Linear growth failure of Ethiopian children : The role of protein, zinc and mycotoxin intake

Linear growth failure manifested as stunting is a major public health problem in developing countries. Stunting is often considered as an important marker of an adverse quality of population’s life and child development. Over 90% of stunted children live in 10 developing countries, in Asia and Africa. Ethiopia is the country with the high burden of linear growth failure. In 2016, it was estimated that about 5 million children suffered from poor linear growth or stunting in Ethiopia. The prevalence of stunting in Ethiopia has been reduced from 52% in 2000 to 37% in 2019, however, the number of stunted children has increased by about 1 million in the same period. There is a high level of commitment to reducing stunting globally and nationally. Although the government of Ethiopia formulated ambitious goals to reduce stunting, the progress to reduce stunting in Ethiopia remains too slow partly due to the fact that the aetiology of linear growth failure is still poorly understood. Stunting or poor linear growth is caused by a diverse and complex interaction of household, environmental, socioeconomic and cultural influences, related to, amongst others, poor nutrition, infectious diseases, unfavorable prenatal conditions and genetic disorders. The aim of this thesis was to contribute to the understanding of the aetiology of poor linear growth and stunting in rural Ethiopia by studying the effect of household-level quality protein maize (QPM) promotion and consumption, and the role of protein, zinc, and mycotoxins intake on linear growth of Ethiopian children. The first chapter provides background information on the role of QPM, protein, and zinc (in soil and serum) in linear growth of children. Furthermore, the research questions were described in detail. Chapter 2 describes a randomized controlled trial conducted in real practice in which households make their own decisions whether to adopt QPM, how much to adopt and cultivate, and whether and how to incorporate QPM into children’s diets. The intervention had two components: a) nutrition-focused adoption encouragement and provision of free QPM seed (AE), and b) a consumption encouragement (CE) primarily targeting female caregivers and encouraging earmarking and integration of QPM into diets for infants and young children. Eligible children (n=873) aged 6-35 months at baseline were randomly assigned to 3 groups: a first intervention group receiving AE only; a second intervention group receiving both AE and CE; and a control group. We hypothesized that promotion and consumption of QPM could improve the protein and amino acids status, which could, in turn, improve linear growth of children. Children consumed QPM based foods on average 4 days per week, while non-QPM based foods were consumed mostly. In addition, the quantitative intake of QPM was low (27 gram per day) contributing to only 5% of their total protein, 12% of lysine and 15% of tryptophan intakes, compared with conventional maize (80 gram per day) contributing to 16%, 9%, 13% of protein, lysine and tryptophan intakes respectively. Encouragement to adopt and feed QPM to infants and young children in a real-life setting had no effect on children’s protein biomarkers (p=0.19) or linear growth (p=0.17). Further evaluation of multi-year interventions is needed to understand how biofortified crops promoted at scale could change behavior and increase intakes at the household level which in turn improve biomarkers and outcomes in target populations. In chapter 3, we performed a cross-sectional analysis using baseline data of the QPM intervention study conducted in chapter 2. We investigated the association between protein intake, and protein and amino acids status with linear growth of children. The results indicated that protein intake (b=0.01, p=0.01) and protein status (b=2.58, p=0.04) as well as tryptophan intake/status (p<0.05) were positively associated with linear growth of children. Furthermore, most children had low energy intake (76%) coupled with high intestinal parasites (48%) and inflammation (35%). Also, protein and amino acids status were negatively correlated with inflammation, which suggests that the current requirement of protein and amino acids may not be adequate for children with low food intake or low energy intake and infection in Ethiopia. Linear growth failure in Ethiopian children is likely associated with low-quality protein intake and inadequate energy intake. Nutrition programs that emphasize improved protein quantity and quality and energy intake may enhance linear growth of young children. In chapter 4, we assessed exposure to aflatoxins and fumonisins measured in serum in two seasons, post-harvest and pre-harvest, and we also assessed mechanisms through which linear growth of children was affected. Children (n=873) 6-35 months old were enrolled in an intervention trial on quality protein maize consumption in rural Ethiopia as described in chapter 2. These children were stratified by baseline stunting status, and 102 children (50 stunted and 52 non-stunted) were randomly selected for this sub-study. Blood samples were collected during pre-harvest (August-September 2015) and post-harvest (February 2016) season. In the pre-harvest season, the proportions of children exposed to AFG1 (8%), AFG2 (33%) and AFM1 (7%) were higher than in the post-harvest season (4%, 28% and 4%, respectively). Likewise, the proportion of children exposed to any aflatoxin was higher in the pre-harvest than in the post-harvest season (51% vs. 41%). Exposure to fumonisins ranged from 0-11%, depending on the type of fumonisins. Exposure to any aflatoxin was not associated with inflammation (p>0.05), serum transthyretin (p >0.05) or serum IGF-1 (p >0.05), nor with linear growth (p >0.05) after adjusting for potential confounders. Our study revealed that exposure to most aflatoxins was high in pre-harvest season. Good practices in both post-harvest (to reduce accumulation of aflatoxins) and pre-harvest (to reduce aflatoxin levels) are needed for preventing contamination of aflatoxin. The mechanism in which aflatoxin affects linear growth of children is not clear. Aflatoxins are carcinogenic properties and the current exposure is a major public health problem that warrants intervention. Future studies on mechanisms between aflatoxin exposure and linear growth and sources of exposure with large sample size needed. In addition, future research is also needed on the complex and interacting pathophysiology of multiple mycotoxins and exposure management. In chapter 5, we use data from the cross-sectional, nationally representative Ethiopian National Micronutrient Survey (n=1776), which provided anthropometric and serum zinc (n=1171) data on children aged 6–59 months. Data on soil zinc levels were extracted for each child from the Africa Soil Information Service. With these data, we assessed the geographic distribution of poor soil zinc, poor zinc status and growth faltering at the national level. Zinc deficiency in soil was prevalent (20%) at the national level, with a higher prevalence in low land of Ethiopia (87%). Nationally, one in four children was zinc deficient, as measured by serum zinc level. High zinc in agricultural soils was positively associated with zinc status (b=0.9, p=0.02), however, linear growth of children was not associated with soil zinc or serum zinc. The findings from our study suggest that agricultural biofortification of zinc could be an alternative strategy for reducing zinc deficiency in developing countries. In Ethiopia most households consume food that comes from own production, however, crop production on zinc-deficient soils and its effect on human health has not yet been studied. Therefore, a future longitudinal experimental study on the effects of soil zinc application on crop zinc content and human serum zinc levels will help to elucidate this relationship. The phytate content of foods may affect zinc bioavailability. Future research is also needed on the effect of phytate on zinc bioavailability of crops grown on zinc-deficient soils. Finally, chapter 6 discusses the main findings, and the internal and external validity of the studies addressed in this thesis. Furthermore, the public health perspective including recommendations for possible future research is presented. Overall, we can conclude that low protein (of low quality) intake, high prevalence of zinc deficiency and high exposure to multiple aflatoxins are public health problems in Ethiopia. Linear growth of children is positively associated with protein intake, energy intake, as well as protein status, but not with zinc soil levels, zinc status or multiple aflatoxin exposure. Our study has demonstrated that the implementation of QPM in real life had no effect on the protein and amino acids status nor on linear growth of children. Therefore, in our study and also in other nutrition intervention programs, measuring intermediate indicators as outcomes of improved linear growth may be a more feasible approach than measuring linear growth or stunting

Mapping geographical inequalities in childhood diarrhoeal morbidity and mortality in low-income and middle-income countries, 2000-17: analysis for the Global Burden of Disease Study 2017

Background: Across low-income and middle-income countries (LMICs), one in ten deaths in children younger than 5 years is attributable to diarrhoea. The substantial between-country variation in both diarrhoea incidence and mortality is attributable to interventions that protect children, prevent infection, and treat disease. Identifying subnational regions with the highest burden and mapping associated risk factors can aid in reducing preventable childhood diarrhoea. Methods: We used Bayesian model-based geostatistics and a geolocated dataset comprising 15 072 746 children younger than 5 years from 466 surveys in 94 LMICs, in combination with findings of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, to estimate posterior distributions of diarrhoea prevalence, incidence, and mortality from 2000 to 2017. From these data, we estimated the burden of diarrhoea at varying subnational levels (termed units) by spatially aggregating draws, and we investigated the drivers of subnational patterns by creating aggregated risk factor estimates. Findings: The greatest declines in diarrhoeal mortality were seen in south and southeast Asia and South America, where 54·0% (95% uncertainty interval [UI] 38·1–65·8), 17·4% (7·7–28·4), and 59·5% (34·2–86·9) of units, respectively, recorded decreases in deaths from diarrhoea greater than 10%. Although children in much of Africa remain at high risk of death due to diarrhoea, regions with the most deaths were outside Africa, with the highest mortality units located in Pakistan. Indonesia showed the greatest within-country geographical inequality; some regions had mortality rates nearly four times the average country rate. Reductions in mortality were correlated to improvements in water, sanitation, and hygiene (WASH) or reductions in child growth failure (CGF). Similarly, most high-risk areas had poor WASH, high CGF, or low oral rehydration therapy coverage. Interpretation: By co-analysing geospatial trends in diarrhoeal burden and its key risk factors, we could assess candidate drivers of subnational death reduction. Further, by doing a counterfactual analysis of the remaining disease burden using key risk factors, we identified potential intervention strategies for vulnerable populations. In view of the demands for limited resources in LMICs, accurately quantifying the burden of diarrhoea and its drivers is important for precision public health. Funding: Bill & Melinda Gates Foundation

Mapping geographical inequalities in childhood diarrhoeal morbidity and mortality in low-income and middle-income countries, 2000-17: analysis for the Global Burden of Disease Study 2017

Background: Across low-income and middle-income countries (LMICs), one in ten deaths in children younger than 5 years is attributable to diarrhoea. The substantial between-country variation in both diarrhoea incidence and mortality is attributable to interventions that protect children, prevent infection, and treat disease. Identifying subnational regions with the highest burden and mapping associated risk factors can aid in reducing preventable childhood diarrhoea. Methods: We used Bayesian model-based geostatistics and a geolocated dataset comprising 15 072 746 children younger than 5 years from 466 surveys in 94 LMICs, in combination with findings of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, to estimate posterior distributions of diarrhoea prevalence, incidence, and mortality from 2000 to 2017. From these data, we estimated the burden of diarrhoea at varying subnational levels (termed units) by spatially aggregating draws, and we investigated the drivers of subnational patterns by creating aggregated risk factor estimates. Findings: The greatest declines in diarrhoeal mortality were seen in south and southeast Asia and South America, where 54·0% (95% uncertainty interval [UI] 38·1–65·8), 17·4% (7·7–28·4), and 59·5% (34·2–86·9) of units, respectively, recorded decreases in deaths from diarrhoea greater than 10%. Although children in much of Africa remain at high risk of death due to diarrhoea, regions with the most deaths were outside Africa, with the highest mortality units located in Pakistan. Indonesia showed the greatest within-country geographical inequality; some regions had mortality rates nearly four times the average country rate. Reductions in mortality were correlated to improvements in water, sanitation, and hygiene (WASH) or reductions in child growth failure (CGF). Similarly, most high-risk areas had poor WASH, high CGF, or low oral rehydration therapy coverage. Interpretation: By co-analysing geospatial trends in diarrhoeal burden and its key risk factors, we could assess candidate drivers of subnational death reduction. Further, by doing a counterfactual analysis of the remaining disease burden using key risk factors, we identified potential intervention strategies for vulnerable populations. In view of the demands for limited resources in LMICs, accurately quantifying the burden of diarrhoea and its drivers is important for precision public health. Funding: Bill & Melinda Gates Foundation

Anemia prevalence in women of reproductive age in low- and middle-income countries between 2000 and 2018

: Anemia is a globally widespread condition in women and is associated with reduced economic productivity and increased mortality worldwide. Here we map annual 2000-2018 geospatial estimates of anemia prevalence in women of reproductive age (15-49 years) across 82 low- and middle-income countries (LMICs), stratify anemia by severity and aggregate results to policy-relevant administrative and national levels. Additionally, we provide subnational disparity analyses to provide a comprehensive overview of anemia prevalence inequalities within these countries and predict progress toward the World Health Organization's Global Nutrition Target (WHO GNT) to reduce anemia by half by 2030. Our results demonstrate widespread moderate improvements in overall anemia prevalence but identify only three LMICs with a high probability of achieving the WHO GNT by 2030 at a national scale, and no LMIC is expected to achieve the target in all their subnational administrative units. Our maps show where large within-country disparities occur, as well as areas likely to fall short of the WHO GNT, offering precision public health tools so that adequate resource allocation and subsequent interventions can be targeted to the most vulnerable populations