Effects of prenatal small-quantity lipid-based nutrient supplements on pregnancy, birth, and infant outcomes: a systematic review and meta-analysis of individual participant data from randomized controlled trials in low- and middle-income countries.

BACKGROUND: Undernutrition during pregnancy increases the risk of giving birth to a small vulnerable newborn. Small-quantity lipid-based nutrient supplements (SQ-LNSs) contain both macro- and micronutrients and can help prevent multiple nutritional deficiencies. OBJECTIVES: We examined the effects of SQ-LNSs provided during pregnancy compared with 1) iron and folic acid or standard of care (IFA/SOC) or 2) multiple micronutrient supplements (MMSs) and identified characteristics that modified the estimates of effects of SQ-LNSs on birth outcomes. METHODS: We conducted a 2-stage meta-analysis of individual participant data from 4 randomized controlled trials of SQ-LNSs provided during pregnancy (n = 5273). We generated study-specific and subgroup estimates of SQ-LNS compared with IFA/SOC or MMS and pooled the estimates. In sensitivity analyses, we examined whether the results differed depending on methods for gestational age dating, birth anthropometry, or study design. RESULTS: SQ-LNSs (compared with IFA/SOC) increased birth weight [mean difference: +49 g; 95% confidence interval (CI): 26, 71 g] and all birth anthropometric z-scores (+0.10-0.13 standard deviation); they reduced risk of low birth weight by 11%, newborn stunting by 17%, newborn wasting by 11%, and small head size by 15%. Only 2 trials compared SQ-LNSs and MMSs; P values for birth outcomes were >0.10 except for head circumference (e.g., z-score for gestational age: +0.11; 95% CI: -0.01, 0.23). Effect estimates for SQ-LNSs compared with IFA/SOC were greater among female infants and, for certain outcomes, among mothers with body mass index <20 kg/m2, inflammation, malaria, or household food insecurity. Effect estimates for SQ-LNSs compared with MMSs were greater for certain outcomes among female infants, first-born infants, and mothers <25 y. CONCLUSIONS: SQ-LNSs had positive impacts on multiple outcomes compared to IFA/SOC, but further research directly comparing SQ-LNSs and MMSs is needed. Targeting SQ-LNSs to vulnerable subgroups may be worth considering. CLINICAL TRIAL REGISTRY: This study was registered at PROSPERO as CRD42021283391.

Perinatal intervention strategies providing food with micronutrients to pregnant and breastfeeding women in low- and middle-income countries: A scoping review.

In resource-constrained settings, pregnant and breastfeeding women and girls (PBW/G) are particularly vulnerable to undernutrition. Micronutrient-fortified balanced energy protein (BEP) supplementation may be provided to boost maternal nutritional status and improve birth and infant outcomes. We conducted a scoping review of the published literature to determine the impact of BEP and other related nutrition interventions that provided fortified food or cash along with a minimum of 3 micronutrients on maternal, birth, and infant/child outcomes in low- and middle-income countries. We conducted a PubMed search using pre-defined keywords and controlled vocabulary search terms. All titles and abstracts were reviewed for eligibility by two independent reviewers, and data were extracted according to outcome type. We identified 149 eligible research articles that reported on a total of 21 trials and/or programme evaluations which assessed the health impact of one or more products (fortified lipid-based nutrient supplement [LNS, n = 12], fortified blended flours [n = 5], milk-based beverages [n = 2], and local food/snacks [n = 3]) that provided 118-750 kcal/day and varying levels of protein and micronutrients. Only one of these programme evaluations assessed the impact of the provision of cash and fortified food. Effects on maternal outcomes such as gestational weight gain and duration of gestation were promising but inconsistent. Birth outcomes were reported in 15 studies, and the effects on birthweight and birth length were generally positive. Seven studies demonstrated sustained benefits on infant and child growth out of the 15 studies that reported at least one of these outcomes, although data were sparse. Additional research is needed to investigate issues of dose, cost-effectiveness, and incorporation into multi-component interventions.

Mandatory large-scale food fortification programmes can reduce the estimated prevalence of inadequate zinc intake by up to 50% globally.

Large-scale food fortification (LSFF) can increase dietary micronutrient intake and improve micronutrient status. Here we used food balance sheet data from the Food and Agriculture Organization of the United Nations to estimate current country-specific prevalences of inadequate zinc intake. We assessed the potential effects of improving existing LSFF programmes for cereal grains or implementing new programmes in 40 countries where zinc deficiency is a potential public health problem. Accounting for LSFF programmes as currently implemented, 15% of the global population (1.13 billion individuals) is estimated to have inadequate zinc intake. In countries where zinc deficiency is a potential public health problem, the implementation of high-quality mandatory LSFF programmes that include zinc as a fortificant would substantially increase the availability of zinc in the national food supply, reducing the estimated prevalence of inadequate zinc intake by up to 50% globally. Investments in strong LSFF programmes could have a substantial impact on population zinc status.

Effect of multiple micronutrient-fortified bouillon on micronutrient status among women and children in the Northern Region of Ghana: Protocol for the Condiment Micronutrient Innovation Trial (CoMIT), a community-based randomized controlled trial.

INTRODUCTION: Micronutrient deficiencies are prevalent in West Africa, particularly among women of reproductive age (WRA) and young children. Bouillon is a promising food fortification vehicle due to its widespread consumption. This study aims to evaluate the impact of multiple micronutrient-fortified bouillon cubes, compared to control bouillon cubes (fortified with iodine only), on micronutrient status and hemoglobin concentrations among lactating and non-lactating WRA and young children in northern Ghana. METHODS: This randomized, controlled doubly-masked trial will be conducted in the Kumbungu and Tolon districts in the Northern Region of Ghana, where prior data indicate multiple micronutrient deficiencies are common. Participants will be: 1) non-pregnant non-lactating WRA (15-49 y), 2) children 2-5 y, and 3) non-pregnant lactating women 4-18 months postpartum. Eligible participants will be randomly assigned to receive household rations of one of two types of bouillon cubes: 1) a multiple micronutrient-fortified bouillon cube containing vitamin A, folic acid, vitamin B12, iron, zinc, and iodine, or 2) a control cube containing iodine only. Each participant's household will receive a ration of bouillon cubes every 2 weeks, and households will be advised to prepare meals as usual, using the study-provided cubes. The trial duration will be 9 months for non-pregnant non-lactating WRA and children, and 3 months for lactating women. The primary outcomes will be changes in biomarkers of micronutrient status and hemoglobin among WRA and children and milk micronutrient concentrations among lactating women. Secondary outcomes will include change in prevalence of micronutrient deficiency and anemia; dietary intake of bouillon and micronutrients; inflammation, malaria, and morbidity symptoms; and child growth and development. DISCUSSION: Evidence from this study will inform discussions about bouillon fortification in Ghana and West Africa. TRIAL REGISTRATION: The trial was registered on ClinicalTrials.gov (NCT05178407) and the Pan-African Clinical Trial Registry (PACTR202206868437931). This manuscript reflects protocol version 4 (August 29, 2022).

Acceptability of Multiple Micronutrient-Fortified Bouillon Cubes among Women and Their Households in 2 Districts in The Northern Region of Ghana.

Background: Bouillon is a promising large-scale food fortification vehicle, but there is uncertainty regarding the types and concentrations of micronutrients that are feasible to add without compromising consumer acceptability. Objective: The objective of this study was to evaluate the acceptability of 2 different multiple micronutrient-fortified bouillon cube formulations, compared with a bouillon cube fortified with iodine only. Methods: We conducted a double-blind, randomized, controlled acceptability study in 2 districts in northern Ghana. Two nonproprietary, noncommercialized formulations of multiple micronutrient-fortified bouillon cubes containing iron, zinc, folic acid, vitamins A and B12, and iodine at "upper-level" (45-125% CODEX NRV/2.5g) or "lower-level" (15-50% CODEX NRV/2.5g) concentrations, and a control cube that contained iodine only (50% CODEX NRV/2.5g) were evaluated. Eligible women (n = 84) were invited to participate in 1) center-based sensory evaluations designed to permit within-individual comparisons among the different study products; and 2) in-home evaluation of bouillon acceptability and use, in which participants were randomized to receive 1 of the 3 study products to use in household cooking for a 2-wk period. Acceptance test ratings were based on a 5-point Likert scale (1 = dislike very much, 5 = like very much). Results: In the center-based evaluations, overall liking of the 3 bouillon cube formulations both dry and in prepared dishes ranged from 4.3 to 4.6 on the 5-point Likert scale and did not differ among formulations (P > 0.05). After the 2-wk in-home trial, 93.8% of index participants (n = 75/80) rated their overall liking of the bouillon product formulation to which they were randomly assigned as "like" or "like very much" (4-5 on the 5-point Likert scale) and median apparent intake of study-provided bouillon over 2 wk was 3.6 g/capita/d; neither value differed by study group (P = 0.91 for both). Conclusions: All 3 formulations of bouillon cubes assessed were acceptable to women and their households in 2 districts in northern Ghana.This trial was registered at www.clinicaltrials.gov as NCT05177614.

Consumption of Discretionary Salt and Salt from Bouillon among Households, Women, and Young Children in Northern Region, Ghana: A Mixed-Methods Study with the Condiment Micronutrient Innovation Trial (CoMIT) Project.

Background: Information on salt consumption patterns is needed to inform the need for and design of salt reduction strategies. Objectives: In northern Ghana, this study aimed to estimate household consumption of salt, including salt from bouillon, and compare (estimated) women and children's salt intake to global recommendations; to estimate the proportion of salt consumed from bouillon; and to identify factors, including knowledge, attitudes, and practices, associated with household salt consumption. Methods: Employing mixed-methods methodology, we conducted a pilot survey (n = 369 households enrolled) and focus group discussions (FGDs; n = 20) in Tolon and Kumbungu districts (14 urban, 14 rural clusters) (clinicaltrials.gov registry: NCT04632771). Households reported purchases of discretionary salt (DS, "table salt") and bouillon cubes. DS and total salt (TS; DS+salt from bouillon) consumption for women (15-49 y) and children (2-5 y) were estimated using the Adult Male Equivalent method and compared with global recommendations (<5 g/d women; <3.75 g/d children). Women's salt intake was also predicted from urinary sodium excretion (INTERSALT equation). Associations between DS and TS consumption, as well as household and women's characteristics, were tested with minimally adjusted and multivariable linear mixed-effects models. Qualitative FGD themes were generated using the Framework Method. Results: From household purchase data, estimated TS consumption exceeded global recommendations for 44% of children [median: 2.9 (IQR: 1.9, 5.2) g/d] and 60% of women [6.0 (4.0, 10.2) g/d]; 35% of children and 50% of women exceeded recommendations from DS alone. Bouillon contributed <25% of households' TS consumption. Few characteristics were associated with DS or TS consumption. Salient qualitative themes that shaped salt consumption behaviors included salt's ubiquity as a seasoning, key household members' influence on food procurement and preparation, and perceptions about health. Conclusions: Purchase data suggest salt consumption among women and children exceeds recommendations, even when excluding salt from bouillon; food prepared outside the home likely further contributes. Salt reduction interventions may be warranted in this context.

Lipid-based nutrient supplements for prevention of child undernutrition: when less may be more.

BACKGROUND: Both small-quantity and medium-quantity lipid-based nutrient supplements (LNS) have been used for the prevention of child undernutrition. A meta-analysis of 14 trials of small-quantity lipid-based nutrient supplements (SQ-LNS) - no LNS showed effects on length-for-age z-score {LAZ, +0.14 [95% confidence interval (CI): 0.11, 0.16]} and weight-for-length z-score [WLZ, +0.08 (0.06, 0.10)] z-scores, as well as prevalence ratios (95% CI) for stunting [LAZ < -2, 0.88 (0.85, 0.91)] and wasting [WLZ < -2, 0.86 (0.80, 0.93)]. However, little is known about the effects of medium-quantity lipid-based nutrient supplements (MQ-LNS) on growth. OBJECTIVES: We aimed to examine the effects of preventive MQ-LNS (∼250-499 kcal/d) provided at ∼6-23 mo of age on growth outcomes - no LNS or provision of SQ-LNS. METHODS: We conducted a systematic review of studies of MQ-LNS for prevention, and categorized them as providing <6 mo - ≥6 mo of supplementation; for the latter category, we conducted a meta-analysis, with the main outcomes being change in WLZ and LAZ, and prevalence of wasting and stunting. RESULTS: Three studies provided MQ-LNS for 3-5 mo (seasonal) for children 6-36 mo of age, and did not show consistent effects on growth outcomes. Eight studies provided MQ-LNS for 6-18 mo, generally starting at 6 mo of age; in the meta-analysis (max total n = 13,954), MQ-LNS increased WLZ [+0.09 (95% CI: 0.05, 0.13)] and reduced wasting [0.89 (0.81, 0.97)], but had no effect on LAZ [+0.04 (-0.02, 0.11)] or stunting [0.97 (0.92, 1.02)] - no LNS. Two studies directly compared SQ-LNS and MQ-LNS and showed no significant differences in growth outcomes. CONCLUSIONS: The current evidence suggests that MQ-LNS offer no added benefits over SQ-LNS, although further studies directly comparing MQ-LNS with SQ-LNS would be useful. One possible explanation is incomplete consumption of the MQ-LNS ration and thus lower than desirable intake of certain nutrients. TRIAL REGISTRATION NUMBER: Registry and registry number for systematic reviews or meta-analyses: Registered with PROSPERO as CRD42022382448 on December 18, 2022: =https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022382448.

Comparison of Published Estimates of the National Prevalence of Iron, Vitamin A, and Zinc Deficiency and Sources of Inconsistencies.

Micronutrient deficiencies result in a broad range of adverse health and functional consequences, but the true prevalence of specific deficiencies remains uncertain because limited information is available from nationally representative surveys using recommended biomarkers. The present review compares various reported national deficiency prevalence estimates for nutrients and years where the estimates overlap for individual countries that conducted nationally representative surveys and explores possible reasons for any discrepancies discovered. Nationally representative micronutrient status surveys that were conducted since 2000 among preschool-aged children or women of reproductive age and included assessment of iron, vitamin A, or zinc status based on recognized biomarkers were considered eligible for inclusion, along with any modeled deficiency prevalence estimates for these same countries and years. There was considerable variation across different published prevalence estimates, with larger inconsistencies when the prevalence estimate was based on proxies, such as hemoglobin for iron deficiency and dietary zinc availability for zinc deficiency. Numerous additional methodological issues affected the prevalence estimates, such as which biomarker and what cutoff was used to define deficiency, whether the biomarker was adjusted for inflammation, and what adjustment method was used. For some country-years, the various approaches resulted in fairly consistent prevalence estimates. For other country-years, however, the results differed markedly and changed the conclusions regarding the existence and severity of the micronutrient deficiency as a public health concern. In conclusion, to determine micronutrient status, we consider the assessment of one of the recommended biomarkers in a population representative survey as the best available information. If indicated, results should be adjusted for inflammation and generally acceptable cutoffs should be applied to facilitate comparisons, although individual countries may also apply nationally defined cutoffs to determine when and where to intervene. Global consensus is needed on best practices for presenting survey results and defining the prevalence of deficiency.

The cost-effectiveness of small-quantity lipid-based nutrient supplements for prevention of child death and malnutrition and promotion of healthy development: modelling results for Uganda.

OBJECTIVE: Recent meta-analyses demonstrate that small-quantity lipid-based nutrient supplements (SQ-LNS) for young children significantly reduce child mortality, stunting, wasting, anaemia and adverse developmental outcomes. Cost considerations should inform policy decisions. We developed a modelling framework to estimate the cost and cost-effectiveness of SQ-LNS and applied the framework in the context of rural Uganda. DESIGN: We adapted costs from a costing study of micronutrient powder (MNP) in Uganda, and based effectiveness estimates on recent meta-analyses and Uganda-specific estimates of baseline mortality and the prevalence of stunting, wasting, anaemia and developmental disability. SETTING: Rural Uganda. PARTICIPANTS: Not applicable. RESULTS: Providing SQ-LNS daily to all children in rural Uganda (> 1 million) for 12 months (from 6 to 18 months of age) via the existing Village Health Team system would cost ∼$52 per child (2020 US dollars) or ∼$58·7 million annually. SQ-LNS could avert an average of > 242 000 disability-adjusted life years (DALYs) annually as a result of preventing 3689 deaths, > 160 000 cases of moderate or severe anaemia and ∼6000 cases of developmental disability. The estimated cost per DALY averted is $242. CONCLUSIONS: In this context, SQ-LNS may be more cost-effective than other options such as MNP or the provision of complementary food, although the total cost for a programme including all age-eligible children would be high. Strategies to reduce costs, such as targeting to the most vulnerable populations and the elimination of taxes on SQ-LNS, may enhance financial feasibility.

Insulin-like Growth Factor 1 (IGF1), IGF Binding Protein-3 (IGFBP3) and Growth Response to Daily Zinc Supplementation: A Randomized Trial in Rural Laotian Children.

OBJECTIVES: To assess (a) the impact of daily preventive zinc tablets (7 mg; PZ), zinc-containing multiple micronutrient powder (10 mg zinc, and 13 other micronutrients; MNP) or placebo, delivered for 9 months, on Insulin-like Growth Factor 1 (IGF1) and IGF Binding Protein 3 (IGFBP3) among Laotian children 6-23 months, and (b) whether the effects of PZ and MNP on length-for-age z-scores (LAZ) and weight-for-age z-scores (WAZ) are modified by baseline IGF1 and IGFBP3. DESIGN: A double-blind, placebo-controlled trial (N = 419). METHODS: Plasma IGF1 and IGFBP3 concentrations at baseline and 36 weeks were analyzed by automated chemiluminescent assay. Anthropometry was assessed at baseline, at 18 and 36 weeks. Intervention effects were estimated using ANCOVA. RESULTS: At 36 weeks, geometric mean IGF1 (~39.0-39.2 ng/mL; p = 0.99) and IGFBP3 (2038-2076 ng/mL; p = 0.83) did not differ by group. At 18 weeks (but not at 36 weeks), LAZ in the PZ group (-1.45) was higher than the MNP (-1.70) and control (-1.55) groups (p = 0.01) among children in the highest baseline IGF1 tertile (p for interaction = 0.006). At 36 weeks (but not at 18 weeks), WAZ in the PZ group (-1.55) was significantly higher than the MNP (-1.75) and control (-1.65) groups (p = 0.03), among children in the lowest baseline IGFBP3 tertile (p for interactions = 0.06). CONCLUSIONS: Although IGF1 and IGFBP3 did not respond to PZ and MNP, baseline IGF1 and IGFBP3 significantly modified the impact of PZ on linear and ponderal growth, suggesting that IGF1 bioavailability may drive catch-up growth in zinc-supplemented children.