Risk factors for anaemia among women and their young children hospitalised with suspected thiamine deficiency in northern Lao PDR.

Anaemia among women and young children remains a major public health concern. This secondary study describes the anaemia prevalence among young hospitalised children and their mothers in northern Lao People's Democratic Republic and explores possible nutritional causes and risk factors for anaemia. Hospitalised children (ages 21 days to <18 months) with clinical symptoms suggestive of thiamine deficiency disorders were eligible along with their mothers. Venous blood was collected for determination of haemoglobin, ferritin, soluble transferrin receptor (sTfR), retinol-binding protein (RBP), erythrocyte glutathione reductase activation coefficient (EGRac), thiamine diphosphate (ThDP) and acute phase proteins. Risk factors for anaemia were modelled using minimally adjusted logistic regression controlling for age. Haemoglobin results were available for 436 women (mean ± SD age 24.7 ± 6.4 years; 1.6% pregnant) and 427 children (4.3 ± 3.5 months; 60.3% male). Anaemia prevalence (Hb < 120 g/L for nonpregnant women and <110 g/L for pregnant women and children) was 30.7% among women and 55.2% among children. In bivariate analyses, biomarkers significantly associated with anaemia in women were ferritin, sTfR, RBP, EGRac and ThDP. Other risk factors for women were lower BMI, mid-upper arm circumference < 23.5 cm, lower education, lower socioeconomic index, food insecurity, Hmong ethnicity, not/rarely having attended antenatal care, not having taken antenatal iron-containing supplements and not meeting minimum dietary diversity. Risk factors for anaemia among children were older age, male sex, stunting, sTfR, ThDP and alpha-1-acid-glycoprotein. Anaemia was common among women and their hospitalised children and was associated with micronutrient deficiencies and socioeconomic, dietary and health care-seeking risk factors, suggesting that multiple strategies are required to prevent anaemia among women and children.

Improving Anemia Assessment in Clinical and Public Health Settings.

We aim to provide a practical approach to assess anemia and its primary causes, both in clinical settings and in the context of public health programs. Anemia remains a global challenge; thus, to achieve goals for anemia reduction and assess progress, standardized approaches are required for the assessment of anemia and its causes. We first provide a brief review of how to assess anemia, based on hemoglobin concentrations and cutoffs that correspond to age, sex, and physiologic status. Next, we discuss how to assess the likely causes of anemia in different settings. The causes of anemia are classified as non-nutritional (for example, because of infection, inflammation, blood loss, or genetic disorders) or nutrition-specific (for example, because of deficiencies of iron, vitamin A, riboflavin, vitamin B12, or folate). There is an important overlap between these 2 categories, such as the increased likelihood of iron deficiency in the context of inflammation. Given the multifaceted nature of anemia etiology, we introduce a framework for anemia assessment based on the "ecology of anemia," which recognizes its many overlapping causes. This conceptual framework is meant to inform what data on anemia causes may need to be collected in population surveys. The framework has a supporting table with information on the diagnostic tests, biomarkers and proposed cutoffs, characteristics, and feasibility of collecting the myriad information that can help elucidate the anemia etiology. We also provide examples of how this framework can be applied to interpret the anemia risk factor data from population-based surveys that can inform decisions about context-specific interventions. Finally, we present research gaps and priorities related to anemia assessment.

Child wasting and concurrent stunting in low- and middle-income countries.

Sustainable Development Goal 2.2-to end malnutrition by 2030-includes the elimination of child wasting, defined as a weight-for-length z-score that is more than two standard deviations below the median of the World Health Organization standards for child growth1. Prevailing methods to measure wasting rely on cross-sectional surveys that cannot measure onset, recovery and persistence-key features that inform preventive interventions and estimates of disease burden. Here we analyse 21 longitudinal cohorts and show that wasting is a highly dynamic process of onset and recovery, with incidence peaking between birth and 3 months. Many more children experience an episode of wasting at some point during their first 24 months than prevalent cases at a single point in time suggest. For example, at the age of 24 months, 5.6% of children were wasted, but by the same age (24 months), 29.2% of children had experienced at least one wasting episode and 10.0% had experienced two or more episodes. Children who were wasted before the age of 6 months had a faster recovery and shorter episodes than did children who were wasted at older ages; however, early wasting increased the risk of later growth faltering, including concurrent wasting and stunting (low length-for-age z-score), and thus increased the risk of mortality. In diverse populations with high seasonal rainfall, the population average weight-for-length z-score varied substantially (more than 0.5 z in some cohorts), with the lowest mean z-scores occurring during the rainiest months; this indicates that seasonally targeted interventions could be considered. Our results show the importance of establishing interventions to prevent wasting from birth to the age of 6 months, probably through improved maternal nutrition, to complement current programmes that focus on children aged 6-59 months.

Early-childhood linear growth faltering in low- and middle-income countries.

Globally, 149 million children under 5 years of age are estimated to be stunted (length more than 2 standard deviations below international growth standards)1,2. Stunting, a form of linear growth faltering, increases the risk of illness, impaired cognitive development and mortality. Global stunting estimates rely on cross-sectional surveys, which cannot provide direct information about the timing of onset or persistence of growth faltering-a key consideration for defining critical windows to deliver preventive interventions. Here we completed a pooled analysis of longitudinal studies in low- and middle-income countries (n = 32 cohorts, 52,640 children, ages 0-24 months), allowing us to identify the typical age of onset of linear growth faltering and to investigate recurrent faltering in early life. The highest incidence of stunting onset occurred from birth to the age of 3 months, with substantially higher stunting at birth in South Asia. From 0 to 15 months, stunting reversal was rare; children who reversed their stunting status frequently relapsed, and relapse rates were substantially higher among children born stunted. Early onset and low reversal rates suggest that improving children's linear growth will require life course interventions for women of childbearing age and a greater emphasis on interventions for children under 6 months of age.

Causes and consequences of child growth faltering in low-resource settings.

Growth faltering in children (low length for age or low weight for length) during the first 1,000 days of life (from conception to 2 years of age) influences short-term and long-term health and survival1,2. Interventions such as nutritional supplementation during pregnancy and the postnatal period could help prevent growth faltering, but programmatic action has been insufficient to eliminate the high burden of stunting and wasting in low- and middle-income countries. Identification of age windows and population subgroups on which to focus will benefit future preventive efforts. Here we use a population intervention effects analysis of 33 longitudinal cohorts (83,671 children, 662,763 measurements) and 30 separate exposures to show that improving maternal anthropometry and child condition at birth accounted for population increases in length-for-age z-scores of up to 0.40 and weight-for-length z-scores of up to 0.15 by 24 months of age. Boys had consistently higher risk of all forms of growth faltering than girls. Early postnatal growth faltering predisposed children to subsequent and persistent growth faltering. Children with multiple growth deficits exhibited higher mortality rates from birth to 2 years of age than children without growth deficits (hazard ratios 1.9 to 8.7). The importance of prenatal causes and severe consequences for children who experienced early growth faltering support a focus on pre-conception and pregnancy as a key opportunity for new preventive interventions.

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.

Women in Selected Communities of Punjab, India Have a High Prevalence of Iron, Zinc, Vitamin B12, and Folate Deficiencies: Implications for a Multiply-Fortified Salt Intervention.

Dietary intake and biomarkers of micronutrient status of 100 non-pregnant women of reproductive age (NPWRA) were assessed to determine optimal levels of iron, zinc, vitamin B12, and folic acid to include in multiply-fortified salt (MFS) that will be evaluated in an upcoming trial. Weighed food records were obtained from participants to measure intake of micronutrients and discretionary salt, and to assess adequacy using Indian Nutrient Reference Values (NRVs). Statistical modeling was used to determine optimal fortification levels to reduce inadequate micronutrient intake while limiting intake above the upper limit. Fasting blood samples were obtained to assess iron, zinc, vitamin B12, and folate status. In usual diets, inadequate intake of iron (46%), zinc (95%), vitamin B12 (83%), and folate (36%) was high. Mean intake of discretionary salt was 4.7 g/day. Prevalence estimates of anemia (37%), iron deficiency (67%), zinc deficiency (34%), vitamin B12 insufficiency (37%), and folate insufficiency (70%) were also high. Simulating the addition of optimized MFS to usual diets resulted in percentage point (pp) reductions in inadequate intake by 29 pp for iron, 76 pp for zinc, 81 pp for vitamin B12, and 36 pp for folate. MFS holds potential to reduce the burden of micronutrient deficiencies in this setting.

Maternal and child nutrition in the Lives Saved Tool: Results of a recent update.

Background: The Lives Saved Tool (LiST) is a mathematical modelling tool for estimating the survival, health, and nutritional impacts of scaling intervention coverage in low- and middle-income countries (LMICs). Various nutrition interventions are included in LiST and are regularly (and independently) reviewed and updated as new data emerge. This manuscript describes our latest in-depth review of nutrition evidence, focusing on intervention efficacy, appropriate population-affected fractions, and new interventions for potential inclusion in the LiST model. Methods: An external advisory group (EAG) was assembled to review evidence from systematic reviews on intervention-outcome (I-O) pairs for women and children under five years of age. GRADE quality was assigned to each pair based on a LiST-specific checklist to facilitate consistent decisions during the consideration. For existing interventions with new information, the EAG was asked to recommend whether to update the default efficacy values and population-affected fractions. For the new interventions, the EAG decided whether there was sufficient evidence of benefit, and in affirmative cases, information on the efficacy and affected fraction values that could be used. Decisions were based on expert group consensus. Results: Overall, the group reviewed 53 nutrition-related I-O pairs, including 25 existing and 28 new ones. Efficacy and population-affected fractions were updated for seven I-O pairs; three pairs were updated for efficacy estimates only, three were updated for population-affected fractions only; and nine new I-O pairs were added to the model, bringing the total of nutrition-related I-O pairs to 34. Included in the new I-O pairs were two new nutrition interventions added to LIST: zinc fortification and neonatal vitamin A supplementation. Conclusions: For modelling tools like LiST to be useful, it is crucial to update interventions, efficacy and population-affected fractions as new evidence becomes available. The present updates will enable LiST users to better estimate the potential health, nutrition, and survival benefits of investing in nutrition.

Filipino Children with High Usual Vitamin A Intakes and Exposure to Multiple Sources of Vitamin A Have Elevated Total Body Stores of Vitamin A But Do Not Show Clear Evidence of Vitamin A Toxicity.

Background: Young children exposed to high-dose vitamin A supplements (VAS) and vitamin A (VA)-fortified foods may be at risk of high VA intake and high VA total body stores (TBS). Objectives: TBS and estimated liver VA concentration were compared among children with adequate or high VA intake and different timing of exposure to VAS, and associations between estimated liver VA concentrations and biomarkers of VA toxicity were examined. Methods: Children 12-18 mo of age (n = 123) were selected for 3 groups: 1) retinol intake >600 µg/d and VAS within the past mo, 2) retinol intake >600 µg/d and VAS in the past 3-6 mo, and 3) VA intake 200-500 µg retinol activity equivalents (RAE)/d and VAS in the past 3-6 mo. Dietary intake data were collected to measure VA intakes from complementary foods, breast milk, and low-dose, over-the-counter supplements. TBS were assessed by retinol isotope dilution, and VA toxicity biomarkers were measured. Main outcomes were compared by group. Results: Mean (95% CI) VA intakes excluding VAS were 1184 (942, 1426), 980 (772, 1187), and 627 (530, 724) µg RAE/d, in groups 1-3, respectively; mean VA intake was higher in groups 1 and 2 compared with group 3 (P < 0.05). Geometric mean (GM) (95% CI) TBS were 589 (525, 661), 493 (435, 559), and 466 (411, 528) µmol, respectively. GM TBS and GM liver VA concentrations were higher in group 1 compared with group 3 (liver VA concentration: 1.62 vs. 1.33 µmol/g; P < 0.05). Plasma retinyl ester and 4-oxo-retinoic acid concentrations and serum markers of bone turnover and liver damage did not indicate VA toxicity. Conclusions: In this sample, most children had retinol intakes above the Tolerable Upper Intake Level (UL) and liver VA concentrations above the proposed cutoff for "hypervitaminosis A" (>1 µmol/g liver). There was no evidence of chronic VA toxicity, suggesting that the liver VA cutoff value should be re-evaluated. This trial was registered at www.clinicaltrials.gov as NCT03030339.

Quintuply-fortified salt for the improvement of micronutrient status among women of reproductive age and preschool-aged children in Punjab, India: protocol for a randomized, controlled, community-based trial.

BACKGROUND: Multiple micronutrient (MN) deficiencies remain highly prevalent among women of reproductive age (WRA) and preschool-aged children (PSC) in many areas within India. Salt is an attractive vehicle for MN fortification in this context, as it is universally consumed in fairly consistent amounts and coverage of iodized salt (IS) is 94%. The overall objective of this trial is to evaluate the nutritional impact of quintuply-fortified salt with iron in the form of encapsulated ferrous fumarate, zinc, vitamin B12, folic acid, and iodine (eFF-Q5S) vs. quintuply-fortified salt with iron in the form of ferric pyrophosphate plus EDTA, zinc, vitamin B12, folic acid, and iodine (FePP-Q5S) vs. IS for the improvement of MN status among non-pregnant WRA and PSC. METHODS: The study is a community-based, randomized, controlled trial that will be conducted in Punjab, India. 780 non-pregnant WRA 18-49 years old and 468 PSC 12-59 months old will be enrolled and assigned to one of three intervention groups. Salt will be provided to participants monthly for 12 months. Primary outcomes include changes in mean concentration of biomarkers of iron, zinc, vitamin B12, folate and iodine. Secondary outcomes include changes in the composition of the gut microbiome, and discretionary salt intake of PSC. DISCUSSION: If proven efficacious, multiply-fortified salt (MFS) has the potential to drastically reduce the burden of MN deficiencies in India, and around the world. Although effectiveness research will be needed to examine the impact of MFS under programmatic conditions, salt fortification will piggy-back on existing platforms to produce IS and doubly-fortified salt (DFS), making it possible to scale-up the intervention quickly. TRIAL REGISTRATION: Clinicaltrials.gov: NCT05166980; date of registration: December 22, 2021. Clinical Trials Registry-India: CTRI/2022/040332 and CTRI/2022/02/040333; date of registration: February 15, 2022.

Preventive small-quantity lipid-based nutrient supplements reduce severe wasting and severe stunting among young children: an individual participant data meta-analysis of randomized controlled trials.

BACKGROUND: Meta-analyses show that small-quantity lipid-based nutrient supplements (SQ-LNSs) reduce child wasting and stunting. There is little information regarding effects on severe wasting or stunting. OBJECTIVES: We aimed to identify the effect of SQ-LNSs on prevalence of severe wasting (weight-for-length z score < -3) and severe stunting (length-for-age z score < -3). METHODS: We conducted a 2-stage meta-analysis of individual participant data from 14 randomized controlled trials of SQ-LNSs provided to children 6-24 mo of age. We generated study-specific and subgroup estimates of SQ-LNS compared with control and pooled the estimates using fixed-effects models. We used random-effects meta-regression to examine study-level effect modifiers. In sensitivity analyses, we examined whether results differed depending on study arm inclusion criteria and types of comparisons. RESULTS: SQ-LNS provision led to a relative reduction of 31% in severe wasting [prevalence ratio (PR): 0.69; 95% CI: 0.55, 0.86; n = 34,373] and 17% in severe stunting (PR: 0.83; 95% CI: 0.78, 0.90; n = 36,795) at endline. Results were similar in most of the sensitivity analyses but somewhat attenuated when comparisons using passive control arms were excluded (PR: 0.74; 95% CI: 0.57, 0.96; n = 26,327 for severe wasting and PR: 0.88; 95% CI: 0.81, 0.95; n = 28,742 for severe stunting). Study-level characteristics generally did not significantly modify the effects of SQ-LNSs, but results suggested greater effects of SQ-LNSs in sites with greater burdens of wasting or stunting, or with poorer water quality or sanitation. CONCLUSIONS: Including SQ-LNSs in preventive interventions to promote healthy child growth and development is likely to reduce rates of severe wasting and stunting. This meta-analysis was registered at www.crd.york.ac.uk/PROSPERO as CRD42019146592.

Small-quantity lipid-based nutrient supplements, with or without added zinc, do not cause excessive fat deposition in Burkinabe children: results from a cluster-randomized community trial.

PURPOSE: Public health interventions to address stunting and wasting should be evaluated for possibly contributing to obesity risk. The present study tested the hypothesis that small-quantity lipid-based nutrient supplements (SQ-LNS) might increase fat deposition, and that additional zinc provided via SQ-LNS or in the form of dispersible tablets would increase fat-free mass (FFM) accretion. METHODS: Using a two-stage, cluster-randomized trial design, 34 communities were randomly assigned to the intervention cohort (IC) or non-intervention cohort (NIC), and family compounds within the IC were randomly assigned to receive different amounts of zinc (0, 5 or 10 mg zinc) incorporated in SQ-LNS or 5 mg zinc in the form of dispersible tablets along with treatment for diarrhea, malaria and fever. Body composition was assessed in a subset of IC (n = 201) and NIC (n = 74) children at 9 and 18 months using the deuterium dilution method. A mixed linear model was used to examine average change in FFM and % fat mass (%FM) among intervention groups and by cohort. RESULTS: Children in the IC had significantly greater change in FFM (Mean (95% Confidence Interval)) (1.57 (1.49, 1.64) kg) compared to the NIC (1.35 (1.23, 1.46) kg; p = 0.005). There were no significant differences in the change in %FM between the NIC and IC or among the intervention groups. CONCLUSION: SQ-LNS, along with morbidity treatment increased weight gain and FFM in young children from 9 to 18 months of age without increasing FM deposition. Additional zinc supplementation did not affect changes in FFM or %FM. TRIAL REGISTRATION: The study was registered as a clinical trial with the US National Institute of Health ( www. CLINICALTRIALS: gov ; NCT00944281).

Reconsidering the Tolerable Upper Levels of Zinc Intake among Infants and Young Children: A Systematic Review of the Available Evidence.

Safe upper levels (UL) of zinc intake for children were established based on either (1) limited data from just one study among children or (2) extrapolations from studies in adults. Resulting ULs are less than amounts of zinc consumed by children in many studies that reported benefits of zinc interventions, and usual dietary zinc intakes often exceed the UL, with no apparent adverse effects. Therefore, existing ULs may be too low. We conducted a systematic bibliographic review of studies among preadolescent children, in which (1) additional zinc was provided vs. no additional zinc provided, and (2) the effect of zinc on serum or plasma copper, ceruloplasmin, ferritin, transferrin receptor, lipids, or hemoglobin or erythrocyte super-oxide dismutase were assessed. We extracted data from 44 relevant studies with 141 comparisons. Meta-analyses found no significant overall effect of providing additional zinc, except for a significant negative effect on ferritin (p = 0.001), albeit not consistent in relation to the zinc dose. Interpretation is complicated by the significant heterogeneity of results and uncertainties regarding the physiological and clinical significance of outcomes. Current zinc ULs should be reassessed and potentially revised using data now available for preadolescent children and considering challenges regarding interpretation of results.

Barriers to and Enablers of the Inclusion of Micronutrient Biomarkers in National Surveys and Surveillance Systems in Low- and Middle-Income Countries.

Including biomarkers of micronutrient status in existing or planned national surveys or surveillance systems is a critical step in improving capacity to promote, design, monitor, and evaluate micronutrient policies and programs. We aimed to identify the barriers to and enablers of the inclusion of micronutrient biomarker assessment in national surveys and surveillance systems, to identify the main challenges faced during the survey process, and to review experiences using existing platforms for micronutrient surveys. We conducted a series of key informant interviews with in-country and external representatives from six countries where national-level data on micronutrient status were collected in the past 5 years: Cambodia, Pakistan, Malawi, Uganda, Ghana, and Uzbekistan. Micronutrients associated with specific public health programs were always prioritized for inclusion in the survey. If funding, time, and/or logistics allowed, other considered micronutrients were also included. The most important and frequently reported barrier to inclusion of a more comprehensive panel of micronutrient biomarkers was inadequate funding to cover the laboratory analysis cost for all micronutrients considered at the planning stage. Government support and commitment was stressed as the most important enabling factor by all key informants. Advocacy for funding for micronutrient status assessment is needed.

Applying Zinc Nutrient Reference Values as Proposed by Different Authorities Results in Large Differences in the Estimated Prevalence of Inadequate Zinc Intake by Young Children and Women and in Cameroon.

Nutrient reference values (NRVs) for zinc set by several expert groups differ widely and may affect the predicted prevalence of inadequate zinc intake. We examined this possibility using NRVs published by four different authorities and nationally representative dietary intake data collected among children aged 12-59 months and women in Cameroon. Usual zinc intake was estimated from 24 h recall data using the National Cancer Institute method. Prevalences of total zinc intake below the dietary requirement and of "absorbable zinc intake" below the physiological requirement were estimated using NRVs published by the World Health Organization (WHO), US Institute of Medicine (IOM), International Zinc Nutrition Consultative Group (IZiNCG), and European Food Safety Authority (EFSA). The prevalence of inadequate zinc intake ranged from 10% (IZiNCG-physiological requirement, 95% CI 7-13%) to 81% (EFSA-physiological requirement, 95% CI 78-84%) among children and 9% (WHO-physiological requirement, 95% CI 8-11.0%) to 94% (IOM-physiological requirement, 95% CI 92-95%) among women These differences in the prevalence of inadequate intake translated into sizeable differences in the predicted benefit and cost-effectiveness of zinc fortification programs. Depending on the NRVs applied, assessments differ regarding the need for and design of zinc fortification programs. Efforts are needed to harmonize NRVs for zinc.

Basis for changes in the disease burden estimates related to vitamin A and zinc deficiencies in the 2017 and 2019 Global Burden of Disease Studies.

BACKGROUND: The Global Burden of Disease (GBD) Study provides estimates of death and disability from eighty-seven risk factors, including some micronutrient deficiencies. OBJECTIVES: To review methodological changes that led to large differences in the disease burden estimates for vitamin A and Zn deficiencies between the GBD 2017 and 2019 Studies. METHODS: GBD publications were reviewed; additional information was provided by GBD researchers. RESULTS: Vitamin A deficiency prevalence is based on plasma retinol concentration, whereas the estimate for Zn deficiency prevalence uses dietary adequacy as a proxy. The estimated global prevalence of vitamin A deficiency for children aged 1-4 years in the year 2017 decreased from 0·20 (95 % CI 0·17, 0·24) in GBD 2017 to 0·16 (95 % CI 0·15, 0·19) in GBD 2019, while the global prevalence of Zn deficiency did not change between the two studies (0·09 (95 % CI 0·04, 0·17) and 0·09 (95 % CI 0·03, 0·18)). New to 2019 was that meta-analyses were performed using Meta Regression - Bayesian, Regularized, Trimmed, a method developed for GBD. Due to this and multiple other methodological changes, the estimated number of deaths due to vitamin A deficiency dropped from 233 000 (179 000-294 000) to 24 000 (3000-50 000) from GBD 2017 to 2019, and for Zn deficiency from 29 000 (1000-77 000) to 2800 (700-6500), respectively. CONCLUSION: The changes in the estimated disease burdens due to vitamin A and Zn deficiencies in the GBD reports from 2017 to 2019 are due primarily to changes in the analytical methods employed, so may not represent true changes in disease burden. Additional effort is needed to validate these results.

Characteristics that modify the effect of small-quantity lipid-based nutrient supplementation on child anemia and micronutrient status: an individual participant data meta-analysis of randomized controlled trials.

BACKGROUND: Small-quantity lipid-based nutrient supplements (SQ-LNSs) have been shown to reduce the prevalence of child anemia and iron deficiency, but effects on other micronutrients are less well known. Identifying subgroups who benefit most from SQ-LNSs could support improved program design. OBJECTIVES: We aimed to identify study-level and individual-level modifiers of the effect of SQ-LNSs on child hemoglobin (Hb), anemia, and inflammation-adjusted micronutrient status outcomes. METHODS: We conducted a 2-stage meta-analysis of individual participant data from 13 randomized controlled trials of SQ-LNSs provided to children 6-24 mo of age (n = 15,946). We generated study-specific and subgroup estimates of SQ-LNSs compared with control, and pooled the estimates using fixed-effects models. We used random-effects meta-regression to examine potential study-level effect modifiers. RESULTS: SQ-LNS provision decreased the prevalence of anemia (Hb < 110 g/L) by 16% (relative reduction), iron deficiency (plasma ferritin < 12 µg/L) by 56%, and iron deficiency anemia (IDA; Hb < 110 g/L and plasma ferritin <12 µg/L) by 64%. We observed positive effects of SQ-LNSs on hematological and iron status outcomes within all subgroups of the study- and individual-level effect modifiers, but effects were larger in certain subgroups. For example, effects of SQ-LNSs on anemia and iron status were greater in trials that provided SQ-LNSs for >12 mo and provided 9 (as opposed to <9) mg Fe/d, and among later-born (than among first-born) children. There was no effect of SQ-LNSs on plasma zinc or retinol, but there was a 7% increase in plasma retinol-binding protein (RBP) and a 56% reduction in vitamin A deficiency (RBP < 0.70 µmol/L), with little evidence of effect modification by individual-level characteristics. CONCLUSIONS: SQ-LNSs can substantially reduce the prevalence of anemia, iron deficiency, and IDA among children across a range of individual, population, and study design characteristics. Policy-makers and program planners should consider SQ-LNSs within intervention packages to prevent anemia and iron deficiency.This trial was registered at www.crd.york.ac.uk/PROSPERO as CRD42020156663.