Stunting is characterized by chronic inflammation in Zimbabwean infants.
ABSTRACT: 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.
Project description:BACKGROUND:Stunting affects up to one-third of the children in low-to-middle income countries (LMICs) and has been correlated with decline in cognitive capacity and vaccine immunogenicity. Early identification of infants at risk is critical for early intervention and prevention of morbidity. The aim of this study was to investigate patterns of growth in infants up through 48?months of age to assess whether the growth of infants with stunting eventually improved as well as the potential predictors of growth. METHODS:Height-for-age z-scores (HAZ) of children from Matiari (rural site, Pakistan) at birth, 18?months, and 48?months were obtained. Results of serum-based biomarkers collected at 6 and 9?months were recorded. A descriptive analysis of the population was followed by assessment of growth predictors via traditional machine learning random forest models. RESULTS:Of the 107 children who were followed up till 48?months of age, 51% were stunted (HAZ?<?-?2) at birth which increased to 54% by 48?months of age. Stunting status for the majority of children at 48?months was found to be the same as at 18?months. Most children with large gains started off stunted or severely stunted, while all of those with notably large losses were not stunted at birth. Random forest models identified HAZ at birth as the most important feature in predicting HAZ at 18?months. Of the biomarkers, AGP (Alpha- 1-acid Glycoprotein), CRP (C-Reactive Protein), and IL1 (interleukin-1) were identified as strong subsequent growth predictors across both the classification and regressor models. CONCLUSION:We demonstrated that children most children with stunting at birth remained stunted at 48?months of age. Value was added for predicting growth outcomes with the use of traditional machine learning random forest models. HAZ at birth was found to be a strong predictor of subsequent growth in infants up through 48?months of age. Biomarkers of systemic inflammation, AGP, CRP, IL1, were also strong predictors of growth outcomes. These findings provide support for continued focus on interventions prenatally, at birth, and early infancy in children at risk for stunting who live in resource-constrained regions of the world.
Project description:Environmental enteric dysfunction (EED) is an intestinal disorder common among children in low-resource settings and is associated with increased risk of growth stunting, cognitive deficits, and reduced oral vaccine immunogenicity. The Micronutrient and EED Assessment Tool (MEEDAT) is a multiplexed immunoassay that measures biomarkers previously associated with child growth faltering and/or oral vaccine immunogenicity: intestinal fatty acid-binding protein (I-FABP), soluble CD14 (sCD14), insulin-like growth factor 1 (IGF-1), and fibroblast growth factor 21 (FGF21). MEEDAT also measures systemic inflammation (?1-acid glycoprotein, C-reactive protein), ferritin, soluble transferrin receptor, retinol binding protein 4, thyroglobulin, and Plasmodium falciparum antigenemia (histidine-rich protein 2). The performance of MEEDAT was compared with commercially available enzyme-linked immunosorbent assays (ELISAs) using 300 specimens from Malian infant clinical trial participants. Regression methods were used to test if MEEDAT biomarkers were associated with seroconversion to meningococcal A conjugate vaccine (MenAV), yellow fever vaccine (YFV), and pentavalent rotavirus vaccine (PRV) after 28 days, or with growth faltering over 12 weeks. The Pearson correlations between the MEEDAT and ELISA results were 0.97, 0.86, 0.80, and 0.97 for serum I-FABP, sCD14, IGF-1, and FGF21, respectively. There were significant associations between I-FABP concentration and the probability of PRV IgG seroconversion and between IGF-1 concentration and the probability of YFV seroconversion. In multivariable models neither association remained significant, however there was a significant negative association between AGP concentration and YFV seroconversion. GLP-2 and sCD14 concentrations were significantly negatively associated with 12-week change in weight-for-age z-score and weight-for-height z-score in multivariable models. MEEDAT performed well in comparison to commercially-available ELISAs for the measurement of four analytes for EED and growth hormone resistance. Adoption of MEEDAT in low-resource settings could help accelerate the identification of interventions that prevent or treat child stunting and interventions that boost the immunogenicity of child vaccinations.
Project description:Stunting can afflict up to one-third of children in resource-constrained countries. We hypothesized that low-grade systemic inflammation (defined as elevations in serum C-reactive protein or alpha-1-acid glycoprotein) in infancy suppresses the growth hormone?insulin-like growth factor (IGF) axis and is associated with subsequent stunting. Blood samples of 590 children from periurban Dar es Salaam, Tanzania, were obtained at 6 weeks and 6 months of age as part of a randomized controlled trial. Primary outcomes were stunting, underweight, and wasting (defined as length-for-age, weight-for-age and weight-for-length z-scores < -2) between randomization and endline (18 months after randomization). Cox proportional hazards models were constructed to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) of time to first stunting, underweight, and wasting as outcomes, with measures of systemic inflammation, insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) as exposures, adjusting for numerous demographic and clinical variables. The incidences of subsequent stunting, underweight, and wasting were 26%, 20%, and 18%, respectively. In multivariate analyses, systemic inflammation at 6 weeks of age was significantly associated with stunting (HR: 2.14, 95% CI: 1.23, 3.72; p = 0.002). Children with higher levels of IGF-1 at 6 weeks were less likely to become stunted (HR: 0.58, 95% CI: 0.37, 0.93; p for trend = 0.019); a similar trend was noted in children with higher levels of IGF-1 at 6 months of age (HR: 0.50, 95% CI: 0.22, 1.12; p for trend = 0.07). Systemic inflammation occurs as early as 6 weeks of age and is associated with the risk of future stunting among Tanzanian children.
Project description:BACKGROUND:Stunting is a worldwide public health problem caused by factors that vary across regions, including in Ethiopia. Limited evidence to prevent stunting makes it difficult to design and prioritize appropriate interventions. Therefore, this study investigated the intervention priorities for the prevention of stunting among children 6-59 months old in Kemissie City Administration, northeastern Ethiopia. METHODS:A community-based individual matched case-control study was conducted from January to April 2017 including 107 cases and 214 controls. Controls were selected and matched with cases using the matching variable of child's age. Data were collected by open data kit (ODK) software using a structured questionnaire. Data were analyzed using STATA version 13.0 and WHO (World Health Organization) Anthro 2005. A conditional logistic regression model was used for data analysis. From multivariable conditional logistic regression analysis, determinants of stunting were identified. A statistically significant level was declared by a conditional adjusted odds ratio (cAOR) with 95% confidence interval (CI) and p-value of less than 0.05. MAIN FINDINGS:The wealth index 52 (48.6%) of the cases and 108 (50.5%) controls were categorized as poor. The mean height-for-age z-score (HAZ) for the cases and controls was -2.79±.67 and -0.55±.92, respectively. One-sixth (16.8%) of the cases and 29 (13.6%) of the controls were given prelacteal feeding. A majority 82 (86.9%) of the cases and 137 (69.1%) of the controls had undernourished mothers/care-givers. Slightly less than one-third 35 (32.7%) of cases and one-fourth 53 (24.8%) of controls were affected by repeated episodes of diarrhea. Mother's body mass index (BMI) (conditional adjusted odds ratio [cAOR]) = 2.64; 95% CI: 1.28, 5.43), giving food priority to father (cAOR = 2.42; 95% CI: 1.23, 4.75), lack of exclusive breastfeeding for at least 6 months (cAOR = 2.44; 95% CI: 1.15, 5.17), no intake of meat by child (cAOR = 2.35; 95% CI: 1.21, 4.58) and child having repeated diarrheal episodes (cAOR = 2.0: 95% CI: 1.07, 3.86) were factors associated with childhood stunting. CONCLUSION:Maternal nutritional status, food priority, duration of exclusive breastfeeding, no intake of meat and repeated episodes of diarrhea were the main determinants of stunting among children aged 6-59 months. Therefore, intervention measures to avert childhood stunting should include strengthening action on provision of essential nutrition, providing counseling to parents on giving food priority to children, promotion of optimal duration of breastfeeding and preventing diarrheal disease among children 6-59 months old.
Project description:Background: Optimizing linear growth in children during complementary feeding period (CFP) (6-24 months) are critical for their development. Several interventions, such as micronutrient and food supplements, deworming, maternal education, and water, sanitation and hygiene (WASH), could potentially be provided to prevent stunting, but their comparative effectiveness is currently unclear. In this study, we evaluated comparative effectiveness of interventions under these domains on child linear growth outcomes of height-for-age z-score (HAZ) and stunting (HAZ <-2SD) Methods: For this study, we searched for low- and middle-income country (LMIC)-based randomized clinical trials (RCTs) of aforementioned interventions provided to children during CFP. We searched for reports published until September 17, 2019 and hand-searched bibliographies of existing reviews. We performed random-effects network meta-analysis (NMA) for HAZ and stunting. Results: The evidence base for our NMA was based on 79 RCTs (96 papers) involving 81,786 children. Among the micronutrients, compared to standard-of-care, iron + folic acid (IFA) (mean difference =0.08; 95% credible interval [CrI]: 0.01, 0.15) and multiple micronutrients (MMN) (mean difference =0.06; 95%CrI: 0.01, 0.11) showed improvements for HAZ; MMN also reduced the risks for stunting (RR=0.86; 95%Crl: 0.73, 0.98), whereas IFA did not (RR=0.92; 95%Crl: 0.64, 1.23). For food supplements, flour in the caloric range of 270-340 kcal (RR=0.73; 95%Crl: 0.51, 1.00) and fortified lipid-based nutrient supplements (LNS) containing 220-285 kcal (RR=0.80; 95%Crl: 0.66, 0.97) decreased the risk of stunting compared to standard-of-care, but these interventions and other food supplements did not show improvements for HAZ. Deworming, maternal education, and WASH interventions did not show improvements for HAZ nor stunting. Conclusion: While we found micronutrient and food supplements to be effective for HAZ and/or stunting, the evidence base for other domains in this life stage was limited, highlighting the need for more investigation. Registration: PROSPERO CRD42018110449; registered on 17 October 2018.
Project description:Breastfeeding promotion is regarded as one of the most effective interventions to improve child health, and could reduce under-5-mortality by 8 % globally. Few studies have assessed the health outcomes beyond infancy of interventions promoting exclusive breastfeeding.This study assessed growth in under-five children who participated in a cluster-randomised trial in Eastern Uganda (ClinicalTrials.gov.no.NCT00397150). In the intervention arm, peer counsellors promoted exclusive breastfeeding during the first 6 months of infancy. There were no interventions after 6 months of age. Mother-infant pairs were interviewed at visits scheduled at 3, 6, 12 and 24 weeks after birth and follow-up visits at 2 and 5 years, with 765 included in the analyses.The mean length/height-for-age and weight-for-age-z-score (HAZ, WAZ) decreased with increasing age in both the intervention and control arms. At the three weeks visit, HAZ in the intervention was -0.45 (-0.68;-0.21) and -0.32 (-0.56;-0.07) in the control arm. At the 2 year follow-up, the mean HAZ in the intervention was -1.85 (95 % CI -1.97;-1.73) compared to -1.61 (-1.87;-1.34) in the control. Similarly, at the 5 year follow-up, the mean HAZ in the intervention was -1.78 (-2.08;-1.47) compared to -1.53 (-1.79;-1.28) in the control arm. At the 2 year follow-up visit, 139 (45 %) were stunted (HAZ<-2) in the intervention compared to 109 (37 %) in the control arm, odds ratio (OR) 1.7 (1.1;2.4). Underweight (WAZ<-2) was also more common in the intervention arm than in the control at the five years follow-up (OR 1.7 (1.0;2.8)), with a mean WAZ of -1.28 (-1.47;-1.08) and -1.06 (-1.19;-0.92) in the intervention and control arm, respectively.While stunting was widespread at 2 and 5 years of age in both arms, it was more common in the intervention arm. It is questionable whether community-based support from lay people with short training and focussing only on exclusive breastfeeding, is an appropriate strategy to improve child health and development.ClinicalTrials.gov.no. NCT00397150 . Registered 7th of November 2006.
Project description:Environmental Enteric Dysfunction (EED), a syndrome characterized by chronic gut inflammation, contributes towards stunting and poor response to enteric vaccines in children in developing countries. In this study, we evaluated major putative biomarkers of EED using growth faltering as its clinical proxy. Newborns (n?=?380) were enrolled and followed till 18 months with monthly anthropometry. Biomarkers associated with gut and systemic inflammation were assessed at 6 and 9 months. Linear mixed effects model was used to determine the associations of these biomarkers with growth faltering between birth and 18 months. Fecal myeloperoxidase (neutrophil activation marker) at 6 months [??=?-0.207, p?=?0.005], and serum GLP 2 (enterocyte proliferation marker) at 6 and 9 months [6M: ??=?-0.271, p?=?0.035; 9M: ??=?-0.267, p?=?0.045] were associated with decreasing LAZ score. Ferritin at 6 and 9 months was associated with decreasing LAZ score [6M: ??=?-0.882, p?<?0.0001; 9M: ??=?-0.714, p?<?0.0001] and so was CRP [??=?-0.451, p?=?0.039] and AGP [??=?-0.443, p?=?0.012] at 9 months. Both gut specific and systemic biomarkers correlated negatively with IGF-1, but only weakly correlated, if at all with each other. We therefore conclude that EED may be contributing directly towards growth faltering, and this pathway is not entirely through the pathway of systemic inflammation.
Project description:Stunting, defined as height-for-age Z score equal to or lower than -2, is associated with increased childhood mortality, cognitive impairment, and chronic diseases. The aim of the study was to investigate the relationship between linear growth, intestinal damage, and systemic inflammation in infants at risk of stunting. We followed up 78 infants aged 5-12 months living in rural areas of Peru for 6 months. Blood samples for biomarkers of intestinal damage (intestinal fatty-acid-binding protein [I-FABP] and zonulin) and systemic inflammation (interleukin-1?, interleukin-6, tumor necrosis factor ? [TNF-?], soluble CD14, and lipopolysaccharide-binding protein [LBP]) and fecal samples for microbiome analysis were collected at baseline and closure of the study. The children's growth and health status were monitored through biweekly home visits by trained staff. Twenty-one percent of the children became stunted: compared with non-stunted children, they had worse nutritional parameters and higher levels of serum I-FABP at baseline. The likelihood of becoming stunted was strongly associated with an increase in sCD14 over time; LBP and TNF-? showed a trend toward increase in stunted children but not in controls. The fecal microbiota composition of stunted children had an increased beta diversity compared with that of healthy controls throughout the study. The relative abundance of Ruminococcus 1 and 2, Clostridium sensu stricto, and Collinsella increased in children becoming stunted but not in controls, whereas Providencia abundance decreased. In conclusion, stunting in our population was preceded by an increase in markers of enterocyte turnover and differences in the fecal microbiota and was associated with increasing levels of systemic inflammation markers.
Project description:Disease progression is rapid in human immunodeficiency virus (HIV)-infected infants. Whether intestinal damage and inflammation underlie mortality is unknown.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.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.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.
Project description:Undernutrition among children under 5 years of age continues to be a public health challenge in many low- and middle-income countries and can lead to growth stunting. Infectious diseases may also affect child growth, however their actual impact on the latter can be difficult to quantify. In this paper, we analyse data from 20 Demographic and Health Surveys (DHS) conducted in 13 African countries to investigate the relationship between malaria and stunting. Our objective is to make inference on the association between malaria incidence during the first year of life and height-for-age Z-scores (HAZs).We develop a geostatistical model for HAZs as a function of both measured and unmeasured child-specific and spatial risk factors. We visualize stunting risk in each of the 20 analysed surveys by mapping the predictive probability that HAZ is below - 2. Finally, we carry out a meta-analysis by modelling the estimated effects of malaria incidence on HAZ from each DHS as a linear regression on national development indicators from the World Bank.A non-spatial univariate linear regression of HAZ on malaria incidence showed a negative association in 18 out of 20 surveys. However, after adjusting for spatial risk factors and controlling for confounding effects, we found a weaker association between HAZ and malaria, with a mix of positive and negative estimates, of which 3 out of 20 are significantly different from zero at the conventional 5% level. The meta-analysis showed that this variation in the estimated effect of malaria incidence on HAZ is significantly associated with the amount of arable land.Confounding effects on the association between malaria and stunting vary both by country and over time. Geostatistical analysis provides a useful framework that allows to account for unmeasured spatial confounders. Establishing whether the association between malaria and stunting is causal would require longitudinal follow-up data on individual children.