to changes in fasting plasma glucose. What are the implications for public health practice?: It is highly recommended that women prioritize the use of FAO in order to yield potential benefits in the prevention of GDM.

Effects of iron supplementation on neural indices of habituation in Bangladeshi children.

BACKGROUND: Iron deficiency and anemia have been associated with poor cognition in children, yet the effects of iron supplementation on neurocognition remain unclear. OBJECTIVE: We aimed to examine the effects of supplementation with iron on neural indices of habituation using auditory event-related brain potentials (ERPs). METHODS: This substudy was nested within a 3-arm, double-blind, double-dummy, individual randomized trial in Bangladesh, in which 3300 8-mo-old children were randomly selected to receive 3 mo of daily iron syrup (12.5 mg iron), multiple micronutrient powders (MNPs) (including 12.5 mg iron), or placebo. Children were assessed after 3 mo of intervention (mo 3) and 9 mo thereafter (mo 12). The neurocognitive substudy comprised a randomly selected subset of children from the main trial. Brain activity elicited during an auditory roving oddball task was recorded using electroencephalography to provide an index of habituation. The differential response to a novel (deviant) compared with a repeated (standard) sound was examined. The primary outcome was the amplitude of the mismatch response (deviant minusstandard tone waveforms) at mo 3. Secondary outcomes included the deviant and standard tone-evoked amplitudes, N2 amplitude differences, and differences in mean amplitudes evoked by deviant tones presented in the second compared with first half of the oddball sequence at mo 3 and 12. RESULTS: Data were analyzed from 329 children at month 3 and 363 at mo 12. Analyses indicated no treatment effects of iron interventions compared with placebo on the amplitude of the mismatch response (iron syrup compared with placebo: mean difference (MD) = 0.07µV [95% CI: -1.22, 1.37]; MNPs compared with placebo: MD = 0.58µV [95% CI: -0.74, 1.90]) nor any secondary ERP outcomes at mo 3 or 12, despite improvements in hemoglobin and ferritin concentrations from iron syrup and MNPs in this nested substudy. CONCLUSION: In Bangladeshi children with >40% anemia prevalence, iron or MNP interventions alone are insufficient to improve neural indices of habituation. This trial was registered at the Australian New Zealand Clinical Trials Registry as ACTRN12617000660381.

Intervention Effect of a Soybean-Based Complementary Food Supplement on Anemic Infants in a Poor Rural Region in China: Evidence from Quasi-RCT.

The soybean-based Yingyang Bao complementary food supplement represents a special nutritional improvement method for anemic infants in many intervention projects across China, while its benefits lack rigorous evidence. Using a quasi-randomized controlled trial design, which adhered to randomization and control except for the blinding method, 248 anemic infants were divided randomly into an intervention group (128 cases received the Yingyang Bao intervention based on routine feeding) and a control group (120 cases only received routine feeding). Anthropometric indicators and 16 blood indicators were measured at baseline and 1 year after intervention. The levels of hemoglobin, 1,25-dihydroxy vitamin D, homocysteine, retinol, vitamin D3, and soluble transferrin receptor and the height-age-Z score and weight-age-Z score of the intervention group were significantly improved after the intervention (p < 0.05). The homocysteine level improvement appeared to be moderately negatively correlated with the cobalamin level improvement (p < 0.05). The improvements of five indicators were significant correlated with the intervention duration (p < 0.05), and the corresponding three significant regression equations could predict the intervention effect and the intervention duration to a certain extent. This quasi-randomized controlled trial provided more convincing evidence that Yingyang Bao can effectively improve three kinds of malnutrition compared to previous research which only adopted self before and after comparison.

Low birth weight and its associated factors in East Gojjam Zone, Amhara, Ethiopia.

INTRODUCTION: Low birth weight is a global public health problem, with 15-20% of all births globally, described by weight at birth of less than 2500 g ensuing fetal and neonatal mortality and morbidity, poor cognitive growth, and an increased risk of chronic diseases later in life. The prevalence is critical in East Africa where about 11% have low birth weight out of 54% of neonates whose weight was measured at birth. There are many causes of low birth weight, including early induction of labor or cesarean birth, multiple pregnancies, infections, diabetes, and high blood pressure. Moreover, socioeconomic factors and unhealthy dietary habits could contribute to low birth weight in areas with poor intake of a diversified diet. This study has indicated the association between poor dietary diversity and low birth weight in the study area for the first time. METHODS: An institutional-based cross-sectional study was conducted on eligible 423 pregnant women recruited from Gestational Age of less than 17 weeks until delivery where the birth outcomes were recorded in health institutions in randomly selected five Woredas in East Gojjam Zone, Amhara, Ethiopia from June 2019 to December 2020. Questionnaires were used to collect data on socio-economic-demographic, dietary diversity scores, and food consumption scores. RESULTS: The study found a prevalence of low birth weight of 9.6%, low dietary diversity score of 53.2%, low food consumption score of 19.7%, and preterm delivery of 9.1%. Ever attended school and a higher level of education (diploma and above) decreased the risk of low birth weight with an Adjusted Odds Ratio (AOR) of 0.149 (0.024, 0.973) P ≤ 0.042; 0.059 (0.007, 0.513) P ≤ 0.007; whereas low dietary diversity score group and low food consumption group increased the risk of low birth weight with AOR 2.425 (1.342, 6.192) P ≤ 0.011and 2.983 (1.956, 9.084) P ≤ 0.044 respectively. CONCLUSION AND RECOMMENDATION: Participants with no formal education, no diploma, and above (no college or university training/degree), low diversity score group, and low food consumption group had an increased risk of low birth weight. Therefore the use of a diversified diet, educating women to a higher educational level, and health education on the intake of a diversified food rich in multiple micronutrients are recommended as strategies that will ameliorate the occurrence of low birth weight.

Fortified Balanced Energy-Protein Supplementation, Maternal Anemia, and Gestational Weight Gain: A Randomized Controlled Efficacy Trial among Pregnant Women in Rural Burkina Faso.

BACKGROUND: Anemia and suboptimal gestational weight gain (GWG) are associated with adverse maternal and birth outcomes. Limited research indicates that balanced energy-protein (BEP) supplements reduce the incidence of inadequate GWG. OBJECTIVES: We assessed the efficacy of a micronutrient-fortified BEP supplement on the secondary outcomes of anemia, GWG, GWG rate, and GWG in relation to the Institute of Medicine (IOM)'s recommendations, as compared with an iron-folic acid (IFA) tablet. METHODS: We conducted a randomized controlled trial in Burkina Faso, among pregnant women (15-40 y old) enrolled at <21 weeks of gestation. Women received either BEP and IFA (intervention) or IFA (control). Hemoglobin (g/dL) concentrations were measured at baseline and the third antenatal care visit (ANC), whereas maternal weight was measured at baseline and all subsequent ∼7-weekly ANCs. GWG (kg) was calculated as a woman's last weight measurement (at ∼36 weeks of gestation) minus weight at enrollment, whereas GWG rate (kg/wk) was GWG divided by the time between the first and last weight measurements. GWG adequacy (%) was computed as GWG divided by the IOM's recommendation. Binary outcomes included severely inadequate, inadequate, and excessive GWG. Statistical analyses followed the intention-to-treat principle. Linear regression and probability models were fitted for the continuous and binary outcomes, respectively, adjusting for baseline measurements. RESULTS: Women in the BEP group tended to have higher, but nonsignificantly different, GWG (0.28 kg; 95% CI: -0.05, 0.58 kg; P = 0.099). Furthermore, there were no significant differences in prenatal anemia prevalence, GWG rate, GWG adequacy, or incidence of inadequate or excessive GWG. Findings were robust to model adjustments and complete case and per protocol analyses. CONCLUSIONS: This trial does not provide evidence that fortified BEP supplementation reduces maternal anemia or increases GWG, as compared with IFA. In conjunction with the small, but positive, effects of maternal BEP supplementation on birth outcomes, our findings warrant the investigation of additional biochemical and postnatal outcomes.This trial was registered at clinicaltrials.gov as NCT03533712.

Maternal Periconceptional Folic Acid Supplementation and Risk for Fetal Congenital Heart Defects.

OBJECTIVE: To determine the effects of maternal periconceptional supplementation with folic acid or multiple micronutrients containing folic acid on the prevention of fetal congenital heart defects (CHDs). STUDY DESIGN: Data were drawn from a Prenatal Health Care System and a Birth Defects Surveillance System in a district of Beijing, China. A total of 63 969 singleton births, live or stillborn, 308 CHDs among them, during 2013 to 2018 were included. Associations between different patterns of supplementation and risk for total CHDs or main types of CHDs were evaluated with risk ratios (RRs). RESULTS: For folic acid or multiple micronutrients containing folic acid users compared with nonusers, the adjusted RRs (ARRs) for total CHDs, critical CHD, and ventricular septal defect (VSD) were 0.60 (95% CI, 0.44-0.83), 0.41 (95% CI, 0.26-0.67), and 0.47 (95% CI, 0.30-0.74), respectively. When we compared multiple micronutrients containing folic acid users with folic acid users, the ARRs were 0.84 (95% CI, 0.66-1.09), 0.64 (95% CI, 0.41-1.00), and 0.94 (95% CI, 0.63-1.41) for total CHDs, critical CHD, and VSD, respectively. We also found that, compared with supplementation initiated after conception, supplementation initiated before conception was associated with a lower risk for CHDs: the ARRs were 0.68 (95% CI, 0.48-0.95) for total CHDs and 0.26 (95% CI, 0.10-0.71) for critical CHD, but 1.08 (95% CI, 0.63-1.83) for VSD. CONCLUSIONS: Maternal periconceptional supplementation with folic acid or multiple micronutrients containing folic acid seems to decrease the risk for CHDs, especially critical CHD, in offspring. Supplementation confers a greater protective effect when it is initiated before conception. We did not find any difference between folic acid and multiple micronutrients containing folic acid in terms of preventing CHDs.

Rice with Multilayer Aleurone: A Larger Sink for Multiple Micronutrients.

Diet-related noncommunicable diseases impose a heavy burden on human health worldwide. Rice is a good target for diet-related disease prevention strategies because it is widely consumed. Liu et al. (Proc Natl Acad Sci USA 115(44):11327-11332, 2018. https://doi.org/10.1073/pnas.1806304115 ) demonstrated that increasing the number of cell layers and thickness of putative aleurone in ta2-1 (thick aleurone 2-1) mutant rice enhances simultaneously the content of multiple micronutrients. However, the increases of aleurone-associated nutrients were not proportional to the increases in the aleurone thickness. In this study, first, cytohistological analyses and transmission electron microscopy demonstrated that the multilayer in ta2-1 exhibited aleurone cell structural features. Second, we detected an increase in insoluble fibre and insoluble bound-phenolic compounds, a shift in aleurone-specific neutral non-starch polysaccharide profile, enhancement of phytate and minerals such as iron, zinc, potassium, magnesium, sulphur, and manganese, enrichment of triacylglycerol and phosphatidylcholine but slight reduction in free fatty acid, and an increase in oleic fatty acid composition. These findings support our hypothesis that the expanded aleurone-like layers in ta2-1 maintained some of the distinctive aleurone features and composition. We provide perspectives to achieve even greater filling of this expanded micronutrient sink to provide a means for multiple micronutrient enhancements in rice.

Impact of scaling up prenatal nutrition interventions on human capital outcomes in low- and middle-income countries: a modeling analysis.

BACKGROUND: Prenatal nutrition interventions can lead to improved birth outcomes, which in turn are associated with better education and human capital outcomes later in life. OBJECTIVE: We estimated the impact of scaling up iron-folic acid (IFA), calcium, multiple micronutrient (MMS), and balanced energy protein (BEP) supplementation for pregnant women, on human capital outcomes in low- and middle-income countries (LMIC). METHODS: We used mathematical modeling with proportional reductions in adverse birth outcomes to estimate the potential gains in school years and lifetime income due to scaling up each prenatal nutrition intervention. Estimates of intervention effects on birth outcomes were derived from meta-analyses of randomized trials. Estimates of the associations between birth outcomes and schooling and lifetime income were derived from de novo meta-analyses of observational studies. RESULTS: Across 132 LMIC, scaling up prenatal nutrition interventions to 90% coverage was estimated to increase school years and lifetime income per birth cohort by: 2.28 million y (95% uncertainty intervals (UI): -0.44, 6.26) and $8.26 billion (95% UI: -1.60, 22.4) for IFA; 4.08 million y (95% UI: 0.12, 9.68) and $18.9 billion (95% UI: 0.59, 44.6) for calcium; 5.02 million y (95% UI: 1.07, 11.0) and $18.1 billion (95% UI: 3.88, 39.1) for MMS; and 0.53 million y (95% UI: -0.49, 1.70) and $1.34 billion (95% UI: -1.10, 3.10 billion) for BEP supplementation. South Asia and Sub-Saharan Africa tended to have the largest estimated regional gains in school years for scaling up each intervention due to the large population size and high burden of poor birth outcomes. Absolute income benefits for each intervention were estimated to be the largest in Latin America, where returns to education and incomes are higher relative to other regions. CONCLUSION: Increasing coverage of prenatal nutrition interventions in LMIC may lead to substantial gains in schooling and lifetime income. Decision makers should consider the potential long-term human capital returns of investments in maternal nutrition.

Maternal periconceptional folic acid supplements use and fetus risk for limb defects.

BACKGROUND: Associations between the periconceptional folic acid only (FAO) or multiple micronutrients containing folic acid (MMFA) supplementation and risk for limb defects are inconsistent. OBJECTIVE: To explore the association between periconceptional folic acid supplements use and risk for limb defects, including clubfoot, polydactyly, syndactyly, and limb deficiencies. METHODS: Data were derived from a cohort based on a pregnancy registry in a district of Beijing, China, from 2013 to 2018. Information on maternal periconceptional FAO and MMFA supplementation was collected via face-to-face interviews at first trimester. Pregnancy outcomes including limb defects were ascertained in livebirths, stillbirths, and elective pregnancy terminations and were recorded into the system. Propensity score methods were used to adjust for potential confounders. RESULTS: A total of 63 969 women with a singleton delivery were included. The overall prevalence of limb defects was 47.5 per 10 000 (n = 63 969) singleton deliveries. Decreased prevalence of limb defects was found among FAO/MMFA users compared with women who did not take supplements (nonusers) (46.1 vs. 61.9 per 10 000 births, adjusted risk ratio [RR] 0.80, 95% confidence interval [CI] 0.56, 1.12). Compared with nonusers (n = 6462, 10.2%), women who took either FAO (n = 26 567, 42.0%) or MMFA (n = 30 259, 47.8%) had a lower risk for total clubfoot (RR 0.40, 95% CI 0.20, 0.84), and for isolated clubfoot (RR 0.41, 95% CI 0.17, 0.97). For other limb defects except clubfoot, FAO supplementation did not appear to be associated with reduced risk, while MMFA supplementation group had 30%-50% reduced risks for other limb defects. A lower risk for limb defects or isolated limb defects was found with MMFA supplementation when FAO supplementation was used as a control. CONCLUSIONS: Maternal periconceptional supplements with either FAO or MMFA had inverse association with clubfoot in offspring, and MMFA was associated with lower risk for isolated limb defects compared with FAO.

Preconception micronutrient supplementation positively affects child intellectual functioning at 6 y of age: A randomized controlled trial in Vietnam.

BACKGROUND: Although there is growing evidence on the role of preconception nutrition for birth outcomes, very few studies have evaluated the long-term effects of nutrition interventions during the preconception period on offspring cognitive outcomes. OBJECTIVE: We evaluate the impact of preconception weekly multiple micronutrients (MMs) or iron and folic acid (IFA) supplementation compared with folic acid (FA) alone on offspring intellectual functioning at age 6-7 y. METHODS: We followed 1599 offspring born to women who participated in a double-blinded randomized controlled trial of preconception supplementation in Vietnam. Women received weekly supplements containing either 2800 µg FA only, 60 mg iron and 2800 µg FA, or MMs (15 micronutrients including IFA) from baseline until conception, followed by daily prenatal IFA supplements until delivery. We used the Wechsler Intelligence Scale for Children to measure full-scale IQ (FSIQ) and 4 related domains of intellectual functioning [Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Working Memory Index (WMI), and Processing Speed Index (PSI) scores] at 6-7 y. Group comparisons were done using ANOVA tests for all children and the subgroup born to women who consumed the supplements ≥26 wk before conception (per-protocol analyses). RESULTS: The final sample with data at 6-7 y (n = 1321) was similar for baseline maternal and offspring birth characteristics and age at follow-up by treatment group. Compared with the offspring in the FA group, those in the MM group had higher FSIQ (ß = 1.7; 95% CI: 0.1, 3.3), WMI (ß = 1.7; 95% CI: 0.2, 3.2), and PSI (ß = 2.5; 95% CI: 0.9, 4.1). Similar findings were observed in the per-protocol analyses. There were no significant differences by treatment group for VCI and PRI. CONCLUSIONS: Preconception supplementation with MMs improved certain domains of intellectual functioning at age 6-7 y compared with FA. These findings suggest the potential for preconception micronutrient interventions to have long-term benefits for offspring cognition.

Ten2Twenty-Ghana: Study Design and Methods for an Innovative Randomized Controlled Trial with Multiple-Micronutrient-Fortified Biscuits among Adolescent Girls in Northeastern Ghana.

Investing in adolescent girls' nutrition is vital for health and for breaking the intergenerational cycle of malnutrition and deprivation, but limited knowledge on the type, timing, and efficacy of interventions delays progress. We describe the design of a 26-wk randomized placebo-controlled trial with multiple-micronutrient-fortified biscuits (MMBs) among adolescent girls in northeastern Ghana. Apparently healthy, premenarche (n = 312) and postmenarche (n = 309) girls (10-17 y) were randomly assigned to receive the following for 5 d/wk: 1) MMBs (fortified with 11 vitamins and 7 minerals) or 2) unfortified biscuits. Data included plasma micronutrient status, anthropometry, body composition, cognitive function, psychosocial health, fertility, dietary intake, and sociodemographic and socioeconomic covariates, complemented with in-depth interviews (n = 30) and 4 focus group discussions. We hypothesized an increase in plasma ferritin and retinol-binding protein with a resultant increase in hemoglobin, cognition, vertical height, and psychosocial health. Our study seeks to investigate the efficacy and optimal timing of a multiple-micronutrient food intervention program for adolescent girls. The RCT was registered prospectively with the Netherlands Clinical Trials Register (NL7487).

Consumption of multiple micronutrients or small-quantity lipid-based nutrient supplements containing iodine at the recommended dose during pregnancy, compared with iron and folic acid, does not affect women's urinary iodine concentration in rural Malawi: a secondary outcome analysis of the iLiNS DYAD trial.

OBJECTIVES: Inadequate iodine intake during pregnancy increases the risk of neonatal morbidity and mortality. We aimed to evaluate whether prenatal supplements containing iodine affect urinary iodine concentrations (UIC) of pregnant women in Malawi. DESIGN: A randomised controlled trial. Pregnant women (n 1391) were assigned to consume 60 mg/d Fe and 400 µg/d folic acid (IFA) or 18 vitamins and minerals including 250 µg/d iodine (MMN) or 20 g/d small-quantity lipid-based nutrient supplements (SQ-LNS) with similar nutrient contents as MMN group, plus macronutrients (LNS) until childbirth. In a sub-study (n 317), we evaluated group geometric mean urinary iodine concentration (UIC) (µg/L) at 36 weeks of gestation controlling for baseline UIC and compared median (baseline) and geometric mean (36 weeks) UIC with WHO cut-offs: UIC < 150, 150-249, 250-499 and ≥500 reflecting insufficient, adequate, above requirements and excessive iodine intakes, respectively. SETTING: Mangochi District, Malawi. PARTICIPANTS: Women ≤20 weeks pregnant. RESULTS: Groups had comparable background characteristics. At baseline, overall median (Q1, Q3) UIC (319 (167, 559)) suggested iodine intakes above requirements. At 36 weeks, the geometric mean (95 % CI) UIC of the IFA (197 (171, 226)), MMN (212 (185, 243)) and LNS (220 (192, 253)) groups did not differ (P = 0·53) and reflected adequate intakes. CONCLUSIONS: In this setting, provision of supplements containing iodine at the recommended dose to pregnant women with relatively high iodine intakes at baseline, presumably from iodised salt, has no impact on the women's UIC. Regular monitoring of the iodine status of pregnant women in such settings is advisable. Clinicaltrials.gov identifier: NCT01239693.

Provision of Lipid-Based Nutrient Supplements to Mothers During Pregnancy and 6 Months Postpartum and to Their Infants from 6 to 18 Months Promotes Infant Gut Microbiota Diversity at 18 Months of Age but Not Microbiota Maturation in a Rural Malawian Setting: Secondary Outcomes of a Randomized Trial.

BACKGROUND: Diet may alter the configuration of gut microbiota, but the impact of prenatal and postnatal nutritional interventions on infant gut microbiota has not been investigated. OBJECTIVE: We evaluated whether providing lipid-based nutrient supplements (LNSs) to mother-infant dyads promotes a more diverse and mature infant gut microbiota, compared to maternal supplementation with multiple micronutrients (MMN) or iron and folic acid (IFA). METHODS: We enrolled 869 pregnant women in a randomized trial in Malawi. There were 3 study groups, with women receiving 1 MMN capsule daily during pregnancy and 6 mo postpartum, or 1 LNS sachet (20 g) daily during pregnancy and 6 mo postpartum, or 1 IFA capsule daily (during pregnancy) then a placebo daily (postpartum). Infants in the LNS group received LNS from 6 to 18 mo; infants in the other groups did not receive supplements. The infants' fecal microbiota were characterized by PCR amplification and sequencing of the bacterial 16S rRNA gene (variable region 4). The primary outcomes were microbiota α diversity and maturation [as microbiota-for-age z score (MAZ)]. Specific associations of taxa with intervention were established with indicator species analysis (ISA). RESULTS: Primary outcomes did not differ between IFA and MMN groups, so these groups were combined (IFA + MMN). Mean ± SD α diversity was higher in the LNS group at 18 mo for Shannon index [3.01 ± 0.57 (LNS) compared with 2.91 ± 0.60 (IFA + MMN), P = 0.032] and Pielou's evenness index [0.61 ± 0.08 (LNS) compared with 0.60 ± 0.09 (IFA + MMN), P = 0.043]; no significant differences were observed at 1, 6, 12, or 30 mo. MAZ and ß diversity did not differ at any age. We found 10 and 3 operational taxonomic units (OTUs) positively associated with LNS and IFA + MMN, respectively; however, these associations became nonsignificant following false discovery rate correction at 10%. CONCLUSIONS: Prenatal and postnatal LNS intake promoted infant gut microbiota diversity at 18 mo, after 12 mo of child supplementation, but did not alter microbiota maturation. This trial was registered at clinicaltrials.gov as NCT01239693.

Effect of multi-pronged interventions in reducing low birth weight and maternal anaemia among pregnant women. A community-based interventions research in non-agrarian resource constrained setting of rural Pakistan.

OBJECTIVE: To investigate the effect on maternal and infant health of iron plus folate and multiple micronutrient supplements, along with deworming and health education session provided to pregnant women in rural, nonagrarian and food-insecure areas. METHODS: The quasi-experimental study was conducted in Tharparker and Umerkot districts, Sindh, Pakistan, in 2013-14, and comprised pregnant women in their earlier weeks of pregnancy. The enrolment and follow-up phase entailed 3 visits to each subject. Areas covered by lady health workers were designated as intervention areas, and those with non-LHW population were labelled as non-intervention areas. RESULTS: Of the 1204 subjects, 600(49.8%) were in the intervention group and 604(50.2%) were in the nonintervention group. By the end of the follow-up phase, significantly more women had increased number of meals in the intervention group compared to the non-intervention group (p<0.001). There was a significantly higher increase in mean haemoglobin levels and body mass index of women in the intervention arm after 3 and 6 months of interventions (p<0.05). Significantly higher mean birth weight was recorded in intervention areas compared to nonintervention areas (p<0.05). CONCLUSIONS: Community-based provision of multiple micronutrients to women along with deworming, health education and dietary counselling significantly reduced the prevalence of anaemia and reduced the incidence of low birth weight.

Acknowledging the gap: a systematic review of micronutrient supplementation in infants under six months of age.

Background: Micronutrient deficiencies remain common worldwide, but the consequences to growth and development in early infancy (under six months of age) are not fully understood. We present a systematic review of micronutrient interventions in term infants under six months of age, with a specific focus on iron supplementation. Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid) and Embase (Ovid) from January 1980 through December 2019. Interventions included iron or multiple micronutrients (MMNs). Results: Of 11,109 records identified, 33 publications from 24 trials were included (19 iron and five MMN supplementation trials). All but one trial (evaluating only morbidity and mortality) evaluated the effect of supplementation on biochemical outcomes, ten reported on growth, 15 on morbidity and/or mortality and six on neuro-behavioural development. Low- and middle- income countries made up 88% (22/25) of the total trial locations. Meta-analysis was not possible due to extensive heterogeneity in both exposure and outcome measures.  However, these trials indicated that infants less than six months of age benefit biochemically from early supplementation with iron, but the effect of additional nutrients or MMNs, along with the impacts on growth, morbidity and/or mortality, and neuro-behavioural outcomes remain unclear. Conclusions: Infants less than six months of age appear to benefit biochemically from micronutrient supplementation. However, well-powered randomised controlled trials are required to determine whether routine supplementation with iron or MMNs containing iron should commence before six months of life in exclusively breast-fed infants in low-resource settings.

Maternal Multiple Micronutrient Supplementation Stabilizes Mitochondrial DNA Copy Number in Pregnant Women in Lombok, Indonesia.

BACKGROUND: The Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) in Lombok, Indonesia showed that maternal multiple micronutrients (MMN), as compared with iron and folic acid (IFA), reduced fetal loss, early infant mortality, and low birth weight. Mitochondria play a key role during pregnancy by providing maternal metabolic energy for fetal development, but the effects of maternal supplementation during pregnancy on mitochondria are not fully understood. OBJECTIVE: The aim of this study was to assess the impact of MMN supplementation on maternal mitochondrial DNA copy number (mtDNA-CN). METHODS: We used archived venous blood specimens from pregnant women enrolled in the SUMMIT study. SUMMIT was a cluster-randomized double-blind controlled trial in which midwives were randomly assigned to distribute MMN or IFA to pregnant women. In this study, we selected 108 sets of paired baseline and postsupplementation samples (MMN = 54 and IFA = 54). Maternal mtDNA-CN was determined by real-time quantitative polymerase chain reaction in baseline and postsupplementation specimens. The association between supplementation type and change in mtDNA-CN was performed using rank-based estimation for linear models. RESULTS: In both groups, maternal mtDNA-CN at postsupplementation was significantly elevated compared with baseline (P < 0.001). The regression revealed that the MMN group had lower postsupplementation mtDNA-CN than the IFA group (ß = -4.63, P = 0.003), especially for women with mtDNA-CN levels above the median at baseline (ß = -7.49, P = 0.007). This effect was rapid, and observed within 33 d of initiation of supplementation (ß = -7.39, P = 0.017). CONCLUSION: Maternal MMN supplementation rapidly stabilized mtDNA-CN in pregnant women who participated in SUMMIT, indicating improved mitochondrial efficiency. The data provide a mechanistic basis for the beneficial effects of MMN on fetal growth and survival, and support the transition from routine IFA to MMN supplementation.This trial was registered at www.isrctn.com as ISRCTN34151616.