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Early childhood cognitive development is affected by interactions among illness, diet, enteropathogens and the home environment: findings from the MAL-ED birth cohort study.

ABSTRACT: Millions of children in low-income and middle-income countries (LMICs) are at risk of not reaching their full cognitive potential. Malnutrition and enteric infections in early life are implicated as risk factors; however, most studies on these risks and their associations with cognitive development have failed to adequately account for confounding factors or the accumulation of putative insults. Here, we examine the interaction between infections and illness on cognitive development in LMIC community settings.As part of the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) longitudinal birth cohort study, children from eight LMICs were followed from birth to 24 months to understand the influence of repeated enteric infections on child growth and development. Here, data from six sites were employed to evaluate associations between infection, illness, the home environment, micronutrient intake and status, maternal reasoning, and cognitive development at 24 months.Higher rates of enteropathogen detection and days with illness were associated with lower haemoglobin concentrations, which in turn were associated with lower cognitive scores at 24 months. Children with lower environmental health/safety scores and lower intakes of vitamin B6 and folate had more enteropathogen detections and illness. Strength of associations varied by weight-for-age in the first 17 days of life; lower weight infants were more susceptible to the negative effects of enteropathogens and illness.Enteropathogens were negatively related to child cognitive development. However, other factors were more strongly associated with child cognition. Targeting of interventions to improve cognitive development should include a focus on reducing frequency of illness, improving the safety and healthfulness of the child's environment, and improving dietary intake.

SUBMITTER: MAL-ED Network Investigators

PROVIDER: S-EPMC6058175 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Early childhood cognitive development is affected by interactions among illness, diet, enteropathogens and the home environment: findings from the MAL-ED birth cohort study.

BMJ global health 20180723 4

<h4>Background</h4>Millions of children in low-income and middle-income countries (LMICs) are at risk of not reaching their full cognitive potential. Malnutrition and enteric infections in early life are implicated as risk factors; however, most studies on these risks and their associations with cognitive development have failed to adequately account for confounding factors or the accumulation of putative insults. Here, we examine the interaction between infections and illness on cognitive devel ...[more]

PMID: 30058645

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Project description:BackgroundEnvironmental 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.MethodsNon-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.FindingsChildren 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.InterpretationThe 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.FundingBill & Melinda Gates Foundation.

Project description:BackgroundStunting is the most prevalent manifestation of childhood malnutrition. To characterize factors that contribute to stunting in resource-poor settings, we studied a priori selected biological and social factors collected longitudinally in a cohort of newborns.Methods and findingsWe enrolled 1,868 children across 7 resource-poor settings in Bangladesh, Brazil, India, Nepal, Peru, South Africa, and Tanzania shortly after birth and followed them for 24 months between 2 November 2009 and 28 February 2014. We collected longitudinal anthropometry, sociodemographic factors, maternal-reported illnesses, and antibiotic use; child feeding practices; dietary intake starting at 9 months; and longitudinal blood, urine, and stool samples to investigate non-diarrheal enteropathogens, micronutrients, gut inflammation and permeability, and systemic inflammation. We categorized length-for-age Z-scores into 3 groups (not stunted, ?-1; at risk, <-1 to -2; and stunted, <-2), and used multivariable ordinal logistic regression to model the cumulative odds of being in a lower length-for-age category (at risk or stunted). A total of 1,197 children with complete longitudinal data were available for analysis. The prevalence of having a length-for-age Z-score below -1 increased from 43% (range 37%-47% across sites) shortly after birth (mean 7.7 days post-delivery, range 0 to 17 days) to 74% (16%-96%) at 24 months. The prevalence of stunting increased 3-fold during this same time period. Factors that contributed to the odds of being in a lower length-for-age category at 24 months were lower enrollment weight-for-age (interquartile cumulative odds ratio = 1.82, 95% CI 1.49-2.23), shorter maternal height (2.38, 1.89-3.01), higher number of enteropathogens in non-diarrheal stools (1.36, 1.07-1.73), lower socioeconomic status (1.75, 1.20-2.55), and lower percent of energy from protein (1.39, 1.13-1.72). Site-specific analyses suggest that reported associations were similar across settings. While loss to follow-up and missing data are inevitable, some study sites had greater loss to follow-up and more missing data than others, which may limit the generalizability of the findings.ConclusionsNeonatal and maternal factors were early determinants of lower length-for-age, and their contribution remained important throughout the first 24 months of life, whereas the average number of enteropathogens in non-diarrheal stools, socioeconomic status, and dietary intake became increasingly important contributors by 24 months relative to neonatal and maternal factors.

Project description:BackgroundImmunization programs have leveraged decades of research to maximize oral polio vaccine (OPV) response. Moving toward global poliovirus eradication, the WHO recommended phased OPV-to-IPV replacement on schedules in 2012. Using the MAL-ED prospective birth cohort data, we evaluated the influence of early life exposures impacting OPV immunization by measuring OPV response for serotypes 1 and 3.MethodsPolio neutralizing antibody assays were conducted at 7 and 15?months of age for serotypes 1 and 3. Analyses were conducted on children receiving ?3 OPV doses (n?=?1449). History of vaccination, feeding patterns, physical growth, home environment, diarrhea, enteropathogen detection, and gut inflammation were examined as risk factors for non-response [Log2(titer)?<?3] and Log2(titer) by serotype using multivariate regression.FindingsSerotype 1 seroconversion was significantly higher than serotype 3 (96.6% vs. 89.6%, 15?months). Model results indicate serotypes 1 and 3 failure was minimized following four and six OPV doses, respectively; however, enteropathogen detection and poor socioeconomic conditions attenuated response in both serotypes. At three months of age, bacterial detection in stool reduced serotype 1 and 3 Log2 titers by 0.34 (95% CI 0.14-0.54) and 0.53 (95% CI 0.29-0.77), respectively, and increased odds of serotype 3 failure by 3.0 (95% CI 1.6-5.8). Our socioeconomic index, consisting of Water, Assets, Maternal education, and Income (WAMI), was associated with a 0.79 (95% CI 0.15-1.43) and 1.23 (95% CI 0.34-2.12) higher serotype 1 and 3 Log2 titer, respectively, and a 0.04 (95% CI 0.002-0.40) lower odds of serotype 3 failure. Introduction of solids, transferrin receptor, and underweight were differentially associated with serotype response. Other factors, including diarrheal frequency and breastfeeding practices, were not associated with OPV response.InterpretationUnder real-world conditions, improved vaccination coverage and socio-environmental conditions, and reducing early life bacterial exposures are key to improving OPV response and should inform polio eradication strategies.

Project description:BackgroundMost studies of the causes of diarrhoea in low-income and middle-income countries have looked at severe disease in people presenting for care, and there are few estimates of pathogen-specific diarrhoea burdens in the community.MethodsWe undertook a birth cohort study with not only intensive community surveillance for diarrhoea but also routine collection of non-diarrhoeal stools from eight sites in South America, Africa, and Asia. We enrolled children within 17 days of birth, and diarrhoeal episodes (defined as maternal report of three or more loose stools in 24 h, or one loose stool with visible blood) were identified through twice-weekly home visits by fieldworkers over a follow-up period of 24 months. Non-diarrhoeal stool specimens were also collected for surveillance for months 1-12, 15, 18, 21, and 24. Stools were analysed for a broad range of enteropathogens using culture, enzyme immunoassay, and PCR. We used the adjusted attributable fraction (AF) to estimate pathogen-specific burdens of diarrhoea.FindingsBetween November 26, 2009, and February 25, 2014, we tested 7318 diarrhoeal and 24 310 non-diarrhoeal stools collected from 2145 children aged 0-24 months. Pathogen detection was common in non-diarrhoeal stools but was higher with diarrhoea. Norovirus GII (AF 5·2%, 95% CI 3·0-7·1), rotavirus (4·8%, 4·5-5·0), Campylobacter spp (3·5%, 0·4-6·3), astrovirus (2·7%, 2·2-3·1), and Cryptosporidium spp (2·0%, 1·3-2·6) exhibited the highest attributable burdens of diarrhoea in the first year of life. The major pathogens associated with diarrhoea in the second year of life were Campylobacter spp (7·9%, 3·1-12·1), norovirus GII (5·4%, 2·1-7·8), rotavirus (4·9%, 4·4-5·2), astrovirus (4·2%, 3·5-4·7), and Shigella spp (4·0%, 3·6-4·3). Rotavirus had the highest AF for sites without rotavirus vaccination and the fifth highest AF for sites with the vaccination. There was substantial variation in pathogens according to geography, diarrhoea severity, and season. Bloody diarrhoea was primarily associated with Campylobacter spp and Shigella spp, fever and vomiting with rotavirus, and vomiting with norovirus GII.InterpretationThere was substantial heterogeneity in pathogen-specific burdens of diarrhoea, with important determinants including age, geography, season, rotavirus vaccine usage, and symptoms. These findings suggest that although single-pathogen strategies have an important role in the reduction of the burden of severe diarrhoeal disease, the effect of such interventions on total diarrhoeal incidence at the community level might be limited.

Dataset Information

Early childhood cognitive development is affected by interactions among illness, diet, enteropathogens and the home environment: findings from the MAL-ED birth cohort study.

Publications

Early childhood cognitive development is affected by interactions among illness, diet, enteropathogens and the home environment: findings from the MAL-ED birth cohort study.

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