Large-scale food fortification (LSFF) is a cost-effective intervention that is widely implemented, but there is scope to further increase its potential. To identify gaps and opportunities, we first accessed the Global Fortification Data Exchange (GFDx) to identify countries that could benefit from new fortification programs. Second, we aggregated Fortification Assessment Coverage Toolkit (FACT) survey data from 16 countries to ascertain LSFF coverage and gaps therein. Third, we extended our narrative review to assess current innovations. We identified 84 countries as good candidates for new LSFF programs. FACT data revealed that the potential of oil/ghee and salt fortification is not being met due mainly to low coverage of adequately fortified foods (quality). Wheat, rice and maize flour fortification have similar quality issues combined with lower coverage of the fortifiable food at population-level (<50%). A four-pronged strategy is needed to meet the unfinished agenda: first, establish new LSFF programs where warranted; second, systems innovations informed by implementation research to address coverage and quality gaps; third, advocacy to form new partnerships and resources, particularly with the private sector; and finally, exploration of new fortificants and vehicles (e.g. bouillon cubes; salt fortified with multiple nutrients) and other innovations that can address existing challenges.

Meta-analyses show that small-quantity lipid-based nutrient supplements (SQ-LNSs) reduce child stunting and wasting. Identification of subgroups who benefit most from SQ-LNSs may facilitate program design. We aimed to identify study-level and individual-level modifiers of the effect of SQ-LNSs on child growth outcomes. 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 (n = 37,066). 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. SQ-LNS provision decreased stunting (length-for-age z score < −2) by 12% (relative reduction), wasting [weight-for-length (WLZ) z score < −2] by 14%, low midupper arm circumference (MUAC) (<125 mm or MUAC-for-age z score < −2) by 18%, acute malnutrition (WLZ < −2 or MUAC < 125 mm) by 14%, underweight (weight-for-age z score < −2) by 13%, and small head size (head circumference-for-age z score < −2) by 9%. Effects of SQ-LNSs generally did not differ by study-level characteristics including region, stunting burden, malaria prevalence, sanitation, water quality, duration of supplementation, frequency of contact, or average compliance with SQ-LNS. Effects of SQ-LNSs on stunting, wasting, low MUAC, and small head size were greater among girls than among boys; effects on stunting, underweight, and low MUAC were greater among later-born (than among firstborn) children; and effects on wasting and acute malnutrition were greater among children in households with improved (as opposed to unimproved) sanitation. The positive impact of SQ-LNSs on growth is apparent across a variety of study-level contexts. Policy-makers and program planners should consider including SQ-LNSs in packages of interventions to prevent both stunting and wasting. This trial was registered at www.crd.york.ac.uk/PROSPERO as CRD42019146592.

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. 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. 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. 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 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. 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.

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. 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). 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. 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. 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.

Globally, nearly 250 million children (43% of all children under 5 years of age) are at risk of compromised neurodevelopment due to poverty, stunting, and lack of stimulation. We tested the independent and combined effects of improved water, sanitation, and hygiene (WASH) and improved infant and young child feeding (IYCF) on early child development (ECD) among children enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe. SHINE was a cluster-randomized community-based 2×2 factorial trial. A total of 5,280 pregnant women were enrolled from 211 clusters (defined as the catchment area of 1–4 village health workers [VHWs] employed by the Zimbabwean Ministry of Health and Child Care). Clusters were randomly allocated to standard of care, IYCF (20 g of small-quantity lipid-based nutrient supplement per day from age 6 to 18 months plus complementary feeding counseling), WASH (ventilated improved pit latrine, handwashing stations, chlorine, liquid soap, and play yard), and WASH + IYCF. Primary outcomes were child length-for-age Z-score and hemoglobin concentration at 18 months of age. Children who completed the 18-month visit and turned 2 years (102–112 weeks) between March 1, 2016, and April 30, 2017, were eligible for the ECD substudy. We prespecified that primary inferences would be drawn from findings of children born to HIV-negative mothers; these results are presented in this paper. A total of 1,655 HIV-unexposed children (64% of those eligible) were recruited into the ECD substudy from 206 clusters and evaluated for ECD at 2 years of age using the Malawi Developmental Assessment Tool (MDAT) to assess gross motor, fine motor, language, and social skills; the MacArthur–Bates Communicative Development Inventories (CDI) to assess vocabulary and grammar; the A-not-B test to assess object permanence; and a self-control task. Outcomes were analyzed in the intention-to-treat population. For all ECD outcomes, there was not a statistical interaction between the IYCF and WASH interventions, so we estimated the effects of the interventions by comparing the 2 IYCF groups with the 2 non-IYCF groups and the 2 WASH groups with the 2 non-WASH groups. The mean (95% CI) total MDAT score was modestly higher in the IYCF groups compared to the non-IYCF groups in unadjusted analysis: 1.35 (0.24, 2.46; p = 0.017); this difference did not persist in adjusted analysis: 0.79 (−0.22, 1.68; p = 0.057). There was no evidence of impact of the IYCF intervention on the CDI, A-not-B, or self-control tests. Among children in the WASH groups compared to those in the non-WASH groups, mean scores were not different for the MDAT, A-not-B, or self-control tests; mean CDI score was not different in unadjusted analysis (0.99 [95% CI −1.18, 3.17]) but was higher in children in the WASH groups in adjusted analysis (1.81 [0.01, 3.61]). The main limitation of the study was the specific time window for substudy recruitment, meaning not all children from the main trial were enrolled. We found little evidence that the IYCF and WASH interventions implemented in SHINE caused clinically important improvements in child development at 2 years of age. Interventions that directly target neurodevelopment (e.g., early stimulation) or that more comprehensively address the multifactorial nature of neurodevelopment may be required to support healthy development of vulnerable children. ClinicalTrials.gov NCT01824940

Introduction HIV-exposed uninfected children may be at risk of poor neurodevelopment. We aimed to test the impact of improved infant and young child feeding (IYCF) and improved water, sanitation and hygiene (WASH) on early child development (ECD) outcomes. Methods Sanitation Hygiene Infant Nutrition Efficacy was a cluster randomised 2×2 factorial trial in rural Zimbabwe ClinicalTrials.gov NCT01824940). Pregnant women were eligible if they lived in study clusters allocated to standard-of-care (SOC; 52 clusters); IYCF (20 g small-quantity lipid-based nutrient supplement/day from 6 to 18 months, complementary feeding counselling; 53 clusters); WASH (pit latrine, 2 hand-washing stations, liquid soap, chlorine, play space, hygiene counselling; 53 clusters) or IYCF +WASH (53 clusters). Participants and fieldworkers were not blinded. ECD was assessed at 24 months using the Malawi Developmental Assessment Tool (MDAT; assessing motor, cognitive, language and social skills); MacArthur Bates Communication Development Inventory (assessing vocabulary and grammar); A-not-B test (assessing object permanence) and a self-control task. Intention-to-treat analyses were stratified by maternal HIV status. Results Compared with SOC, children randomised to combined IYCF +WASH had higher total MDAT scores (mean difference +4.6; 95% CI 1.9 to 7.2) and MacArthur Bates vocabulary scores (+8.5 words; 95% CI 3.7 to 13.3), but there was no evidence of effects from IYCF or WASH alone. There was no evidence that that any intervention impacted object permanence or self-control. Conclusions Combining IYCF and WASH interventions significantly improved motor, language and cognitive development in HIV-exposed children. Trial registration number NCT01824940.