Poor growth in early childhood has been considered irreversible after 2-3 years of age and has been associated with morbidity and mortality over the short-term and with poor economic and cognitive ...outcomes over the long-term. The MAL-ED cohort study was performed in eight low-income settings with the goal of evaluating relationships between the child's environment and experience (dietary, illness, and pathogen exposure, among others) and their growth and development. The goal of this analysis is to determine whether there are differences in the factors associated with growth from 24 to 60 months using two different metrics.
Across six MAL-ED sites, 942 children had anthropometry data at 24 and 60 months, as well as information about socioeconomic status, maternal height, gut permeability (lactulose-mannitol z-score (LMZ)), dietary intake from 9 to 24 months, and micronutrient status. Anthropometric changes were in height- or weight-for-age z-score (HAZ, WAZ), their absolute difference from the growth standard median (HAD (cm), WAD (kg)), as well as recovery from stunting/underweight. Outcomes were modeled using multivariate regression.
At 24 months, almost half of the cohort was stunted (45%) and 21% were underweight. Among those who were stunted at 24 months (n = 426), 185 (43%) were no longer stunted at 60 months. Most children increased their HAZ from 24 to 60 months (81%), whereas fewer (33%) had positive changes in their HAD. Linear regression models indicate that girls improved less than boys from 24 to 60 months (HAZ: -0.21 (95% CI -0.27, -0.15); HAD: -0.75 (-1.07, -0.43)). Greater intestinal permeability (higher LMZ) at 0-24 months was associated with lower relative and absolute changes from 24 to 60 months (HAZ: -0.10 (-0.16, -0.04); HAD: -0.47 (-0.73, -0.21)). Maternal height (per 10 cm) was positively associated with changes (HAZ: 0.09 (0.03, 0.15); HAD: 0.45 (0.15, 0.75)). Similar relationships were identified for changes in WAZ and WAD.
The study children demonstrated improved growth from 24 to 60 months of age, but only a subset had positive changes in HAD and WAD. The same environmental factors were associated with growth from 24 to 60 months regardless of metric used (change in HAZ or HAD, or WAZ and WAD).
The Biomarkers of Nutrition for Development (BOND) project is designed to provide evidence-informed advice to anyone with an interest in the role of nutrition in health. The BOND program provides ...information with regard to selection, use, and interpretation of biomarkers of nutrient exposure, status, function, and effect, which will be especially useful for readers who want to assess nutrient status. To accomplish this objective, expert panels are recruited to evaluate the literature and to draft comprehensive reports on the current state of the art with regard to specific nutrient biology and available biomarkers for assessing nutritional status at the individual and population levels. Phase I of the BOND project includes the evaluation of biomarkers for 6 nutrients: iodine, folate, zinc, iron, vitamin A, and vitamin B-12. This review of vitamin A is the current article in this series. Although the vitamin was discovered >100 y ago, vitamin A status assessment is not trivial. Serum retinol concentrations are under homeostatic control due in part to vitamin A’s use in the body for growth and cellular differentiation and because of its toxic properties at high concentrations. Furthermore, serum retinol concentrations are depressed during infection and inflammation because retinol-binding protein (RBP) is a negative acute-phase reactant, which makes status assessment challenging. Thus, this review describes the clinical and functional indicators related to eye health and biochemical biomarkers of vitamin A status (i.e., serum retinol, RBP, breast-milk retinol, dose-response tests, isotope dilution methodology, and serum retinyl esters). These biomarkers are then related to liver vitamin A concentrations, which are usually considered the gold standard for vitamin A status. With regard to biomarkers, future research questions and gaps in our current understanding as well as limitations of the methods are described.
Immunization 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.
Polio 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.
Serotype 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.
Under 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.
BackgroundMillions 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.MethodsAs 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.ResultsHigher 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.ConclusionsEnteropathogens 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.
Children in low-income countries experience multiple illness symptoms in early childhood. Breastfeeding is protective against diarrhea and respiratory infections, and these illnesses are thought to ...be risk factors of one another, but these relationships have not been explored simultaneously. In the eight-site MAL-ED study, 1,731 infants were enrolled near birth and followed for 2 years. We collected symptoms and diet information through twice-weekly household visits. Poisson regression was used to determine if recent illness history was associated with incidence of diarrhea or acute lower respiratory infections (ALRI), accounting for exclusive breastfeeding. Recent diarrhea was associated with higher risk of incident diarrhea after the first 6 months of life (relative risk RR 1.10, 95% confidence interval CI 1.04, 1.16) and with higher risk of incident ALRI in the 3- to 5-month period (RR 1.23, 95% CI 1.03, 1.47). Fever was a consistent risk factor for both diarrhea and ALRI. Exclusive breastfeeding 0-6 months was protective against diarrhea (0-2 months: RR 0.39, 95% CI 0.32, 0.49; 3-5 months: RR 0.83, 95% CI 0.75, 0.93) and ALRI (3-5 months: RR 0.81, 95% CI 0.68, 0.98). Children with recent illness who were exclusively breastfed were half as likely as those not exclusively breastfed to experience diarrhea in the first 3 months of life. Recent illness was associated with greater risk of new illness, causing illnesses to cluster within children, indicating that specific illness-prevention programs may have benefits for preventing other childhood illnesses. The results also underscore the importance of exclusive breastfeeding in the first 6 months of life for disease prevention.
Studies of diarrheal etiology in low- and middle-income countries have typically focused on children presenting with severe symptoms to health centers and thus are best equipped to describe the ...pathogens capable of leading to severe diarrheal disease. The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study was designed to evaluate, via intensive community surveillance, the hypothesis that repeated exposure to enteropathogens has a detrimental effect on growth, vaccine response, and cognitive development, which are the primary outcome measures for this study. In the setting of multiple outcomes of interest, a longitudinal cohort design was chosen. Because many or even the majority of enteric infections are asymptomatic, the collection of asymptomatic surveillance stools was a critical element. However, capturing diarrheal stools additionally allowed for the determination of the principle causes of diarrhea at the community level as well as for a comparison between those enteropathogens associated with diarrhea and those that are associated with poor growth, diminished vaccine response, and impaired cognitive development. Here, we discuss the analytical methods proposed for the MAL-ED study to determine the principal causes of diarrhea at the community level and describe the complex interplay between recurrent exposure to enteropathogens and these critical long-term outcomes.
The paradigm of an ancient warm, wet, and dynamically active Mars, which transitioned into a cold, dry, and internally dead planet, has persisted up until recently despite published Viking-based ...geologic maps that indicate geologic and hydrologic activity extending into the Late Amazonian epoch. This paradigm is shifting to a water-enriched planet, which may still exhibit internal activity, based on a collection of geologic, hydrologic, topographic, chemical, and elemental evidences obtained by the Viking, Mars Global Surveyor (MGS), Mars Odyssey (MO), Mars Exploration Rovers (MER), and Mars Express (MEx) missions. The evidence includes: (1) stratigraphically young rock materials such as pristine lava flows with few, if any, superposed impact craters; (2) tectonic features that cut stratigraphically young materials; (3) features with possible aqueous origin such as structurally controlled channels that dissect stratigraphically young materials and anastomosing-patterned slope streaks on hillslopes; (4) spatially varying elemental abundances for such elements as hydrogen (H) and chlorine (Cl) recorded in rock materials up to 0.33
m depth; and (5) regions of elevated atmospheric methane. This evidence is pronounced in parts of Tharsis, Elysium, and the region that straddles the two volcanic provinces, collectively referred to here as the Tharsis/Elysium corridor. Based in part on field investigations of Solfatara Crater, Italy, recommended as a suitable terrestrial analog, the Tharsis/Elysium corridor should be considered a prime target for Mars Reconnaissance Orbiter (MRO) investigations and future science-driven exploration to investigate whether Mars is internally and hydrologically active at the present time, and whether the persistence of this activity has resulted in biologic activity.
We examined the association among elevations in acute phase proteins, reported illness, and hyporetinolemia in 234 pregnant Nepali women with (cases) and without (controls) night blindness. Serum ...alpha1-acid glycoprotein (AGP) and C-reactive protein (CRP) were inversely associated with serum retinol concentrations. Elevations in the concentration of CRP in both cases and controls and of AGP in cases were associated with significant reductions (approximately 0.2-0.3 micromol/L) in serum retinol. The risk of a low serum retinol concentration (< 0.7 micromol/L) with elevated AGP (> or = 1 g/L) and CRP (> or = 5 mg/L) concentrations was significantly higher in cases (odds ratios = 8.6 and 4.3, respectively) than in controls (odd ratios = 1.9 and 2.4, respectively). A 7-d morbidity history indicated that cases were significantly more likely than controls to report symptoms of infections of the urinary, reproductive, and gastrointestinal tracts. Only a few of these symptoms (diarrhea, nausea, and vomiting) were significantly associated with low serum retinol concentrations. Illness in the previous week and elevated CRP or AGP concentrations were synergistically associated with lower serum retinol. For example, the reduction in serum retinol in women with diarrhea and elevated AGP was 0.54 micromol/L, compared with a reduction of 0.03 micromol/L in those with diarrhea only. AGP and CRP may provide useful information about the effect of reported illness on hyporetinolemia in pregnancy. Infection-related hyporetinolemia may predispose women to night blindness during pregnancy in Nepal.
Iron deficiency remains the most prevalent form of human malnutrition, and current interventions to control it have not decreased the global prevalence. Hookworm control activities are becoming more ...widely implemented, but the importance of these efforts to prevent anemia in populations is not well-defined. We studied the relationships among hookworm infection, intestinal blood loss, and iron status of 203 Zanzibari school children. Helminth infection intensity was quantified by fecal egg counts, and iron deficiency anemia was defined by low hemoglobin and serum ferritin concentrations. Intestinal blood loss was quantified by measuring fecal heme and heme breakdown products as porphyrin, a noninvasive method that has not been used previously to assess hookworm blood loss. Intestinal blood loss was strongly and linearly related to hookworm egg counts. The degree of degradation of fecal heme indicated that blood loss occurred in the upper gastrointestinal tract, compatible with the behavior of hookworms. Trichuris trichiura and Ascaris lumbricoides infections were also common, but did not contribute significantly to intestinal blood loss in this population. The prevalence of iron deficiency anemia increased steadily as hookworm infection intensity and intestinal blood loss increased. In the context of a poor diet, as exists in Zanzibar and many tropical countries, hookworm-related blood loss contributes dramatically to anemia. In such contexts, hookworm control is a feasible and essential component of anemia control. Determination of fecal heme is relatively simple and noninvasive and may be a useful tool for measuring the impact of hookworm control activities.
The effect of vitamin A supplementation on the survival of infants aged <6 mo is unclear. Because most infant deaths occur in the first few month of life, maternal supplementation may improve infant ...survival.
The objective was to assess the effect of maternal vitamin A or beta-carotene supplementation on fetal loss and survival of infants <6 mo of age.
Married women of reproductive age in 270 wards of Sarlahi district, Nepal, were eligible to participate. Wards were randomly assigned to have women receive weekly doses of 7000 microg retinol equivalents as retinyl palmitate (vitamin A), 42 mg all-trans-beta-carotene, or placebo. Pregnancies were followed until miscarriage, stillbirth, maternal death, or live birth of one or more infants, who were followed through 24 wk of age.
A total of 43559 women were enrolled; 15832 contributed 17373 pregnancies and 15987 live born infants to the trial. The rate of fetal loss was 92.0/1000 pregnancies in the placebo group, comparable with rates in the vitamin A and beta-carotene groups, which had relative risks of 1.06 (95% CI: 0.91, 1.25) and 1.03 (95% CI: 0.87, 1.19), respectively. The 24-wk mortality rate was 70.8/1000 live births in the placebo group, comparable with rates in the vitamin A and beta-carotene groups, which had relative risks of 1.05 (95% CI: 0.87, 1.25) and 1.03 (95% CI: 0.86, 1.22), respectively.
Small weekly doses of vitamin A or beta-carotene given to women before conception, during pregnancy, and through 24 wk postpartum did not improve fetal or early infant survival in Nepal.
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