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.

Background: Few data exist for the effects of multiple micronutrient (MM) or food supplementation to undernourished pregnant women on their offsprings’ development. Objective: We aimed to compare the effects on infant development of early (8–10 wk gestation) or usual (≈17 wk gestation) supplementation with food and MM, 30 mg Fe + 400 μg folate, or 60 mg Fe + 400 μg folate. Design: A large, randomized, controlled trial of pregnancy supplementation was conducted in Bangladesh. A subsample of infants (n = 2853) were assessed on 2 problem-solving tests (support and cover tests), the motor index of the Bayley Scales of Infant Development, and Wolke's behavior ratings at 7 mo of age. Results: There were no significant effects of any intervention in the group as a whole. However, infants of undernourished mothers [body mass index (BMI; in kg/m²) < 18.5] who received early food supplementation performed slightly but significantly (P = 0.035) better on the support test than did infants of mothers who received usual food supplementation (z score: 0.17; 95% CI: 0.01, 0.33). There were no benefits in infants of higher-BMI mothers (P = 0.024 for BMI × food interaction). Children of low-BMI mothers who received MMs had slightly better motor scores (z score: 0.28; 95% CI: 0.08, 0.48) and activity ratings (z score: 0.24; 95% CI: 0.037, 0.45) than did those who received 30 mg Fe + 400 μg folate, whereas other children did not benefit (P = 0.05 for both motor scores and BMI × micronutrients and for activity and BMI × micronutrients). Conclusions: Small benefits from early food and MM supplementation were found in infants of low-BMI but not of high-BMI mothers. However, the benefits were of doubtful functional importance, and longer follow-up is required to determine programmatic implications.

Poor nutrition and hygiene make children vulnerable to delays in growth and development. We aimed to assess the effects of water quality, sanitation, handwashing, and nutritional interventions individually or in combination on the cognitive, motor, and language development of children in rural Bangladesh. In this cluster-randomised controlled trial, we enrolled pregnant women in their first or second trimester from rural villages of Gazipur, Kishoreganj, Mymensingh, and Tangail districts of central Bangladesh, with an average of eight women per cluster. Groups of eight geographically adjacent clusters were block-randomised, using a random number generator, into six intervention groups (all of which received weekly visits from a community health promoter for the first 6 months and every 2 weeks for the next 18 months) and a double-sized control group (no intervention or health promoter visit). The six intervention groups were: chlorinated drinking water; improved sanitation; handwashing with soap; combined water, sanitation, and handwashing; improved nutrition through counselling and provision of lipid-based nutrient supplements; and combined water, sanitation, handwashing, and nutrition. Here, we report on the prespecified secondary child development outcomes: gross motor milestone achievement assessed with the WHO module at age 1 year, and communication, gross motor, personal social, and combined scores measured by the Extended Ages and Stages Questionnaire (EASQ) at age 2 years. Masking of participants was not possible. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01590095. Between May 31, 2012, and July 7, 2013, 5551 pregnant women residing in 720 clusters were enrolled. Index children of 928 (17%) enrolled women were lost to follow-up in year 1 and an additional 201 (3%) in year 2. 4757 children were assessed at 1 year and 4403 at 2 years. At year 1, compared with the control group, the combined water, sanitation, handwashing, and nutrition group had a higher rate of attaining the standing alone milestone (hazard ratio 1·19, 95% CI 1·01–1 ·40), and the nutrition group had a higher rate of attaining the walking alone milestone (1·32, 95% CI 1·07–1·62). The combined water, sanitation, handwashing, and nutrition group had a higher rate of attaining the walking alone milestone than those in the water, sanitation, and handwashing group (1·29, 1·01–1·65). At 2 years, we noted beneficial effects in the combined EASQ score in all intervention groups, with effect sizes smallest in the water treatment group (difference 0·15, 95% CI 0·04 to 0·26 vs control) and largest in the combined water, sanitation, handwashing, and nutrition treatment group (0·37, 0·27–0·46). Improvements in water quality, handwashing, sanitation, or nutrition supported by intensive interpersonal communication, when delivered either individually or in combination, contributed to improvements in child development. A crucial next step is to establish whether similar effects can be achieved with reduced intensity of promoter contacts that could be supported in large-scale interventions. Bill & Melinda Gates Foundation.

An estimated one-third of children younger than 5 years in low- and middle-income countries fail to meet their full developmental potential. The first year of life is a period of critical brain development and is also when most of the morbidity from infection is suffered. We aimed to determine if clinical and biological markers of inflammation in the first year of life predict cognitive, language, and motor outcomes in children living in an urban slum in Bangladesh.

The aim of this study was to evaluate the massive efforts to lower water arsenic concentrations in Bangladesh. In our large mother-child cohort in rural Matlab, we measured the arsenic concentrations (and other elements) in drinking water and evaluated the actual exposure (urinary arsenic), from early gestation to 10 years of age (n=1017). Median drinking water arsenic decreased from 23 (2002-2003) to 50 m) explained much of the lower water arsenic concentrations, but increased the manganese concentrations. The highest manganese concentrations (~900 μg/L) appeared in 50-100 m wells. Low arsenic and manganese concentrations (17% of the children) occurred mainly in >100 m wells. The decrease in urinary arsenic concentrations over time was less apparent, from 82 to 58 μg/L, indicating remaining sources of exposure, probably through food (mean 133 μg/kg in rice). Despite decreased water arsenic concentrations in rural Bangladesh, the children still have elevated exposure, largely from food. Considering the known risks of severe health effects in children, additional mitigation strategies are needed.

Young children with iron deficiency anemia (IDA) usually have poor development, but there is limited information on their response to psychosocial in