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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.

We developed the School-Age Health, Activity, Resilience, Anthropometry and Neurocognitive (SAHARAN) toolbox to address the shortage of school-age assessment tools that combine growth, physical and cognitive function. Here we present i) development, acceptability and feasibility of the SAHARAN toolbox; ii) characteristics of a pilot cohort; and iii) associations between the domains measured in the cohort. Growth was measured with anthropometry, knee-heel length and skinfold thicknesses. Bioimpedance analysis measured lean mass index and phase angle. Cognition was assessed using the mental processing index, derived from the Kaufman Assessment Battery for Children version 2, a fine motor finger-tapping task, and School Achievement Test (SAT). Physical function combined grip strength, broad jump and the 20m shuttle-run test to produce a total physical score. A caregiver questionnaire was performed in parallel. The SAHARAN toolbox was feasible to implement in rural Zimbabwe, and highly acceptable to children and caregivers following some minor modifications. Eighty children with mean (SD) age 7.6 (0.2) years had mean height-for-age (HAZ) and weight-for-age Z-scores (WAZ) of -0.63 (0.81) and -0.55 (0.85), respectively. Lean mass index and total skinfold thicknesses were related to WAZ and BMI Z-score, but not to HAZ. Total physical score was associated with unit rises in HAZ (1.29, 95% CI 0.75, 1.82, p<0.001), and lean mass index (0.50, 95% CI 0.16, 0.83, p = 0.004), but not skinfold thicknesses. The SAT was associated with unit increases in the mental processing index and child socioemotional score. The caregiver questionnaire identified high levels of adversity and food insecurity. The SAHARAN toolbox provided a feasible and acceptable holistic assessment of child growth and function in mid-childhood. We found clear associations between growth, height-adjusted lean mass and physical function, but not cognitive function. The SAHARAN toolbox could be deployed to characterise school-age growth, development and function elsewhere in sub-Saharan Africa.

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.

Infants commonly develop fever after vaccination, meaning distinguishing illness from postvaccine symptoms is challenging. C reactive-protein (CRP) is often measured in febrile infants for consideration of antibiotics to treat a bacterial infection1; however, a rise in CRP post vaccination was reported in healthy children in Canada and Korea.2 3 The median CRP after meningococcal B vaccination was 12 mg/L in UK children (peak 160 mg/L).4

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.

IntroductionMaternal responsiveness, defined as a mother’s ability to perceive her infant’s behaviour and respond appropriately, may be compromised with maternal depression and thereby impact early child development (ECD). These relationships have not been studied comprehensively in sub-Saharan Africa, where two-thirds of children are at risk of not reaching their developmental potential. This sub-study of the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe evaluated the relationship between maternal-child interaction, maternal depressive symptoms and ECD using validated tools.MethodsThe Edinburgh Postnatal Depression Scale (EPDS) and Observed Mother-Child Interaction (OMCI) tool were administered to mother-infant dyads in the cluster-randomised trial. ECD was assessed using the Malawi Developmental Assessment Tool (MDAT) and MacArthur-Bates Communicative Development Inventory (CDI). Generalised estimating equations were used to estimate effect sizes while accounting for within-cluster correlation and primary results were adjusted for confounding factors.ResultsA total of 540 mother-infant dyads were included. 5.5% of mothers met the EPDS cut-off score for depressive symptoms. There was a positive association between OMCI score and MDAT motor, language and MacArthur-Bates CDI. For every 10 unit change in total OMCI score, there was a rise of 5.1 units (95% CI 3.6 to 6.6) in total MDAT score (out of 138 points), equivalent to a 0.54 SD increase. There was no statistically significant association between EPDS score and OMCI or ECD scores.ConclusionWithin a sample of rural Zimbabwean mother-infant dyads undergoing directly observed assessment, quality of maternal-child interaction was associated with ECD scores at 24 months of age.

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.

Globally, over 16 million children were exposed to HIV during pregnancy but remain HIV-free at birth and throughout childhood by 2022. Children born HIV-free (CBHF) have higher morbidity and mortality and poorer neurodevelopment in early life compared to children who are HIV-unexposed (CHU), but long-term outcomes remain uncertain. We characterised school-age growth, cognitive and physical function in CBHF and CHU previously enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe. The SHINE trial enrolled pregnant women between 2012 and 2015 across 2 rural Zimbabwean districts. Co-primary outcomes were height-for-age Z-score and haemoglobin at age 18 months (clinicaltrials.gov NCT01824940). Children were re-enrolled if they were aged 7 years, resident in Shurugwi district, and had known pregnancy HIV-exposure status. From 5,280 pregnant women originally enrolled, 376 CBHF and 2016 CHU reached the trial endpoint at 18 months in Shurugwi; of these, 264 CBHF and 990 CHU were evaluated at age 7 years using the School-Age Health, Activity, Resilience, Anthropometry and Neurocognitive (SAHARAN) toolbox. Cognitive function was evaluated using the Kaufman Assessment Battery for Children (KABC-II), with additional tools measuring executive function, literacy, numeracy, fine motor skills, and socioemotional function. Physical function was assessed using standing broad jump and handgrip for strength, and the shuttle-run test for cardiovascular fitness. Growth was assessed by anthropometry. Body composition was assessed by bioimpedance analysis and skinfold thicknesses. A caregiver questionnaire measured demographics, socioeconomic status, nurturing, child discipline, food, and water insecurity. We prespecified the primary comparisons and used generalised estimating equations with an exchangeable working correlation structure to account for clustering. Adjusted models used covariates from the trial (study arm, study nurse, exact child age, sex, calendar month measured, and ambient temperature). They also included covariates derived from directed acyclic graphs, with separate models adjusted for contemporary variables (socioeconomic status, household food insecurity, religion, social support, gender norms, caregiver depression, age, caregiver education, adversity score, and number of children's books) and early-life variables (length-for-age-Z-score) at 18 months, birthweight, maternal baseline depression, household diet, maternal schooling and haemoglobin, socioeconomic status, facility birth, and gender norms. We applied a Bonferroni correction for the 27 comparisons (0.05/27) with threshold of p < 0.00185 as significant. We found strong evidence that cognitive function was lower in CBHF compared to CHU across multiple domains. The KABC-II mental processing index was 45.2 (standard deviation (SD) 10.5) in CBHF and 48.3 (11.3) in CHU (mean difference 3.3 points [95% confidence interval (95% CI) 2.0, 4.5]; p < 0.001). The school achievement test score was 39.0 (SD 26.0) in CBHF and 45.7 (27.8) in CHU (mean difference 7.3 points [95% CI 3.6, 10.9]; p < 0.001); differences remained significant in adjusted analyses. Executive function was reduced but not significantly in adjusted analyses. We found no consistent evidence of differences in growth or physical function outcomes. The main limitation of our study was the restriction to one of two previous study districts, with possible survivor and selection bias. In this study, we found that CBHF had reductions in cognitive function compared to CHU at 7 years of age across multiple domains. Further research is needed to define the biological and psychosocial mechanisms underlying these differences to inform future interventions that help CBHF thrive across the life-course. ClinicalTrials.gov The SHINE follow-up study was registered with the Pan-African Clinical Trials Registry (PACTR202201828512110). The original SHINE trial was registered at NCT https://clinicaltrials.gov/study/NCT01824940.

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.

IntroductionStunting or linear growth faltering, measured by length-for-age Z-score (LAZ), remains a significant public health challenge, particularly in rural low-income and middle-income countries. It is a marker of inadequate environments in which infants are born and raised. However, the contributions of household resource insecurities, such as food and water, to growth and growth trajectory are understudied.MethodsWe used the cluster-randomised Sanitation Hygiene and Infant Nutrition Efficacy trial to determine the association of household-level food insecurity (FI) and water insecurity (WI) on LAZ and LAZ trajectory among infants during early life. Dimensions of FI (poor access, household shocks, low availability and quality) and WI (poor access, poor quality, low reliability) were assessed with the multidimensional household food insecurity and the multidimensional household water insecurity measures. Infant length was converted to LAZ based on the 2006 WHO Child Growth Standards. We report the FI and WI fixed effects from multivariable growth curve models with repeated measures of LAZ at 1, 3, 6, 12 and 18 months (M1–M18).ResultsA total of 714 and 710 infants were included in our analyses of LAZ from M1 to M18 and M6 to M18, respectively. Mean LAZ values at each time indicated worsening linear growth. From M1 to M18, low food availability and quality was associated with lower LAZ (β=−0.09; 95% −0.19 to –0.13). From M6 to M18, poor food access was associated with lower LAZ (β=−0.11; 95% −0.20 to –0.03). None of the WI dimensions were associated with LAZ, nor with LAZ trajectory over time.ConclusionFI, but not WI, was associated with poor linear growth among rural Zimbabwean infants. Specifically, low food availability and quality and poor food access was associated with lower LAZ. There is no evidence of an effect of FI or WI on LAZ trajectory.