Environmental enteropathy (EE), the adverse impact of frequent and numerous enteric infections on the gut resulting in a state of persistent immune activation and altered permeability, has been proposed as a key determinant of growth failure in children in low- and middle-income populations. A theory-driven systems model to critically evaluate pathways through which enteropathogens, gut permeability, and intestinal and systemic inflammation affect child growth was conducted within the framework of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) birth cohort study that included children from eight countries. Non-diarrheal stool samples (N=22,846) from 1253 children from multiple sites were evaluated for a panel of 40 enteropathogens and fecal concentrations of myeloperoxidase, alpha-1-antitrypsin, and neopterin. Among these same children, urinary lactulose:mannitol (L:M) (N=6363) and plasma alpha-1-acid glycoprotein (AGP) (N=2797) were also measured. The temporal sampling design was used to create a directed acyclic graph of proposed mechanistic pathways between enteropathogen detection in non-diarrheal stools, biomarkers of intestinal permeability and inflammation, systemic inflammation and change in length- and weight- for age in children 0-2years of age. Children in these populations had frequent enteric infections and high levels of both intestinal and systemic inflammation. Higher burdens of enteropathogens, especially those categorized as being enteroinvasive or causing mucosal disruption, were associated with elevated biomarker concentrations of gut and systemic inflammation and, via these associations, indirectly associated with both reduced linear and ponderal growth. Evidence for the association with reduced linear growth was stronger for systemic inflammation than for gut inflammation; the opposite was true of reduced ponderal growth. Although Giardia was associated with reduced growth, the association was not mediated by any of the biomarkers evaluated. The large quantity of empirical evidence contributing to this analysis supports the conceptual model of EE. The effects of EE on growth faltering in young children were small, but multiple mechanistic pathways underlying the attribution of growth failure to asymptomatic enteric infections had statistical support in the analysis. The strongest evidence for EE was the association between enteropathogens and linear growth mediated through systemic inflammation. Bill & Melinda Gates Foundation.

Iron deficiency anemia and child mortality are public health problems requiring urgent attention. However, the degree to which iron deficiency anemia contributes to child mortality is unknown. Here, we utilized an exhaustive article search and screening process to identify articles containing both anemia and mortality data for children aged 28 days to 12 years. We then estimated the reduction in risk of mortality associated with a 1-g/dL increase in hemoglobin (Hb). Our meta-analysis of nearly 12,000 children from six African countries revealed a combined odds ratio of 0.76 (0.62–0.93), indicating that for each 1-g/dL increase in Hb, the risk of death falls by 24%. The feasibility of a 1-g/dL increase in Hb has been demonstrated via simple iron supplementation strategies. Our finding suggests that ~1.8 million deaths in children aged 28 days to five years could be avoided each year by increasing Hb in these children by 1 g/dL.

Globally more than 150 million children under age 5 years were stunted in 2018, primarily in low- and middle-income countries (LMICs), and the impact of early-onset, persistent stunting has not been well explored. To explore the association between early-onset persistent stunting in children and cognitive development at 5 years of age, and to identify the factors associated with early-onset stunting. Children from the MAL-ED cohort study were followed from birth to 5 years of age in six LMICs. The Wechsler Preschool Primary Scales of Intelligence (WPPSI) was used to assess cognitive abilities (fluid reasoning) at 5 years and was adapted for each culture. Stunting was categorized as early-onset persistent (first stunted at 1–6 months and persisting at 60 months), early-onset recovered (first stunted at 1–6 months and not stunted at 60 months), late-onset persistent (first stunted at 7–24 months and persisting at 60 months), late-onset recovered (first stunted at 7–24 months and not stunted at 60 months), and never (never stunted). Mixed effects linear models were used to estimate the relationship between stunting status and cognitive development. Children with early-onset persistent stunting had significantly lower cognitive scores (-2.10 (95% CI: -3.85, -0.35)) compared with those who were never stunted. Transferrin receptor (TfR) was also negatively associated with cognitive development (-0.31 (95% CI: -0.49, -0.13)), while the HOME inventory, an index of quality of the home environment (0.46 (95% CI: 0.21, 0.72)) and socio-economic status (1.50 (95% CI: 1.03, 1.98)) were positively associated with cognitive development. Early-onset persistent stunting was associated with lower cognitive development in children at 5 years of age in this cohort of children.

Information on the association between stunting and child development is limited from low‐income settings including Bangladesh where 36% of children under‐ 5 are stunted. This study aimed to explore differences in early childhood development (ECD) between stunted (length‐for‐age z‐score [LAZ] < −2) and nonstunted (LAZ ≥ −2) children in Bangladesh. Children (n = 265) aged 6–24 months who participated in the MAL‐ED birth cohort study were evaluated by trained psychologists at 6, 15, and 24 months of age using the Bayley Scales of Infant and Toddler Development‐III; child length and weight were measured using standard procedures. ECD scores (z‐scores derived from cognitive, motor, language and socio‐emotional skills) were compared between stunted, underweight (weight‐for‐age z‐score < −2), and wasted (weight‐for‐length z‐score < −2) children, controlling for child age and sex and maternal age, education, body mass index (BMI), and depressive symptoms. Stunted children had significantly lower ECD scores than their nonstunted peers on cognitive (P = .049), motor (P < .001), language (P < .001) and social–emotional (P = .038) scales where boys had significantly lower fine motor skills compared with girls (P = .027). Mother's schooling and BMI were significant predictors of ECD. Similar to stunting, underweight children had developmental deficits in all domains (cognitive: P = .001; fine motor: P = .039, and P < .001 for both gross motor and total motor; expressive communication: P = .032; total language: P = .013; social–emotional development: P = .017). Wasted children had poor motor skills (P = .006 for the fine motor; P < .001 for both gross motor and total motor development) compared with the nonwasted peers. Early childhood stunting and underweight were associated with poor developmental outcomes in Bangladesh.

Iron deficiency remains the most prevalent micronutrient deficiency globally, but few studies have examined how iron status relates to cognition in adolescents. Iron biofortification of staple food crops is being scaled up, yet it is unknown whether consuming biofortified crops can benefit cognition. Our objective was to determine the efficacy of iron-biofortified pearl millet in improving attention and memory in Indian school-going adolescents. A double-blind, randomized, intervention study was conducted in 140 Indian boys and girls, aged 12–16 y, who were assigned to consume iron-biofortified [Fe = 86 parts per million (ppm)] or conventional (Fe = 21–52 ppm) pearl millet. Hemoglobin, ferritin, and transferrin receptor (TfR) were measured and body iron (BI) was calculated at baseline and after 4 and 6 mo. Five measures of cognitive function were obtained at baseline and 6 mo: simple reaction time (SRT), Go/No-Go (GNG) task, Attentional Network Task (ANT), Composite Face Effect (CFE) task, and Cued Recognition Task (CRT). Intention-to-treat analysis was used. Daily iron intake from pearl millet was higher in those consuming biofortified compared with conventional pearl millet (19.6 compared with 4.8 mg/d). Effects on ferritin, TfR, and BI at 4 mo, and on TfR at 6 mo (all P < 0.05), indicated efficacy of biofortified pearl millet over conventional pearl millet in improving iron status. Compared with conventional pearl millet, the consumption of biofortified pearl millet resulted in greater improvement in attention (SRT, GNG, and ANT) and memory (CFE and CRT). Reaction time decreased twice as much from 0 to 6 mo in those consuming biofortified compared with conventional pearl millet on attention tasks (SRT: −123 compared with −63 ms; GNG: −67 compared with −30 ms; ANT double cue: −74 compared with −32 ms; all P < 0.01). Consuming iron-biofortified pearl millet improves iron status and some measures of cognitive performance in Indian adolescents. This trial was registered at http://www.clinicaltrials.gov as NCT02152150.

More epidemiological data are needed on risk and protective factors for child development. In The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study, we assessed child development in a harmonious manner across 8 sites in Bangladesh, Brazil, India, Nepal, Pakistan, Peru, South Africa, and Tanzania. From birth to 24 months, development and language acquisition were assessed via the Bayley Scales of Infant and Toddler Development and a modified MacArthur Communicative Development Inventory. Other measures were infant temperament, the child's environment, maternal psychological adjustment, and maternal reasoning abilities. We developed standard operating procedures and used multiple techniques to ensure appropriate adaptation and quality assurance across the sites. Test adaptation required significant time and human resources but is essential for data quality; funders should support this step in future studies. At the end of this study, we will have a portfolio of culturally adapted instruments for child development studies with examination of psychometric properties of each tool used.