Drivers of the trend in child stunting and the role of omega-3 long-chain polyunsaturated fatty acids in relation to child growth and development in rural Ethiopia

Abstract

Despite the significant progress the world has made over the past few decades, millions of children in low- and middle-income countries still suffer from poor growth and development. Growth faltering during the critical window period of the first 1,000 days after conception is associated with multiple adverse consequences limiting human potential and economic growth. Recognizing the magnitude of the problem and its severe consequences, the World Health Assembly in 2012 endorsed a Comprehensive Implementation Plan on Maternal, Infant, and Young Child Nutrition with six global targets, chief among which is the target to reduce the number of stunted children by 40% in 2025. Identifying priority areas of action in high nutrition-burden countries is the first step to accelerate current progress and achieve the global nutrition targets. For the purpose of facilitating evidence-based decision-making, the first part of this Ph.D. thesis explores nutrition-specific and -sensitive factors that can contribute to a reduction in chronic child undernutrition in low- and middle-income countries. We pooled data from 50 Demographic and Health Surveys conducted in 14 low- and middle-income countries to explain the trend in under-five stunting prevalence over the past two decades. A four-level mixed-effects linear probability model, accounting for clustering of data by sampling clusters, survey-rounds, and countries, was fitted to estimate the association between the change in a range of distal to proximal determinants at a country-level and stunting risk for an individual child while adjusting for time trend and child-level covariates. Furthermore, innovative approaches that maximize the impact of existing nutrition interventions are highly required to assist the progress in low- and middle-income countries. Complementary feeding interventions in low-income settings to date have been focused on the energy and micronutrient content of diets and yielded only small to moderate effects on growth and development. Increasing evidence support the hypothesis that environmental enteric dysfunction, chronic gut inflammation with morphological and functional derangements, and systemic inflammation occurring at a high prevalence in children living in poor settings, could be an important missing link that mediates and reduces the expected benefits from interventions. There is evidence that omega-3 long-chain polyunsaturated fatty acids (n-3 LCPs) may improve gut integrity, reduce inflammation and enhance maturation of the immune system, which could lead to amelioration of this condition and the associated growth impairment. Additionally, some studies in high-income populations showed that n-3 LCPs may have benefits for infant neurocognitive development. However, there is limited evidence from studies testing these potential benefits in infants and young children in a low-income setting. Therefore, in the second part of the PhD thesis, we hypothesized that an increased intake of n-3 LCPs would result in reduced morbidity and inflammation, and improved growth and development of children aged 6-24 months in a low-income setting. To test these proposed hypotheses, we conducted the OME3JIM project involving a 2 x 2 factorial randomized controlled trial of n-3 LCPs-rich fish-oil supplementation (500 mg/day n-3-LCPs) through lactation (MI), complementary feeding (CI), or a combination of both (MCI). We enrolled 360 pairs of lactating mothers and their infants 6-12 months old from three rural communities in Jimma district, southwest Ethiopia. The primary study outcomes were child linear growth, i.e., monthly changes in length-for-age z score (LAZ) over the 12 months intervention follow-up, and the evolution of developmental performance from baseline through 6 and 12 months of the intervention, using the Denver II and the Ages and Stages Questionnaire: Social Emotional tools. Secondary outcomes included LCP concentrations in maternal milk and child blood, anthropometry measurements of weight-for-length z score (WLZ), head-circumference and mid-upper arm circumference (MUAC), nutritional status (stunting, wasting and anemia), common childhood morbidities, and inflammation using C-reactive protein. Chapter 3 presents results of the study on the trend in child stunting. Stunting followed a declining trend in all the 14 countries studied at an average annual reduction rate of 1.04 percentage points (pp). Among the distal factors assessed, a decrease in the Gini coefficient, an improvement in women’s decision-making, and an increase in urbanization over time within a country were significantly associated with a lower risk of stunting. Improvements in households’ access to improved sanitation facilities and drinking water sources, and children’s access to basic vaccinations were the important intermediate service-related drivers of stunting risk identified, whereas an improvement in early initiation of breastfeeding and a decrease in the prevalence of low birthweight were the important proximal drivers. Our findings indicate that although there has been progress in reducing stunting, the rate of reduction in the studied countries was below the average 3.9 pp annual reduction rate required to meet the global target set for 2025. Furthermore, our findings reinforce the need for a combination of nutrition-specific and -sensitive interventions on top of economic development to tackle the problem of chronic childhood undernutrition. The identified drivers will help to guide global efforts to further accelerate stunting reduction and monitor progress against chronic child undernutrition. Results of the OME3JIM study are presented and discussed in Chapters 4-6. From the total of 360 mother-infant pairs enrolled, 87% completed all the 12 months study follow-ups and the mean (SD) duration of supplementation was 11.0 (2.9) months. Compliance rate for the child and the maternal interventions were ~80% and ~70%, with no difference between study arms. All statistical analyses were conducted following the intention-to-treat principle. In Chapter 4, we present the efficacy of fishoil supplementation of lactating mothers on human milk LCP concentrations using a random sub-sample of 154 study participants. Fish-oil supplementation during lactation increased maternal milk concentrations of docosahexaenoic acid (DHA) by 39.0% (P < 0.001) and eicosapentaenoic acid (EPA) by 36.2% (P < 0.001), whereas the ratio of arachidonic acid (AA)/(DHA + EPA) decreased by 53.5% (P < 0.001), compared to the control. However, the maternal milk DHA concentration still remained lower than international norms after the intervention. The results demonstrate that fish-oil supplementation during lactation improves n-3 LCPs status of the maternal milk. In these mothers with a very low baseline breastmilk DHA status, which further declines over the course of lactation, a higher dose of supplementation may be required to attain optimal breastmilk DHA levels. Chapter 5 presents the independent and combined effects of the fish-oil intervention through lactation and complementary food on child n-3 LCPs status, health and growth. Fish-oil supplementation significantly increased child blood n-3 LCPs concentrations (P < 0.01) and decreased the AA/(DHA + EPA) ratio (P < 0.001) in all the MI, CI and MCI intervention arms as compared to the control. Fish-oil intervention also resulted in a better ponderal growth of children, as indicated by the small, but statistically significant, positive effects on monthly WLZ changes in the CI (effect size: 0.022/month; 95% CI: 0.005, 0.039/month; P = 0.012) and MCI arms (effect size: 0.018/month; 95% CI: 0.001, 0.034/month; P = 0.041). We also noted a non-significant trend towards larger monthly MUAC increments in the CI and MCI arms compared to the control. No further effects were detected on the primary study outcome linear growth or on the other secondary outcomes of growth, nutritional status, morbidity, and inflammation. Chapter 6 presents the effects of the same intervention on child development performance. There was no difference between study arms on the evolution of overall and social-emotional developmental performance over time (intervention by time interaction: F = 1.09; P = 0.35, and F = 0.61; P = 0.61, respectively). Overall, the findings from the OME3JIM trial did not support our primary study hypotheses that dietary n-3 LCPs supplementation through lactation and/or complementary feeding improves linear growth and development of infants and young children from a rural setting in Ethiopia. n-3 LCP supplementation given directly to children or in combination with maternal supplementation was found to modestly increase relative weight gain. In conclusion, this PhD research provides evidence on a set of potentially important proximal to distal factors that can contribute to reduction in chronic childhood undernutrition in low- and middle-income countries. It also contributes to the limited literature on the effects of n-3 LCP supplementation in infants and young children in a rural sub-Saharan African setting. In Chapter 7 the implications of the study findings are discussed and recommendations for future research and policy are provided. It is underlined that economic development and nutrition-sensitive interventions, on top of nutrition-specific programs, could play an important role in further reduction of the high stunting burden in low- and middle-income countries. Future follow-up of the OME3JIM cohort is also recommended to determine whether there are long-term effects of the fish-oil intervention