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Almost all existing evidence that sanitation benefits human health comes from cross-sectional, prospective cohort, case-control, and non-randomised intervention studies. [...] all have methodological issues, including potential confounding by socioeconomic status, lack of adequate control in before-after programme assessments, and inadequate statistical power when a single control community is compared with a single intervention community.17 Nonetheless, many of these studies have documented benefits on child growth.18 Indeed, in an analysis of demographic and health survey data from eight countries, Esrey19 estimated that improvements in sanitation were associated with length-for-age Z score increments of 0.06-0.62 in children living in rural areas and 0.26-0.65 in children living in urban areas, which are similar to the growth effects of dietary interventions reviewed earlier in this report4 (ie, 0.00-0.64). [...] from a mean length-for-age Z score (SD) of -1.69 (1.45) in rural children and -1.19 (1.45) in urban children, these increments correspond to 4-37% and 20-46% decreases in stunting prevalence in rural and urban children, respectively, suggesting a considerably greater effect than the 2.4% decrease previously estimated in the Lancet Series.7 Undoubtedly, the complex problem of child undernutrition will not be solved with toilets and handwashing alone.

Stunting affects one-in-five children globally and is associated with greater infectious morbidity, mortality and neurodevelopmental deficits. Recent evidence suggests that the early-life gut microbiome affects child growth through immune, metabolic and endocrine pathways. Using whole metagenomic sequencing, we map the assembly of the gut microbiome in 335 children from rural Zimbabwe from 1–18 months of age who were enrolled in the Sanitation, Hygiene, Infant Nutrition Efficacy Trial (SHINE; NCT01824940), a randomized trial of improved water, sanitation and hygiene (WASH) and infant and young child feeding (IYCF). Here, we show that the early-life gut microbiome undergoes programmed assembly that is unresponsive to the randomized interventions intended to improve linear growth. However, maternal HIV infection is associated with over-diversification and over-maturity of the early-life gut microbiome in their uninfected children, in addition to reduced abundance of Bifidobacterium species. Using machine learning models (XGBoost), we show that taxonomic microbiome features are poorly predictive of child growth, however functional metagenomic features, particularly B-vitamin and nucleotide biosynthesis pathways, moderately predict both attained linear and ponderal growth and growth velocity. New approaches targeting the gut microbiome in early childhood may complement efforts to combat child undernutrition. Here, using metagenomics, the authors show that the gut microbiome of rural Zimbabwean infants undergoes programmed maturation that is unresponsive to sanitation and nutrition interventions but is strongly associated with maternal HIV infection and can moderately predict linear growth.

Background Three large new trials of unprecedented scale and cost, which included novel factorial designs, have found no effect of basic water, sanitation and hygiene (WASH) interventions on childhood stunting, and only mixed effects on childhood diarrhea. Arriving at the inception of the United Nations’ Sustainable Development Goals, and the bold new target of safely managed water, sanitation and hygiene for all by 2030, these results warrant the attention of researchers, policy-makers and practitioners. Main body Here we report the conclusions of an expert meeting convened by the World Health Organization and the Bill and Melinda Gates Foundation to discuss these findings, and present five key consensus messages as a basis for wider discussion and debate in the WASH and nutrition sectors. We judge these trials to have high internal validity, constituting good evidence that these specific interventions had no effect on childhood linear growth, and mixed effects on childhood diarrhea. These results suggest that, in settings such as these, more comprehensive or ambitious WASH interventions may be needed to achieve a major impact on child health. Conclusion These results are important because such basic interventions are often deployed in low-income rural settings with the expectation of improving child health, although this is rarely the sole justification. Our view is that these three new trials do not show that WASH in general cannot influence child linear growth, but they do demonstrate that these specific interventions had no influence in settings where stunting remains an important public health challenge. We support a call for transformative WASH, in so much as it encapsulates the guiding principle that – in any context – a comprehensive package of WASH interventions is needed that is tailored to address the local exposure landscape and enteric disease burden.

Stunting affects one-third of children in developing countries, but the causes remain unclear. We hypothesized that enteropathy leads to low-grade inflammation, which suppresses the growth hormone-IGF axis and mediates stunting. We conducted a case-control study of 202 HIV-unexposed Zimbabwean infants who were stunted (height-for-age Z-score (HAZ) <-2; cases) or non-stunted (HAZ >-0.5; controls) at 18 months. We measured biomarkers of intestinal damage (I-FABP), inflammation (CRP, AGP, IL-6) and growth hormone-IGF axis (IGF-1, IGFBP3) in infant plasma at 6 weeks and 3, 6, 12 and 18 months, and in paired maternal-infant plasma at birth. Adjusted mean differences between biomarkers were estimated using regression models. Multivariate odds ratios of stunting were estimated by logistic regression. At birth, cases were shorter (median (IQR) HAZ -1.00 (-1.53, -0.08) vs 0.03 (-0.57, 0.62,); P<0.001) than controls and their mothers had lower levels of IGF-1 (adjusted mean difference (95%CI) -21.4 (-39.8, -3.1) ng/mL). From 6 weeks to 12 months of age, levels of CRP and AGP were consistently higher and IGF-1 and IGFBP3 lower in cases versus controls; IGF-1 correlated inversely with inflammatory markers at all time-points. I-FABP increased between 3-12 months, indicating extensive intestinal damage during infancy, which was similar in cases and controls. In multivariate analysis, higher log10 levels of CRP (aOR 3.06 (95%CI 1.34, 6.99); P = 0.008) and AGP (aOR 7.87 (95%CI 0.74, 83.74); P = 0.087) during infancy were associated with stunting. There were no associations between levels of I-FABP, IL-6, sCD14 or EndoCAb and stunting. Stunting began in utero and was associated with low maternal IGF-1 levels at birth. Inflammatory markers were higher in cases than controls from 6 weeks of age and were associated with lower levels of IGF-1 throughout infancy. Higher levels of CRP and AGP during infancy were associated with stunting. These findings suggest that an extensive enteropathy occurs during infancy and that low-grade chronic inflammation may impair infant growth.

The ZVITAMBO trial recruited 14,110 mother-infant pairs to a randomized controlled trial of vitamin A between 1997 and 2000, before the availability of antiretroviral therapy for HIV prophylaxis or treatment in Zimbabwe. The HIV status of mothers and infants was well characterized through 1-2 years of follow-up, leading to the largest cohort to date of HIV-exposed uninfected (HEU) infants (n = 3135), with a suitable comparison group of HIV-unexposed infants (n = 9510). Here, we draw on 10 years of published findings from the ZVITAMBO trial. HEU infants had increased morbidity compared to HIV-unexposed infants, with 50% more hospitalizations in the neonatal period and 30% more sick clinic visits during infancy, particularly for skin infections, lower respiratory tract infections, and oral thrush. HEU children had 3.9-fold and 2.0-fold higher mortality than HIV-unexposed children during the first and second years of life, respectively, most commonly due to acute respiratory infections, diarrhea/dysentery, malnutrition, sepsis, and meningitis. Infant morbidity and mortality were strongly related to maternal HIV disease severity, and increased morbidity remained until maternal CD4 counts were >800 cells/μL. HEU infants were more likely to be premature and small-for-gestational age than HIV-unexposed infants, and had more postnatal growth failure. Here, we propose a conceptual framework to explain the increased risk of infectious morbidity, mortality, and growth failure among HEU infants, hypothesizing that immune activation and inflammation are key drivers of both infection susceptibility and growth failure. Future studies should further dissect the causes of infection susceptibility and growth failure and determine the impact of ART and cotrimoxazole on outcomes of this vulnerable group of infants in the current era.

Children who are HIV-exposed but uninfected have increased infectious mortality compared to HIV-unexposed children, raising the possibility of immune abnormalities following exposure to maternal viraemia, immune dysfunction, and co-infections during pregnancy. In a secondary analysis of the SHINE trial in rural Zimbabwe we explored biological pathways underlying infant mortality, and maternal factors shaping immune development in HIV-exposed uninfected infants. Maternal inflammation and cytomegalovirus viraemia were independently associated with infant deaths: mortality doubled for each log 10 rise in maternal C-reactive protein (adjusted hazard ratio (aHR) 2.09; 95% CI 1.33–3.27), and increased 1.6-fold for each log 10 rise in maternal cytomegalovirus viral load (aHR 1.62; 95% CI 1.11–2.36). In girls, mortality was more strongly associated with maternal C-reactive protein than cytomegalovirus; in boys, mortality was more strongly associated with cytomegalovirus than C-reactive protein. At age one month, HIV-exposed uninfected infants had a distinct immune milieu, characterised by raised soluble CD14 and an altered CD8 + T-cell compartment. Alterations in immunophenotype and systemic inflammation were generally greater in boys than girls. Collectively, these findings show how the pregnancy immune environment in women with HIV underlies mortality and immune development in their offspring in a sex-differentiated manner, and highlights potential new intervention strategies to transform outcomes of HIV-exposed children. ClinicalTrials.gov/NCT01824940. HIV exposed but uninfected infants may face an increased risk of serious infection and mortality. In this work, the authors utilise a cohort from rural Zimbabwe to explore the biological mechanisms underlying infant mortality.

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. 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. 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. ClinicalTrials.gov NCT01824940.

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. 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. 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. The SHINE wealth index developed here is a valid and robust measure of wealth in the sample.

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. 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. 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. 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.

BackgroundChildren who are stunted (length-for-age Z-score<-2) are at greater risk of infectious morbidity and mortality. Previous studies suggest that stunted children have elevated inflammatory biomarkers, but no studies have characterised their capacity to respond to new infections (i.e., their immune function). We hypothesised that antibacterial immune function would differ between stunted and non-stunted children and relate to their health and environment during early life.MethodsWe enrolled a cross-sectional cohort of 113 HIV-negative children nested within a longitudinal cluster-randomised controlled trial of household-level infant and young child feeding (IYCF) and water, sanitation and hygiene (WASH) interventions in rural Zimbabwe (SHINE; Clinical trials registration: NCT01824940). Venous blood was collected at 18 months of age and cultured for 24 h without antigen or with bacterial antigens: heat-killed Salmonella typhimurium (HKST) or Escherichia coli lipopolysaccharide (LPS). TNFα, IL-6, IL-8, IL-12p70, hepcidin, soluble (s)CD163, myeloperoxidase (MPO) and IFNβ were quantified in culture supernatants by ELISA to determine antigen-specific immune function. The effect of stunting status and early-life exposures (anthropometry, inflammation at 18 months, maternal health during pregnancy, household WASH) on immune function was tested in logit and censored log-normal (tobit) regression models.ResultsChildren who were stunted (n = 44) had higher proportions (86.4% vs. 65.2%; 88.6% vs . 73.4%) and concentrations of LPS-specific IL-6 (geometric mean difference (95% CI): 3.46 pg/mL (1.09, 10.80), p = 0.035) and IL-8 (3.52 pg/mL (1.20, 10.38), p = 0.022) than non-stunted children (n = 69). Bacterial antigen-specific pro-inflammatory cytokine concentrations were associated with biomarkers of child enteropathy at 18 months and biomarkers of systemic inflammation and enteropathy in their mothers during pregnancy. Children exposed to the WASH intervention (n = 33) produced higher LPS- (GMD (95% CI): 10.48 pg/mL (1.84, 60.31), p = 0.008) and HKST-specific MPO (5.10 pg/mL (1.77, 14.88), p = 0.003) than children in the no WASH group (n = 80). There was no difference in antigen-specific immune function between the IYCF (n = 55) and no IYCF groups (n = 58).ConclusionsAntibacterial immune function among 18-month-old children in a low-income setting was shaped by their stunting status and prior exposure to maternal inflammation and household WASH. Heterogeneity in immune function due to adverse exposures in early life could plausibly contribute to infection susceptibility.