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In 2011, one in every four (26%) children under 5 years of age worldwide was stunted. The realization that most stunting cannot be explained by poor diet or by diarrhoea, nor completely reversed by optimized diet and reduced diarrhoea has led to the hypothesis that a primary underlying cause of stunting is subclinical gut disease. Essentially, ingested microbes set in motion two overlapping and interacting pathways that result in linear growth impairment. Firstly, partial villous atrophy results in a reduced absorptive surface area and loss of digestive enzymes. This in turn results in maldigestion and malabsorption of much needed nutrients. Secondly, microbes and their products make the gut leaky, allowing luminal contents to translocate into systemic circulation. This creates a condition of chronic immune activation, which (i) diverts nutrient resources towards the metabolically expensive business of infection fighting rather than growth; (ii) suppresses the growth hormone ‐ IGF axis and inhibits bone growth, leading to growth impairment; and (iii) causes further damage to the intestinal mucosa thereby exacerbating the problem. As such, the unhygienic environments in which infants and young children live and grow must contribute to, if not be the overriding cause of, this environmental enteric dysfunction. We suggest that a package of baby ‐ WASH interventions (sanitation and water improvement, handwashing with soap, ensuring a clean play and infant feeding environment and food hygiene) that interrupt specific pathways through which feco ‐ oral transmission occurs in the first two years of a child's life may be central to global stunting reduction efforts. [ABSTRACT FROM AUTHOR]

Environmental enteric dysfunction (EED) is a virtually ubiquitous, but poorly defined, disorder of the small intestine among people living in conditions of poverty, which begins early in infancy and persists. EED is characterized by altered gut structure and function, leading to reduced absorptive surface area and impaired intestinal barrier function. It is hypothesized that recurrent exposure to fecal pathogens and changes in the composition of the intestinal microbiota initiate this process, which leads to a self-perpetuating cycle of pathology. We view EED as a primary gut disorder that drives chronic systemic inflammation, leading to growth hormone resistance and impaired linear growth. There is currently no accepted case definition or gold-standard biomarker of EED, making field studies challenging. The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in Zimbabwe is evaluating the independent and combined effects of a package of infant feeding and/or water, sanitation, and hygiene interventions on stunting and anemia. SHINE therefore provides an opportunity to longitudinally evaluate EED in a well-characterized cohort of infants, using a panel of biomarkers along the hypothesized causal pathway. Our aims are to describe the evolution of EED during infancy, ascertain its contribution to stunting, and investigate the impact of the randomized interventions on the EED pathway. In this article, we describe current concepts of EED, challenges in defining the condition, and our approach to evaluating EED in the SHINE trial. [ABSTRACT FROM AUTHOR]

Linear growth failure is the most common form of undernutrition globally. With an estimated 165 million children below 5 years of age affected, stunting has been identified as a major public health priority, and there are ambitious targets to reduce the prevalence of stunting by 40% between 2010 and 2025. We view this condition as a 'stunting syndrome' in which multiple pathological changes marked by linear growth retardation in early life are associated with increased morbidity and mortality, reduced physical, neurodevelopmental and economic capacity and an elevated risk of metabolic disease into adulthood. Stunting is a cyclical process because women who were themselves stunted in childhood tend to have stunted offspring, creating an intergenerational cycle of poverty and reduced human capital that is difficult to break. In this review, the mechanisms underlying linear growth failure at different ages are described, the short-, medium- and long-term consequences of stunting are discussed, and the evidence for windows of opportunity during the life cycle to target interventions at the stunting syndrome are evaluated. [ABSTRACT FROM AUTHOR]

In the context of a prevention of mother to child transmission of HIV program promoting exclusive breast-feeding (EBF) to 6 mo and offering HIV-PCR testing at ∼6 mo, we ascertained the feasibility of expressing and heat-treating (EHT) all breast milk fed to HIV-exposed, uninfected infants following 6 mo of EBF. Twenty mother-baby pairs were enrolled from a hospital in rural Zimbabwe. Research nurses provided lactation, EHT, and complementary feeding counseling through 21 home visits conducted over an 8-wk period and collected quantitative and qualitative data on the mothers' EHT experiences, children's diets, and anthropometric measurements. Mothers kept daily logs of EHT volumes and direct breast-feeding episodes. Mothers successfully initiated and sustained EHT for 4.5 mo (range, 1-11 mo), feeding 426 ± 227 mL/d (mean ± SD). By wk 2 of follow-up, children were receiving EHT and Nutributter-enriched complementary foods that satisfied 100% of their energy requirements. During the 8-wk follow-up period, no growth faltering was experienced [changes in weight-for-age, weight-for-length, and length-for-age Z scores = +0.03 ± 0.50; +0.77 ± 1.59; and +0.02 ± 0.85 (mean ± SD), respectively]. Stigma was not a major deterrent, likely due to a social marketing campaign for EBF that promoted EHT as a practice to sustain breast-feeding for all women. This study provides evidence that resource-poor rural women can initiate and sustain EHT given family and health systems support. EHT provides a strategy for improving the diets of HIV-exposed but uninfected children after direct breast-feeding has ceased. [ABSTRACT FROM AUTHOR]

The author reflects on the contribution of sanitation and hygiene to the growth of children in developing countries. She notes that 32% of children in developing countries have stunted growth and 20% are underweight. She explores how diarrhea can contribute to the poor growth of children. She also notes several studies which showed that most healthy adults and children in developing countries had morphological enteropathy. She stresses the importance of safe stool disposal and handwashing in disease prevention.

Objectives. We assessed the association between exposure to an educational intervention that emphasized safer breastfeeding practices and postnatal HIV transmission among 437 HIV-positive mothers in Zimbabwe, 365 of whom did not know their infection status. Methods. Mothers were tested for HIV and were encouraged--but not required--to learn their HIV status. Intervention exposure was assessed by a questionnaire, Turnbull methods were used to estimate postnatal HIV transmission, and multivariate Cox proportional hazard models were constructed to assess the association between intervention exposure and postnatal HIV transmission. Results. Cumulative postnatal HIV transmission was 8.2%; each additional intervention contact was associated with a 38% reduction in postnatal HIV transmission. HIV-positive mothers who were exposed to both print and video materials were 79% less likely to infect their infants compared with mothers who had no exposure. These findings were similar for mothers who did not know their HIV status. Conclusions. The promotion of exclusive breastfeeding has the potential to reduce postnatal HIV transmission among women who do not know their HIV status, and child survival and HIV prevention programs should support this practice. (Am J Public Health. 2007;97:1249-1254.) [ABSTRACT FROM AUTHOR]

Background. Low maternal serum retinol level is a risk factor for mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV). Multiple-large-dose vitamin A supplementation of HIV-positive children reduces mortality. The World Health Organization recommends single-large-dose vitamin A supplementation for postpartum women in areas of prevalent vitamin A deficiency, neonatal dosing is under consideration. We investigated the effect that single-large-dose maternal/neonatal vitamin A supplementation has on MTCT, HIV-free survival, and mortality in HIV-exposed infants. Methods. A total of 14,110 mother-infant pairs were enrolled ⩽96 h after delivery, and both mother and infant, mother only, infant only, or neither received vitamin A supplementation in a randomized, placebo-controlled trial with a 2 × 2 factorial design. All but 4 mothers initiated breast-feeding. A total of 4495 infants born to HIV-positive women were included in the present analysis. Results. Neither maternal nor neonatal vitamin A supplementation significantly affected postnatal MTCT or overall mortality between baseline and 24 months. However, the timing of infant HIV infection modified the effect that supplementation had on mortality. Vitamin A supplementation had no effect in infants who were polymerase chain reaction (PCR) negative for HIV at baseline. In infants who were PCR negative at baseline and PCR positive at 6 weeks, neonatal supplementation reduced mortality by 28% (P = .01), but maternal supplementation had no effect. In infants who were PCR negative at 6 weeks, all 3 vitamin A regimens were associated with ∼2-fold higher mortality (P ⩽ .05). Conclusions. Targeted vitamin A supplementation of HIV-positive children prolongs their survival. However, postpartum maternal and neonatal vitamin A supplementation may hasten progression to death in breast-fed children who are PCR negative at 6 weeks. These findings raise concern about universal maternal or neonatal vitamin A supplementation in HIV-endemic areas. [ABSTRACT FROM AUTHOR]

Background. Low maternal serum retinol level is a risk factor for mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV). Multiple-large-dose vitamin A supplementation of HIV-positive children reduces mortality. The World Health Organization recommends single-large-dose vitamin A supplementation for postpartum women in areas of prevalent vitamin A deficiency; neonatal dosing is under consideration. We investigated the effect that single-large-dose maternal/neonatal vitamin A supplementation has on MTCT, HIV-free survival, and mortality in HIV-exposed infants. Methods. A total of 4495 HIV-positive women and their infants were enrolled ⩽96 h after delivery, and both mother and infant, mother only, infant only, or neither received vitamin A supplementation in a randomized, placebo-controlled trial with a 2 × 2 factorial design. Results. Neither maternal nor neonatal vitamin A supplementation significantly affected postnatal MTCT or overall infant mortality. However, the timing of infant HIV infection modified the effect that supplementation had on mortality. Vitamin A supplementation had no effect in infants who were polymerase chain reaction (PCR) negative for HIV at baseline. In infants who were PCR negative at baseline and PCR positive at 6 weeks, neonatal supplementation reduced mortality by 28% (P = .01), but maternal supplementation had no effect. In infants who were PCR negative at 6 weeks, all 3 vitamin A regimens were associated with ∼2-fold higher mortality (P⩽.05). Conclusions. Targeted vitamin A supplementation of HIV-positive children prolongs their survival. However, postpartum maternal and neonatal vitamin A supplementation may hasten progression to death in breast-fed infants who are PCR negative at 6 weeks. These findings raise concern about universal maternal or neonatal vitamin A supplementation in HIV-endemic areas. [ABSTRACT FROM AUTHOR]

Background: Anemia is common in HIV infection and independently associated with disease progression and mortality. The pathophysiology of HIV-related anemia is not well understood especially in infancy. Methods: We conducted a longitudinal cohort study nested within the Zimbabwe Vitamin A for Mothers and Babies Project. We measured hemoglobin, erythropoietin (EPO), serum transferrin receptor (TfR) and serum ferritin at 6 weeks, 3 and 6 months of age and hemoglobin at 9 and 12 months in 3 groups of randomly selected infants: 136 born to HIV-negative mothers, and 99 born to HIV-positive mothers and who were infected themselves by 6 weeks of age, and 324 born to HIV-positive mothers but who did not become infected in the 6 months following birth. Results: At one year of age, HIV-positive infants were 5.26 (adjusted odds ratio, P < 0.001) times more likely to be anemic compared to HIV-negative infants. Among, HIV-negative infants, EPO was or tended to be inversely associated with hemoglobin and was significantly positively associated with TfR throughout the first 6 months of life; TfR was significantly inversely associated with ferritin at 6 months; and EPO explained more of the variability in TfR than did ferritin. Among infected infants, the inverse association of EPO to hemoglobin was attenuated during early infancy, but significant at 6 months. Similar to HIV-negative infants, EPO was significantly positively associated with TfR throughout the first 6 months of life. However, the inverse association between TfR and ferritin observed among HIV-negative infants at 6 months was not observed among infected infants. Between birth and 6 months, mean serum ferritin concentration declined sharply (by ~90%) in all three groups of babies, but was significantly higher among HIV-positive compared to HIV-negative babies at all time points. Conclusion: HIV strongly increases anemia risk and confounds interpretation of hematologic indicators in infants. Among HIV-infected infants, the EPO response to anemia is attenuated near the time of infection in the first weeks of life, but normalizes by 6 months. [ABSTRACT FROM AUTHOR]

Vitamin A deficiency is very prevalent and contributes substantially to morbidity and mortality among young children in developing countries. We identify and quantify three causes of vitamin A deficiency in young children based on data available in the literature: maternal vitamin A deficiency resulting in low concentrations of vitamin A in breast milk, inadequate dietary intake of vitamin A during and after weaning and prevalent illness. We developed a set of recursive equations to estimate the amount of vitamin A in the liver as a function of age over the first 2 y of life. To apply the equations, we selected a best estimate value for each input parameter as the most representative of a typical child in a developing country. Because of the great variability that exists for each variable, we also carried out sensitivity analyses, substituting more extreme values for input parameters. We then estimated stores, assuming a child in a developing country also receives the newly revised vitamin A supplementation regimen recommended by the World Health Organization. Without supplementation, a typical child in a developing country is not able to attain and maintain "minimally adequate" liver vitamin A stores. To overcome this deficit by eating fruits and vegetables alone, the child would need to increase portion sizes about 10-fold. If the child receives the new supplementation regimen, his or her liver stores will still be far short of the average American child (i.e., exceedingly far from toxic levels). However, our estimates indicate that the new supplementation regimen will permit a typical child in a developing country setting to attain minimally adequate vitamin A stores during the first 2 y of life. [ABSTRACT FROM AUTHOR]

Examines the delicate balance between life-saving benefits and the HIV infection risks of breastfeeding for babies born to HIV-positive women in Africa. Breastfeeding transmission of HIV; Safer breastfeeding practices to reduce HIV risks.

Stunting affects almost one‐quarter of children globally, leading to reduced human capacity and increased long‐term risk of chronic disease. Despite intensive infant and young child feeding (IYCF) interventions, many children do not meet their requirements for essential nutrients. This study aimed to assess the feasibility of implementing an IYCF intervention utilizing nutrient‐dense powders from egg, biofortified sugar beans and Moringa oleifera leaf in rural Zimbabwe. A mixed‐methods formative study was conducted comprising the following: (i) a recipe formulation trial, (ii) trials of improved practices to assess acceptability of the intervention, and (iii) a participatory message formulation process to develop counselling modules for the IYCF‐plus intervention. Twenty‐seven mother–baby pairs were recruited between November 2019 and April 2020. Key domains affecting IYCF practices that emerged were time, emotional and physical space, cultural and religious beliefs, indigenous knowledge systems and gender dynamics. Household observations and sensory evaluation indicated high acceptability of the new ingredients. Recipe formulation and participatory message formulation by participants instilled community ownership and served to demystify existing misconceptions about the new food products. Families noted the potential for intervention sustainability because the foods could be grown locally. Supplementing complementary foods with nutrient‐dense local food ingredients as powders has the potential to sustainably address nutrient‐gaps in the diets of young children living in rural lower‐ and middle‐income countries. Comprehensive IYCF counselling utilizing a gender‐lens approach, family support and indigenous knowledge systems or resources are key elements to support positive behaviour change in complementary feeding interventions. Key messages: Incorporating locally available solid foods into complementary feeding is a major challenge for caregivers in rural communities. There are several barriers that hinder mothers from feeding nutrient‐dense solid foods such as animal source foods, fruits and vegetables, resulting in nondiversified complementary diets.Formulation of nutrient‐dense, high‐quality protein complementary meals using powdered locally available food supplements is feasible, well tolerated and allows young children to be fed nutrient‐dense complementary meals in rural LMICs.Utilizing traditionally recognized functional foods such as Moringa olifeira encourages the involvement of elderly women/grandmothers in infant and young child feeding, enabling support for mothers.Integrated complementary feeding interventions incorporating behaviour change communication, provision/promotion of specific nutrient‐dense complementary foods (SQ‐LNS and local foods as powdered supplements), family support and agricultural production has potential for success in rural settings. [ABSTRACT FROM AUTHOR]

Studies the adverse immune responses of a single large dose of vitamin A or placebo among HIV-infected women of reproductive age. How the study was conducted; Tolerance on the administration of vitamin A; Impact of supplementation on vitamin A status.

Reports on the study that determined the relative protection afforded by two large doses of vitamin A against subclinical vitamin A deficiency among 345 preschool children in Indonesia. Overview on the nature and global prevalence of vitamin A deficiencies; Description of the subjects of the study; Recommended prophylactic dose of vitamin A.

Determines whether a priming dose of vitamin A would extend the protection of a 60,000-microgram retinol equivalent (RE) oral dose. Comparison of serum retinol concentration measurements among xerophthalmic and non-xerophthalmic pre-school children.

Argues that vitamin A supplementation of infants up to six months should be increased. Several studies which show that supplementation is of little or no benefit on infants of this age; Opinion that vitamin A supplementation is necessary in infants; Safety and benefits of supplementation.

Introduction: Infant and neonatal mortality estimates are typically derived from retrospective birth histories collected through surveys in countries with unreliable civil registration and vital statistics systems. Yet such data are subject to biases, including under-reporting of deaths and age misreporting, which impact mortality estimates. Prospective population-based cohort studies are an underutilized data source for mortality estimation that may offer strengths that avoid biases. Methods: We conducted a secondary analysis of data from the Child Health Epidemiology Reference Group, including 11 population-based pregnancy or birth cohort studies, to evaluate the appropriateness of vital event data for mortality estimation. Analyses were descriptive, summarizing study designs, populations, protocols, and internal checks to assess their impact on data quality. We calculated infant and neonatal morality rates and compared patterns with Demographic and Health Survey (DHS) data. Results: Studies yielded 71,760 pregnant women and 85,095 live births. Specific field protocols, especially pregnancy enrollment, limited exclusion criteria, and frequent follow-up visits after delivery, led to higher birth outcome ascertainment and fewer missing deaths. Most studies had low follow-up loss in pregnancy and the first month with little evidence of date heaping. Among studies in Asia and Latin America, neonatal mortality rates (NMR) were similar to DHS, while several studies in Sub-Saharan Africa had lower NMRs than DHS. Infant mortality varied by study and region between sources. Conclusions: Prospective, population-based cohort studies following rigorous protocols can yield high-quality vital event data to improve characterization of detailed mortality patterns of infants in low- and middle-income countries, especially in the early neonatal period where mortality risk is highest and changes rapidly. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about the effectiveness of vitamin A supplementation in improving infant survival.

Background: Despite achieving relatively high rates of antenatal care, institutional delivery, and HIV antiretroviral therapy for women during pregnancy, neonatal mortality has remained stubbornly high in Zimbabwe. Clearer understanding of causal pathways is required to inform effective interventions. Methods: This study was a secondary analysis of data from the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial, a cluster-randomized community-based trial among pregnant women and their infants, to examine care during institutional and non-institutional deliveries in rural Zimbabwe and associated birth outcomes. Results: Among 4423 pregnant women, 529 (11.9%) delivered outside a health institution; hygiene practices were poorer and interventions to minimise neonatal hypothermia less commonly utilised for these deliveries compared to institutional deliveries. Among 3441 infants born in institutions, 592 (17.2%) were preterm (< 37 weeks gestation), while 175/462 (37.9%) infants born outside health institutions were preterm (RR: 2.20 (1.92, 2.53). Similarly, rates of stillbirth [1.2% compared to 3.0% (RR:2.38, 1.36, 4.15)] and neonatal mortality [2.4% compared to 4.8% (RR: 2.01 1.31, 3.10)] were higher among infants born outside institutions. Among mothers delivering at home who reported their reason for having a home delivery, 221/293 (75%) reported that precipitous labor was the primary reason for not having an institutional delivery while 32 (11%), 34 (12%), and 9 (3%), respectively, reported distance to the clinic, financial constraints, and religious/personal preference. Conclusions: Preterm birth is common among all infants in rural Zimbabwe, and extremely high among infants born outside health institutions. Our findings indicate that premature onset of labor, rather than maternal choice, may be the reason for many non-institutional deliveries in low-resource settings, initiating a cascade of events resulting in a two-fold higher risk of stillbirth and neonatal mortality amongst children born outside health institutions. Interventions for primary prevention of preterm delivery will be crucial in reducing neonatal mortality in Zimbabwe. Trial registration: The trial is registered with ClinicalTrials.gov, number NCT01824940. [ABSTRACT FROM AUTHOR]

Background: Despite achieving relatively high rates of antenatal care, institutional delivery, and HIV antiretroviral therapy for women during pregnancy, neonatal mortality has remained stubbornly high in Zimbabwe. Clearer understanding of causal pathways is required to inform effective interventions. Methods: This study was a secondary analysis of data from the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial, a cluster-randomized community-based trial among pregnant women and their infants, to examine care during institutional and non-institutional deliveries in rural Zimbabwe and associated birth outcomes. Results: Among 4423 pregnant women, 529 (11.9%) delivered outside a health institution; hygiene practices were poorer and interventions to minimise neonatal hypothermia less commonly utilised for these deliveries compared to institutional deliveries. Among 3441 infants born in institutions, 592 (17.2%) were preterm (< 37 weeks gestation), while 175/462 (37.9%) infants born outside health institutions were preterm (RR: 2.20 (1.92, 2.53). Similarly, rates of stillbirth [1.2% compared to 3.0% (RR:2.38, 1.36, 4.15)] and neonatal mortality [2.4% compared to 4.8% (RR: 2.01 1.31, 3.10)] were higher among infants born outside institutions. Among mothers delivering at home who reported their reason for having a home delivery, 221/293 (75%) reported that precipitous labor was the primary reason for not having an institutional delivery while 32 (11%), 34 (12%), and 9 (3%), respectively, reported distance to the clinic, financial constraints, and religious/personal preference. Conclusions: Preterm birth is common among all infants in rural Zimbabwe, and extremely high among infants born outside health institutions. Our findings indicate that premature onset of labor, rather than maternal choice, may be the reason for many non-institutional deliveries in low-resource settings, initiating a cascade of events resulting in a two-fold higher risk of stillbirth and neonatal mortality amongst children born outside health institutions. Interventions for primary prevention of preterm delivery will be crucial in reducing neonatal mortality in Zimbabwe. Trial registration: The trial is registered with ClinicalTrials.gov, number NCT01824940. [ABSTRACT FROM AUTHOR]

Background Globally, 15 million children are born preterm each year and 10.7 million are born at term but with low birthweight (<2500 g). Methods The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) cluster-randomized trial enrolled 5280 pregnant women between 22 November 2012 and 27 March 2015 to test the impact of improved water supply, sanitation and hygiene, and improved infant feeding, on child growth and anaemia. We conducted a secondary analysis to estimate the prevalence and risk factors of miscarriage, stillbirth, preterm birth, size small for gestational age (SGA), low birthweight (LBW), perinatal mortality, and neonatal mortality, and to estimate the effects of adverse birth outcomes on infant survival and growth.  Results The prevalence of adverse birth outcomes was: miscarriage: 5.0% [95% confidence interval (CI), 4.4, 5.7]; stillbirth: 2.3% (95% CI 1.9, 2.7); preterm birth: 18.2% (95% CI 16.9, 19.5); SGA: 16.1% (95% CI 15.0, 17.3); LBW: 9.8% (95% CI 9.0, 10.7); and neonatal mortality: 31.4/1000 live births (95% CI 26.7, 36.5). Modifiable risk factors included maternal HIV infection, anaemia, lack of antenatal care and non-institutional delivery. Preterm infants had higher neonatal mortality [risk ratio (RR): 6.1 (95% CI 4.0, 9.2)], post-neonatal infant mortality [hazard ratio (HR): 2.1 (95% CI 1.1, 4.1)] and stunting at 18 months of age [RR: 1.5 (95% CI 1.4, 1.7)] than term infants; 56% of stillbirths and 57% of neonatal deaths were among preterm births.  Conclusions Neonatal mortality and stillbirth are high in Zimbabwe and appear to be driven by high preterm birth. Interventions for primary prevention of preterm birth and strengthened management of preterm labour and ill and small neonates are required to reduce neonatal mortality in Zimbabwe and other African countries with similar profiles. [ABSTRACT FROM AUTHOR]

The article discusses a study which examined the mother to child transmission of HIV among Zimbabwean women who seroconverted after giving birth. The study included pairs of mother and infants in urban Zimbabwe, included in the Zimbabwe Vitamin A for Mothers and Babies (ZVITAMBO) trial from 1997 to 2001. Study authors found that the risk of HIV transmission through breastfeeding is higher during the first three to six months after maternal infection.

The relationship between iron status & HIV infection is complex & poorly understood. While anemia is a major complication of HIV infection, higher iron stores may be associated with disease progression. It is uncertain if increased iron stores are a cause of disease progression or a consequence. There is limited & conflicting data available from Africa, & none that examine this relationship prospectively. We examined the association between post-partum iron status & viral load (VL), progression (maternal death by 12 months), & MTCT of HIV in 643 HIV+ Zimbabwean women. In non-anemic women a log10 increase in SF was associated with a 2.3-fold increase in VL (p=0.02); this association was absent in anemic women. At the same time, Hb was negatively associated with VL (p<0.01). In prospective analyses, a log10 increase in SF was associated with a 3.5-fold increase in the risk of death by 12 months (p=0.01), but there was no association with MTCT. Controlling for AGP, a marker of inflammation, attenuated the association between SF & VL or progression, but these remained significant. These results are consistent with the hypothesis that high iron stores have adverse consequences in HIV infection, however AGP may not fully control for the effect of HIV on SF (reverse causality). If adverse consequences are real, our data suggest that they occur at SF levels > 45 ug/L, and do not include MTCT. [ABSTRACT FROM AUTHOR]

Introduction: Over one billion people live with disability worldwide, of whom 80% are in developing countries. Robust childhood disability data are limited, particularly as tools for identifying disability function poorly at young ages. Methods: A subgroup of children enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial (a cluster-randomised, community-based, 2x2 factorial trial in two rural districts in Zimbabwe) had neurodevelopmental assessments at 2 years of age. We evaluated functional difficulty prevalence in HIV-exposed and HIV-unexposed children using the Washington Group Child Functioning Module (WGCFM), comparing absolute difference using chi-squared or Fisher's exact tests. Concurrent validity with the Malawi Developmental Assessment Tool (MDAT) was assessed using logistic regression with cohort MDAT score quartiles, linear regression for unit-increase in raw scores and a Generalised Estimating Equation approach (to adjust for clusters) to compare MDAT scores of those with and without functional difficulty. A 3-step, cluster-adjusted multivariable regression model was then carried out to examine risk factors for functional difficulty. Findings: Functional Difficulty prevalence was 4.2% (95%CI: 3.2%, 5.2%) in HIV-unexposed children (n = 1606) versus 6.1% (95%CI: 3.5%, 8.9%) in HIV-exposed children (n = 314) (absolute difference 1.9%, 95%CI: -0.93%, 4.69%; p = 0.14). Functional difficulty score correlated negatively with MDAT: for each unit increase in WGCFM score, children completed 2.6 (95%CI: 2.2, 3.1) fewer MDAT items (p = 0.001). Children from families with food insecurity and poorer housing were more at risk of functional difficulty. Interpretation: Functional difficulty was identified in approximately 1-in-20 children in rural Zimbabwe, which is comparable to prevalence in previous studies. WGCFM showed concurrent validity with the MDAT, supporting its use in early childhood. [ABSTRACT FROM AUTHOR]

Calcium intake remains inadequate in many low‐ and middle‐income countries, especially in Africa and South Asia, where average intakes can be below 400 mg/day. Given the vital role of calcium in bone health, metabolism, and cell signaling, countries with low calcium intake may want to consider food‐based approaches to improve calcium consumption and bioavailability within their population. This is especially true for those with low calcium intake who would benefit the most, including pregnant women (by reducing the risk of preeclampsia) and children (by reducing calcium‐deficiency rickets). Specifically, some animal‐source foods that are naturally high in bioavailable calcium and plant foods that can contribute to calcium intake could be promoted either through policies or educational materials. Some food processing techniques can improve the calcium content in food or increase calcium bioavailability. Staple‐food fortification with calcium can also be a cost‐effective method to increase intake with minimal behavior change required. Lastly, biofortification is currently being investigated to improve calcium content, either through genetic screening and breeding of high‐calcium varieties or through the application of calcium‐rich fertilizers. These mechanisms can be used alone or in combination based on the local context to improve calcium intake within a population. [ABSTRACT FROM AUTHOR]

Most low‐ and middle‐income countries present suboptimal intakes of calcium during pregnancy and high rates of mortality due to maternal hypertensive disorders. Calcium supplementation during pregnancy is known to reduce the risk of these disorders and associated complications, including preeclampsia, maternal morbidity, and preterm birth, and is, therefore, a recommended intervention for pregnant women in populations with low dietary calcium intake (e.g., where ≥25% of individuals in the population have intakes less than 800 mg calcium/day). However, this intervention is not widely implemented in part due to cost and logistical issues related to the large dose and burdensome dosing schedule (three to four 500‐mg doses/day). WHO recommends 1.5–2 g/day but limited evidence suggests that less than 1 g/day may be sufficient and ongoing trials with low‐dose calcium supplementation (500 mg/day) may point a path toward simplifying supplementation regimens. Calcium carbonate is likely to be the most cost‐effective choice, and it is not necessary to counsel women to take calcium supplements separately from iron‐containing supplements. In populations at highest risk for preeclampsia, a combination of calcium supplementation and food‐based approaches, such as food fortification with calcium, may be required to improve calcium intakes before pregnancy and in early gestation. [ABSTRACT FROM AUTHOR]

There is scarce research and programmatic evidence on the effect of poor water, sanitation, and hygiene (WASH) conditions of the physical environment on early child cognitive, sensorimotor, and socioemotional development. Furthermore, many common WASH interventions are not specifically designed to protect babies in the first 3 years of life, when gut health and linear growth are established. We review evidence linking WASH, anemia, and child growth, and highlight pathways through which WASH may affect early child development, primarily through inflammation, stunting, and anemia. Environmental enteropathy, a prevalent subclinical condition of the gut, may be a key mediating pathway linking poor hygiene to developmental deficits. Current early child development research and programs lack evidence-based interventions to provide a clean play and infant feeding environment in addition to established priorities of nutrition, stimulation, and child protection. Solutions to this problem will require appropriate behavior change and technologies that are adapted to the social and physical context and conducive to infant play and socialization. We propose the concept of baby WASH as an additional component of early childhood development programs. [ABSTRACT FROM AUTHOR]

Objective: The BED assay was developed to estimate the proportion of recent HIV infections in a population. We used the BED assay as a proxy for acute infection to quantify the associated risk of mother-to-child-transmission (MTCT) during pregnancy and delivery. Design A total of 3773 HIV-1 sero-positive women were tested within 96 h of delivery using the BED assay, and CD4 cell count measurements were taken. Mothers were classified according to their likelihood of having recently seroconverted.Methods: The risk of MTCT in utero and intra-partum was assessed comparing different groups defined by BED and CD4 cell count, adjusting for background factors using multinomial logistic models.Results: Compared with women with BED ≥ 0.8/CD4 ≥ 350 (typical of HIV-1 chronic patients) there was insufficient evidence to conclude that women presenting with BED < 0.8/CD4 ≥ 350 (typical of recent infections) were more likely to transmit in utero [adjusted odds ratio (aOR) = 1.37, 96% confidence interval (CI) 0.90-2.08, P = 0.14], whereas women with BED < 0.8/CD4 200-349 (possibly recently infected patients) had a 2.57 (95% CI 1.39-4.77, P-value < 0.01) odds of transmitting in utero. Women who had BED < 0.8/CD4 < 200 were most likely to transmit in utero (aOR 3.73, 95% CI 1.27-10.96, P = 0.02). BED and CD4 cell count were not predictive of intra-partum infections.Conclusions: These data provide evidence that in utero transmission of HIV might be higher among women who seroconvert during pregnancy. [ABSTRACT FROM AUTHOR]

Oral rotavirus vaccine (RVV) immunogenicity is considerably lower in low- versus high-income populations; however, the mechanisms underlying this remain unclear. Previous evidence suggests that the gut microbiota may contribute to differences in oral vaccine efficacy. We performed whole metagenome shotgun sequencing on stool samples and measured anti-rotavirus immunoglobulin A in plasma samples from a subset of infants enrolled in a cluster randomized 2 × 2 factorial trial of improved water, sanitation and hygiene and infant feeding in rural Zimbabwe (SHINE trial: NCT01824940). We examined taxonomic microbiome composition and functional metagenome features using random forest models, differential abundance testing and regression analyses to explored associations with RVV immunogenicity. Among 158 infants with stool samples and anti-rotavirus IgA titres, 34 were RVV seroconverters. The median age at stool collection was 43 days (IQR: 35–68), corresponding to a median of 4 days before the first RVV dose. The infant microbiome was dominated by Bifidobacterium longum. The gut microbiome differed significantly between early (≤42 days) and later samples (>42 days) however, we observed no meaningful differences in alpha diversity, beta diversity, species composition or functional metagenomic features by RVV seroconversion status. Bacteroides thetaiotaomicron was the only species associated with anti-rotavirus IgA titre. Random forest models poorly classified seroconversion status by both composition and functional microbiome variables. RVV immunogenicity is low in this rural Zimbabwean setting, however it was not associated with the composition or function of the early-life gut microbiome in this study. Further research is warranted to examine the mechanisms of poor oral RVV efficacy in low-income countries. [ABSTRACT FROM AUTHOR]

Background: Schistosoma haematobium is a parasitic helminth that causes urogenital pathology. The impact of urogenital schistosomiasis during pregnancy on birth outcomes and child growth is poorly understood.Methods: Risk factors for urogenital schistosomiasis were characterized among 4437 pregnant women enrolled in a cluster-randomized community-based trial in rural Zimbabwe. Infection was defined via urine microscopy (≥1 S. haematobium egg) and urinalysis (hematuria). Associations between infection and pregnancy outcomes were assessed in case-control analyses using conditional logistic regression. The association of maternal infection with birthweight and length-for-age Z scores (LAZ) at 1 and 18 months of age were assessed using generalized estimating equations.Results: Urogenital schistosomiasis (egg positive and/or hematuria positive) was detected in 26.8% of pregnant women. Risk factors significantly associated with infection were maternal age, education, marital status, and religion; household drinking water source and latrine; study region; and season. Urogenital schistosomiasis was not significantly associated with adverse pregnancy outcomes (miscarriage, stillbirth, preterm, and small-for-gestational age), birthweight, neonatal death, or LAZ.Conclusions: Including pregnant women in antihelminthic treatment programs would benefit a large number of women in rural Zimbabwe. However, clearance of the low-intensity infections that predominate in this context is unlikely to have additive benefits for pregnancy outcomes or child growth.Clinical Trials Registration: NCT01824940. [ABSTRACT FROM AUTHOR]

Between birth and 2 years, children's well‐being depends on the quality of care they receive from caregivers, primarily their mothers. We developed a quantitative survey instrument to assess seven psychosocial characteristics of women that determine their caregiving ability ('maternal capabilities': physical health, mental health, decision‐making autonomy, social support, mothering self‐efficacy, workload and time stress, and gender norm attitudes). We measured maternal capabilities in 4,025 mothers and growth in their 4,073 children participating in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe. We used generalized estimating equation models with exchangeable correlation structure to test the association between each maternal capability during pregnancy, and infant length‐for‐age Z (LAZ) at 18 months, accounting only for within‐cluster correlation and intervention arms in unadjusted analyses and for potential confounders in adjusted analyses to examine the association between each capability, assessed during pregnancy, with child LAZ at 18 months of age. In adjusted models, each unit increase in gender norm attitudes score (reflecting more equitable gender norm attitudes) was associated with +0.09 LAZ (95% CI: 0.02, 0.16) and a decreased odds of stunting (adjusted odds ratio [AOR]: 0.86; 95% CI: 0.74, 1.01); each unit increase in social support score was associated with +0.11 LAZ (95% CI: 0.05, 0.17, p < 0.010) and decreased odds of stunting (AOR: 0.83; 95% CI: 0.73, 0.96). Each unit increase in decision‐making autonomy was associated with a 6% reduced odds of stunting (AOR: 0.94; 95% CI: 0.89, 0.996, p = 0.04). Interventions and social programming that strengthen these maternal capabilities may improve child nutritional status. [ABSTRACT FROM AUTHOR]

Background: Young children require high-quality care for healthy growth and development. We defined "maternal capabilities" as factors that influence mothers' caregiving ability (physical and mental health, social support, time, decision-making autonomy, gender norm attitudes, and mothering self-efficacy), and developed survey tools to assess them.Objectives: We hypothesized that mothers with stronger capabilities during pregnancy would be more likely to practice improved care behaviors after their child was born.Methods: We assessed maternal capabilities among 4667 pregnant women newly enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial. Several improved child-care practices were promoted until 18 mo postpartum, the trial endpoint. Care practices were assessed by survey, direct observation, or transcription from health records during postpartum research visits. We used logistic regression to determine the predictive association between maternal capabilities during pregnancy and child-care practices.Results: Mothers with more egalitarian gender norm attitudes were more likely to have an institutional delivery [adjusted OR (AOR), 2.06; 95% CI, 1.57-2.69], initiate breastfeeding within 1 h of delivery (AOR, 1.38; 95% CI, 1.03-1.84), exclusively breastfeed (EBF) from birth to 3 mo (AOR, 2.55; 95% CI, 1.95-3.35) and 3-6 mo (AOR, 1.75; 95% CI, 1.36-2.25), and, among households randomized to receive extra modules on sanitation and hygiene, have soap and water at a handwashing station (AOR, 1.76; 95% CI, 1.29-2.39). Mothers experiencing time stress were less likely to EBF from birth to 3 mo (AOR, 0.79; 95% CI, 0.66-0.93). Greater social support was associated with institutional delivery (AOR, 1.53; 95% CI, 1.37-1.98) and, among mothers randomized to receive extra complementary feeding modules, feeding children a minimally diverse diet (AOR, 1.18; 95% CI, 1.01-1.37). Depressed mothers were 37% and 33%, respectively, less likely to have an institutional delivery (AOR, 0.63; 95% CI, 0.44-0.88) and a fully immunized child (AOR, 0.67; 95% CI, 0.50-0.90).Conclusions: Interventions to reduce maternal depression, time stress, inadequate social support, and inequitable gender norms may improve maternal child caregiving. [ABSTRACT FROM AUTHOR]

Background Clinical outcomes of children who are human immunodeficiency virus (HIV)–exposed in sub-Saharan Africa remain uncertain. Methods The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial evaluated improved infant and young child feeding (IYCF) and/or improved water, sanitation, and hygiene in 2 rural Zimbabwean districts with 15% antenatal HIV prevalence and > 80% prevention of mother-to-child transmission (PMTCT) coverage. Children born between February 2013 and December 2015 had longitudinal HIV testing and anthropometry. We compared mortality and growth between children who were HIV-exposed and HIV-unexposed through 18 months. Children receiving IYCF were excluded from growth analyses. Results Fifty-one of 738 (7%) children who were HIV-exposed and 198 of 3989 (5%) children who were HIV-unexposed (CHU) died (hazard ratio, 1.41 [95% confidence interval {CI}, 1.02–1.93]). Twenty-five (3%) children who were HIV-exposed tested HIV positive, 596 (81%) were HIV-exposed uninfected (CHEU), and 117 (16%) had unknown HIV status by 18 months; overall transmission estimates were 4.3%–7.7%. Mean length-for-age z score at 18 months was 0.38 (95% CI,.24–.51) standard deviations lower among CHEU compared to CHU. Among 367 children exposed to HIV in non-IYCF arms, 147 (40%) were alive, HIV-free, and nonstunted at 18 months, compared to 1169 of 1956 (60%) CHU (absolute difference, 20% [95% CI, 15%–26%]). Conclusions In rural Zimbabwe, mortality remains 40% higher among children exposed to HIV, vertical transmission exceeds elimination targets, and half of CHEU are stunted. We propose the composite outcome of "alive, HIV free, and thriving" as the long-term goal of PMTCT programs. Clinical Trials Registration NCT01824940. [ABSTRACT FROM AUTHOR]

Introduction: Exposure to maternal HIV may affect early child development (ECD), although previous studies have reported heterogeneous findings. We evaluated ECD among children who were HIV‐exposed uninfected (CHEU) and children who were HIV‐unexposed (CHU) recruited to the SHINE trial in rural Zimbabwe. Methods: SHINE was a community‐based cluster‐randomized trial of improved infant feeding and/or improved water, sanitation and hygiene. Pregnant women were enrolled between 2012 and 2015. We assessed ECD in a sub‐study at 24 months of age, between 2016 and 2017, using the Malawi Developmental Assessment Tool (MDAT; assessing motor, cognitive, language and social development); MacArthur‐Bates Communicative Development Inventory (CDI) (assessing vocabulary and grammar); A‐not‐B test (assessing object permanence); and a self‐control task. Mothers and infants were tested longitudinally for HIV. We used generalized estimating equations to compare ECD scores between CHEU and CHU, accounting for the cluster‐randomized design. Primary results were adjusted for trial‐related factors that could affect measurement reliability of ECD: study nurse, age of child, calendar month of birth, sex and randomized arm. Results: A total of 205 CHEU and 1175 CHU were evaluated. Mean total MDAT score was 90.6 (SD 8.7) in CHEU compared to 92.4 (9.1) in CHU (adjusted mean difference −1.3, 95% CI: −2.3, −0.3), driven mostly by differences in gross motor (−0.5, 95% CI: −0.9, −0.2) and language scores (−0.6, 95% CI: −1.1, −0.1). There was evidence that fine motor scores were lower in CHEU (adjusted mean difference −0.4, 95% CI: −0.8, 0.0) but no evidence of a difference in social scores (0.1, 95% CI: −0.2, 0.4). Mean MacArthur‐Bates CDI vocabulary score was 57.9 (SD 19.2) in CHEU compared to 61.3 (18.8) in CHU (adjusted mean difference −2.9 words, 95% CI: −5.7, −0.1). Object permanence and self‐control scores were similar between groups. Conclusions: CHEU in rural Zimbabwe had total child development and vocabulary scores that were approximately 0.15 standard deviations lower than CHU at two years of age. More detailed and specific studies are now needed to unravel the reasons for developmental delay in CHEU and the likelihood that these delays persist in the longer term. [ABSTRACT FROM AUTHOR]

Background: We assessed the impact of water, sanitation, and hygiene (WASH) and infant and young child feeding (IYCF) interventions on enteric infections in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe.Methods: We tested stool samples collected at 1, 3, 6, and 12 months of age and during diarrhea using quantitative molecular diagnostics for 29 pathogens. We estimated the effects of the WASH, IYCF, and combined WASH + IYCF interventions on individual enteropathogen prevalence and quantity, total numbers of pathogens detected, and incidence of pathogen-attributable diarrhea.Results: WASH interventions decreased the number of parasites detected (difference in number compared to non-WASH arms, -0.07 [95% confidence interval, -.14 to -.02]), but had no statistically significant effects on bacteria, viruses, or the prevalence and quantity of individual enteropathogens after accounting for multiple comparisons. IYCF interventions had no significant effects on individual or total enteropathogens. Neither intervention had significant effects on pathogen-attributable diarrhea.Conclusions: The WASH interventions implemented in SHINE (improved pit latrine, hand-washing stations, liquid soap, point-of-use water chlorination, and clean play space) did not prevent enteric infections. Transformative WASH interventions are needed that are more efficacious in interrupting fecal-oral microbial transmission in children living in highly contaminated environments. [ABSTRACT FROM AUTHOR]

Oral rotavirus vaccines (RVV) have poor immunogenicity in low-income countries, for reasons that remain unclear. This study identified the determinants of RVV immunogenicity among infants in rural Zimbabwe. Anti-rotavirus IgA titres were measured among a sub-group of infants enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial (NCT01824940). SHINE was a cluster-randomized trial of improved infant and young child feeding, and improved water, sanitation and hygiene (WASH) in two rural Zimbabwean districts. Infants received RVV as part of the national immunisation programme. Among HIV-unexposed infants in the non-WASH trial arms, we evaluated associations between potential risk factors (vaccine schedule and dose, maternal and infant nutritional status, infant diarrhoea, and household environment) and RVV immunogenicity (seroconversion, seropositivity and geometric mean titres) using multivariable regression. Among 219 infants with seroconversion data, 43 (20%) successfully seroconverted and 176 (80%) failed to seroconvert to RVV. Seroconversion was positively associated with a higher length-for-age Z-score (LAZ) around the time of vaccination (adjusted RR 1.27 (95% CI 1.04, 1.55), P = 0.021), and negatively associated with concurrent OPV and RVV administration (adjusted RR 0.36 (0.19, 0.71), P = 0.003). Among 472 infants with post-vaccination titres, a higher LAZ score was associated with increased seropositivity (aRR 1.21 (95% CI 1.06, 1.38), P = 0.004), and higher birthweight was associated with increased IgA titres (0.45 (95%CI 0.18, 1.09) U/mL greater per 100 g gain in birthweight; P = 0.001). Infant ponderal and linear growth were positively associated with RVV immunogenicity, while concurrent administration of OPV was negatively associated with RVV immunogenicity. Together, these findings suggest that improving foetal growth and separating RVV and OPV administration are plausible approaches to increasing RVV immunogenicity. [ABSTRACT FROM AUTHOR]

Background: Environmental enteric dysfunction (EED) may be an important modifiable cause of child stunting. We described the evolution of EED biomarkers from birth to 18 months in rural Zimbabwe and tested the independent and combined effects of improved water, sanitation, and hygiene (WASH), and improved infant and young child feeding (IYCF), on EED. Methodology and findings: The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial was a 2x2 factorial cluster-randomised trial of improved IYCF and improved WASH on child stunting and anaemia at 18 months of age. 1169 infants born to HIV-negative mothers provided plasma and faecal specimens at 1, 3, 6, 12, and 18 months of age. We measured EED biomarkers that reflect all domains of the hypothesized pathological pathway. Markers of intestinal permeability and intestinal inflammation declined over time, while markers of microbial translocation and systemic inflammation increased between 1–18 months. Markers of intestinal damage (I-FABP) and repair (REG-1β) mirrored each other, and citrulline (a marker of intestinal epithelial mass) increased from 6 months of age, suggesting dynamic epithelial turnover and regeneration in response to enteric insults. We observed few effects of IYCF and WASH on EED after adjustment for multiple comparisons. The WASH intervention decreased plasma IGF-1 at 3 months (β:0.89, 95%CI:0.81,0.98) and plasma kynurenine at 12 months (β: 0.92, 95%CI:0.87,0.97), and increased plasma IGF-1 at 18 months (β:1.15, 95%CI:1.05,1.25), but these small WASH effects did not translate into improved growth. Conclusions: Overall, we observed dynamic trends in EED but few effects of IYCF or WASH on biomarkers during the first 18 months after birth, suggesting that these interventions did not impact EED. Transformative WASH interventions are required to prevent or ameliorate EED in low-income settings. Author summary: Child stunting remains a global health challenge rooted in an intergenerational cycle of poor health, reduced neurodevelopment and poverty. Environmental enteric dysfunction (EED) is an acquired condition of the small intestine likely resulting from frequent faecal-oral microbial exposure, which is hypothesized to underlie stunting. We found dynamic changes in EED biomarkers between 1 and 18 months of age in a cohort of rural Zimbabwean infants, suggesting a complex developmental period of intestinal maturation, adaptation and response to environmental insults. Randomized improved infant and young child feeding, and improved water, sanitation and hygiene (WASH) interventions had no meaningful impact on EED. Greater investment in transformative WASH is needed to prevent EED in low-income countries. [ABSTRACT FROM AUTHOR]

Background Oral vaccines have lower efficacy in developing compared to developed countries. Poor water, sanitation, and hygiene (WASH) may contribute to reduced oral vaccine immunogenicity. Methods We conducted a cluster-randomized 2 × 2 factorial trial in rural Zimbabwe. Pregnant women and their infants were eligible if they lived in clusters randomized to (1) standard of care (52 clusters); (2) improved infant feeding (53 clusters); (3) WASH: ventilated improved pit latrine, 2 hand-washing stations, liquid soap, chlorine, infant play space, and hygiene counseling (53 clusters); or (4) feeding plus WASH (53 clusters). This substudy compared oral rotavirus vaccine (RVV) seroconversion (primary outcome), and seropositivity and geometric mean titer (GMT) (secondary outcomes), in WASH vs non-WASH infants by intention-to-treat analysis. Results We included 801 infants with documented RVV receipt and postvaccine titer measurements (329 from 84 WASH clusters; 472 from 102 non-WASH clusters); 328 infants with prevaccination titers were included in the primary outcome. Thirty-three of 109 (30.3%) infants in the WASH group seroconverted following rotavirus vaccination, compared to 43 of 219 (19.6%) in the non-WASH group (absolute difference, 10.6% [95% confidence interval {CI},.54%–20.7%]; P =.031). In the WASH vs non-WASH groups, 90 of 329 (27.4%) vs 107 of 472 (22.7%) were seropositive postvaccination (absolute difference, 4.7% [95% CI, –1.4% to 10.8%]; P =.130), and antirotavirus GMT was 18.4 (95% CI, 15.6–21.7) U/mL vs 14.9 (95% CI, 13.2–16.8) U/mL (P =.072). Conclusions Improvements in household WASH led to modest but significant increases in seroconversion to RVV in rural Zimbabwean infants. Clinical Trials Registration NCT01824940. [ABSTRACT FROM AUTHOR]

Background: 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.Methods and Findings: 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.Conclusions: 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.Trial Registration: ClinicalTrials.gov NCT01824940. [ABSTRACT FROM AUTHOR]

Background: 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. Methods and findings: 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. Conclusions: 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. Trial registration: ClinicalTrials.gov NCT01824940 In this substudy from a 2x2 factorial cluster-randomized trial, Melissa Gladstone and colleagues assess whether improved WASH and/or feeding provide a benefit to early child development. Author summary: Why was this study done?: Some 43% of children globally fail to reach their full developmental potential due to stunting and poverty. Current evidence shows that improved nutrition has a modest effect on early child development. Improving water, sanitation, and hygiene (WASH) may plausibly benefit neurodevelopment through reduced illness and improved gut health (through improving nutrient absorption and optimizing gut–brain communication). What did the researchers do and find?: The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial tested the individual and combined effects of improved complementary feeding (provision of a small quantity of lipid-based nutrient supplement from 6 to 18 months of age, with complementary feeding counseling) and improved household WASH (provision of a pit latrine, handwashing stations, soap, chlorine, and hygiene counseling) on early child development at 24 months. In all, 1,655 children born to HIV-negative women were assessed for gross motor, fine motor, language, cognitive, and social development using tools that were designed and adapted for rural Zimbabwe. We found little evidence that the complementary feeding or WASH interventions tested improved child neurodevelopment at 2 years of age. What do these findings mean?: Complementary feeding and WASH interventions (as described above) may not have a clinically significant impact on child neurodevelopment. More holistic approaches and interventions that explicitly target early child development may be needed to substantially impact child neurodevelopment. [ABSTRACT FROM AUTHOR]

Background: Poverty and human capital development are inextricably linked and therefore research on human capital typically incorporates measures of economic well-being. In the context of randomized trials of health interventions, for example, such measures are used to: 1) assess baseline balance; 2) estimate covariate-adjusted analyses; and 3) conduct subgroup analyses. Many factors characterize economic well-being, however, and analysts often generate summary measures such as indices of household socio-economic status or wealth. In this paper, a household wealth index is developed and tested for participants in the cluster-randomized Sanitation, Hygiene, Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe. Methods: Building on the approach used in the Zimbabwe Demographic and Health Survey (ZDHS), we combined a set of housing characteristics, ownership of assets and agricultural resources into a wealth index using principal component analysis (PCA) on binary variables. The index was assessed for internal and external validity. Its sensitivity was examined considering an expanded set of variables and an alternative statistical approach of polychoric PCA. Correlation between indices was determined using the Spearman’s rank correlation coefficient and agreement between quintiles using a linear weighted Kappa statistic. Using the 2015 ZDHS data, we constructed a separate index and applied the loadings resulting from that analysis to the SHINE study population, to compare the wealth distribution in the SHINE study with rural Zimbabwe. Results: The derived indices using the different methods were highly correlated (r>0.9), and the wealth quintiles derived from the different indices had substantial to near perfect agreement (linear weighted Kappa>0.7). The indices were strongly associated with a range of assets and other wealth measures, indicating both internal and external validity. Households in SHINE were modestly wealthier than the overall population of households in rural Zimbabwe. Conclusion: The SHINE wealth index developed here is a valid and robust measure of wealth in the sample. [ABSTRACT FROM AUTHOR]

Background. Human immunodeficiency virus (HIV)-infected pregnant women increasingly receive antiretroviral therapy (ART) to prevent mother-to-child transmission (PMTCT). Studies suggest HIV-exposed uninfected (HEU) children face higher mortality than HIV-unexposed children, but most evidence relates to the pre-ART era, breastfeeding of limited duration, and considerable maternal mortality. Maternal ART and prolonged breastfeeding while on ART may improve survival, although this has not been reliably quantified. Methods. Individual data on 19 219 HEU children from 21 PMTCT trials/cohorts undertaken from 1995 to 2015 in Africa and Asia were pooled to estimate the association between 24-month mortality and maternal/infant factors, using random-effects Cox proportional hazards models. Adjusted attributable fractions of risks computed using the predict function in the R package "frailtypack" were used to estimate the relative contribution of risk factors to overall mortality. Results. Cumulative incidence of death was 5.5% (95% confidence interval, 5.1-5.9) by age 24 months. Low birth weight (LBW <2500 g, adjusted hazard ratio (aHR, 2.9), no breastfeeding (aHR, 2.5), and maternal death (aHR, 11.1) were significantly associated with increased mortality. Maternal ART (aHR, 0.5) was significantly associated with lower mortality. At the population level, LBW accounted for 16.2% of 24-month mortality, never breastfeeding for 10.8%, mother not receiving ART for 45.6%, and maternal death for 4.3%; combined, these factors explained 63.6% of deaths by age 24 months. Conclusions. Survival of HEU children could be substantially improved if public health practices provided all HIV-infected mothers with ART and supported optimal infant feeding and care for LBW neonates. [ABSTRACT FROM AUTHOR]

Background: Environmental enteric dysfunction (EED) is commonly defined as an acquired subclinical disorder of the small intestine, characterized by villous atrophy and crypt hyperplasia. EED has been proposed to underlie stunted growth among children in developing countries. A collection of biomarkers, organized into distinct domains, has been used to measure different aspects of EED. Here, we examine whether these hypothesized relationships, among EED domains and between each domain and stunting, are supported by data from recent studies. Methodology: A systematic literature search was conducted using PubMed, MEDLINE, EMBASE, Web of Science, and CINAHL between January 1, 2010 and April 20, 2017. Information on study objective, design, population, location, biomarkers, and results were recorded, as well as qualitative and quantitative definitions of EED. Biomarkers were organized into five EED domains, and the number of studies that support or do not support relationships among domains and between each domain with stunting were summarized. Results: There was little evidence to support the pathway from intestinal permeability to microbial translocation and from microbial translocation to stunting, but stronger support existed for the link between intestinal inflammation and systemic inflammation and for intestinal inflammation and stunting. There was conflicting evidence for the pathways from intestinal damage to intestinal permeability and intestinal damage to stunting. Conclusions: These results suggest that certain EED biomarkers may require reconsideration, particularly those most difficult to measure, such as microbial translocation and intestinal permeability. We discuss several issues with currently used biomarkers and recommend further analysis of pathogen-induced changes to the intestinal microbiota as a pathway leading to stunting. [ABSTRACT FROM AUTHOR]

Background: Disease progression is rapid in human immunodeficiency virus (HIV)-infected infants. Whether intestinal damage and inflammation underlie mortality is unknown.Methods: We measured plasma intestinal fatty acid binding protein (I-FABP), soluble CD14 (sCD14), interleukin 6 (IL-6), and C-reactive protein (CRP) at 6 weeks and 6 months of age in 272 HIV-infected infants who either died (cases) or survived (controls), and in 194 HIV-exposed uninfected (HEU) and 197 HIV-unexposed infants. We estimated multivariable odds ratios for mortality and postnatal HIV transmission for each biomarker using logistic regression.Results: At 6 weeks, HIV-infected infants had higher sCD14 and IL-6 but lower I-FABP than HIV-exposed and HIV-unexposed infants (P < .001). CRP was higher in HIV-exposed than HIV-unexposed infants (P = .02). At 6 months, HIV-infected infants had highest sCD14, IL-6, and CRP concentrations (P < .001) and marginally higher I-FABP than other groups (P = .07). CRP remained higher in HIV-exposed vs HIV-unexposed infants (P = .04). No biomarker was associated with mortality in HIV-infected infants, or with odds of breast-milk HIV transmission in HIV-exposed infants.Conclusions: HIV-infected infants have elevated inflammatory markers by 6 weeks of age, which increase over time. In contrast to adults and older children, inflammatory biomarkers were not associated with mortality. HEU infants have higher inflammation than HIV-unexposed infants until at least 6 months, which may contribute to poor health outcomes. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) acquisition and inflammation were evaluated in 231 human immunodeficiency virus (HIV)-exposed uninfected (HEU) and 100 HIV-unexposed Zimbabwean infants aged 6 weeks. The HEU and HIV-unexposed infants had a similarly high prevalence of CMV (81.4% vs 74.0%, respectively; P = .14), but HEU infants had higher CMV loads (P = .005) and >2-fold higher C-reactive protein (CRP) concentrations (P < .0001). The CMV-positive HEU infants had higher CRP than the CMV-negative HEU infants; this association disappeared after adjusting for maternal HIV load. Overall, CMV acquisition is high in early life, but HEU infants have higher CMV loads and a proinflammatory milieu, which may be driven partly by maternal HIV viremia. [ABSTRACT FROM AUTHOR]

Background: In sub-Saharan Africa, one-third of all births are small for gestational age (SGA), and 4.4 million children are stunted; both conditions increase the risk of child mortality. SGA has also been shown to increase the risk of stunting.Objective: We tested whether the association between SGA and postneonatal mortality is mediated by stunting.Methods: We used longitudinal data from children aged 6 wk to 24 mo (n = 12,155) enrolled in the ZVITAMBO (Zimbabwe Vitamin A for Mothers and Babies) trial. HIV exposure was defined based on maternal HIV status at baseline. SGA was defined as birthweight <10th percentile of the INTERGROWTH-21st (International Fetal and Newborn Growth Consortium for the 21st Century) standards. We used a standard mediation approach by comparing the attenuation of the risk when the mediator was added to the model. We used Cox proportional hazards models first to regress SGA on postneonatal mortality, controlling for age. Stunting (length-for-age z score <-2) was then included in the model to test mediation.Results: Approximately 20% of children were term SGA, and 23% were stunted before their last follow-up visit. In this cohort, 31% of children were exposed to HIV; the HIV-exposed group represented a pooled group of HIV-infected and HIV-exposed but uninfected children. Postneonatal mortality was significantly higher among children born SGA (HR: 1.5; 95% CI: 1.3, 1.7). This association was attenuated and not statistically significant when stunting was included in the model, suggesting a mediation effect (HR: 1.1; 95% CI: 0.91, 1.3). When stratified by HIV exposure status, we observed a significant attenuation of the risk, suggesting mediation, only among HIV-exposed children (model 1, HR: 1.3; 95% CI: 1.1, 1.6; model 2, HR: 1.1; 95% CI: 0.88, 1.3).Conclusions: This analysis aids in investigating pathways that underlie an observed SGA-mortality relation and may inform survival interventions in undernourished settings. [ABSTRACT FROM AUTHOR]

Access to water and sanitation are important determinants of behavioral responses to hygiene and sanitation interventions. We estimated cluster-specific water access and sanitation coverage to inform a constrained randomization technique in the SHINE trial. Technicians and engineers inspected all public access water sources to ascertain seasonality, function, and geospatial coordinates. Households and water sources were mapped using open-source geospatial software. The distance from each household to the nearest perennial, functional, protected water source was calculated, and for each cluster, the median distance and the proportion of households within <500 m and >1500 m of such a water source. Cluster-specific sanitation coverage was ascertained using a random sample of 13 households per cluster. These parameters were included as covariates in randomization to optimize balance in water and sanitation access across treatment arms at the start of the trial. The observed high variability between clusters in both parameters suggests that constraining on these factors was needed to reduce risk of bias. [ABSTRACT FROM AUTHOR]