Malnutrition and Catch-Up Growth during Childhood and Puberty

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Introduction

Stunting and wasting are conditions that arise from malnutrition, with or without disease. Children suffering from wasting are prone to weakened immunity and increased risk of morbidity and mortality, while children affected by stunting are susceptible to long-term developmental delays which may adversely affect their socioeconomic status as adults [1]. According to the UNICEF, WHO, and the World Bank report published in March 2020 [1], the rates of children with malnutrition remain alarming, and this condition is still far from being eliminated. As of 2020, globally, 144.0 million children under 5 suffer from stunting, 47.0 million children under 5 are wasted, 14.3 million of whom are severely wasted. Lower middle income countries are still most severely affected by malnutrition, with two-thirds of all stunted children and three-quarters of all wasted children in the world living there. These countries reduced their stunting prevalence since 2000 by only one-third. In contrast, over the same time, upper-middle-income countries reduced their stunting prevalence by more than two-thirds [1]. Although many countries are moving in the right direction, this report reveals that the progress is insufficient to attain the World Health Assembly targets set for 2025 and the Sustainable Development Goals set for 2030. This chapter reviews the most recent data on childhood malnutrition and catch-up growth, published between July 1, 2019 and June 30, 2020, and addresses several topics. Most of the studies in this chapter deal with the outcomes of different intervention strategies to treat malnutrition and undernutrition. This includes three RCTs [2–4], two non-randomized intervention studies [5, 6], and one meta-analysis [7]. Other papers selected for the chapter introduce various interesting topics, such as the etiology of catchup growth [8], new assessment approaches [9], pediatric sarcopenia [10] and bacteriophages and childhood stunting [11].
 

Outcomes of Different Intervention Strategies to Treat Malnutrition and Undernutrition

Body composition during outpatient treatment of severe acute malnutrition: Results from a randomised trial testing different doses of ready-to-use therapeutic foods

Comments: Severe acute malnutrition (SAM) in children with no medical complications is treated at home with a ready-to-use-formula (RUTF) prescribed according to the child’s body weight. In a previous publication by the same authors, treatment with a reduced dose of RUTF in an outpatient setting resulted in a similar rate of weight gain compared to the standard dose [12]. In the current publication, changes in body composition between admission and recovery from SAM were presented, in children aged 6–59 months who received either a full dose of RUTF (n = 237) or a reduced dose (n = 215). Body composition, measured using bioelectrical impedance analysis, was also compared to that of non-malnourished community controls (n = 97). Nutritional recovery was defined as: WHZ ≥–2 for those admitted with a WHZ <–3 only, MUAC ≥125 mm for those admitted with a MUAC <115 mm only, or WHZ ≥–2 and MUAC ≥125 mm for those admitted with WHZ <–3 and MUAC <115 mm, on two consecutive visits with no evidence of illness. Maximal treatment duration was 16 weeks beyond which children were defined as non-response to treatment if the recovery criteria were not attained.

During intervention, the average weight increased by 1.2 kg, of which 0.55 kg (45%) was fat-free mass (FFM) and 0.67 kg (55%) was fat mass (FM). Recovery rates were similar in both arms. At recovery, children treated for SAM had 1.27 kg lower weight, 0.38 kg lower FFM, and 0.90 kg lower FM compared to community controls. However, their fat-free mass index (FFMI) was not different from community controls (Δ 0.2 kg/ m2; 95% CI: 0.1–0.4). No differences were observed in FFM, FM, or fat mass index between the study arms at recovery, however, FFMI was 0.35 kg/m2 higher at recovery with the reduced compared to standard dose (p = 0.007). The implication of this finding on long-term outcome is unknown. The main strength of this study is that body composition was examined both at admission and at recovery from SAM, which enabled the evaluation of change in body composition parameters. The study provides high-quality data as it is designed as an RCT and also has a control group of non-malnourished children. Reducing the dose of RUTF could help reduce the high costs of intervention and seems to be non-inferior to standard doses in these particular settings. Further research is required to examine the generalizability of the findings in other age groups and treatment regimens.

 

Restitution of gut microbiota in Ugandan children administered with probiotics (Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp. lactis BB-12) during treatment for severe acute malnutrition

Comments: Gut microbiota (GM) dysbiosis may be involved in the development or non-resolution of acute malnutrition [13]. Therefore, it has been suggested that probiotic supplementation may be able to improve the repairing or normalization of the GM in malnourished children. In a previous RCT, administration of probiotics was associated with a significant reduction in days with diarrhea during the outpatient phase of treatment of SAM [14]. In the current study, the authors investigated the changes in GM during recovery from SAM, the impact of probiotics on the GM, and whether GM composition and development was associated with the clinical outcomes of the previously mentioned ProbiSAM trial. Four hundred children aged 6–59 months participated in the study, with an additional 22 healthy children of the same age who served as a control group. Both study arms received standard treatment for SAM, and a daily dose of either two probiotic strains (Lactobacillus rhamnosus GG [LGG] and Bifidobacterium animalis subsp. lactis [BB-12]) or placebo. Fecal samples were obtained at admission, at discharge, and 8 weeks after discharge. Children in the intervention arm whose fecal sample demonstrated at least one of the probiotic strains were regarded as responders, while children where the probiotic strains were not detected were defined as non-responders.

Supplementation of probiotics did not affect the β-diversity (compositional difference) of GM at discharge or follow-up, but it did increase (p < 0.05) the number of observed species (SE: >4.5). Children who were defined as responders had lower cumulative incidence (p < 0.001) of diarrhea during the follow-up period compared to non-responders, and children receiving placebo. No clinical predictors of response versus non-response were found. The importance of this study is that it adds high-quality data to the much-needed evaluation of the potential benefit of probiotic intervention in malnutrition. The results support previous findings suggesting that probiotics may be beneficial to children recovering from SAM. However, important questions regarding cost-effectiveness and number needed to treat remain unanswered.

 

Effectiveness of wheat soya blend supplementation during pregnancy and lactation on pregnancy outcomes and nutritional status of their infants at 6 months of age in Thatta and Sujawal districts of Sindh, Pakistan: A cluster randomized-controlled trial

Comments: Maternal malnutrition is associated with increased rates of complication, including infections, obstructed labor and small-for-gestational-age (SGA) babies. Evidence from low- and middle-income countries demonstrates that nutritional intervention during pregnancy and lactation is safe and can improve fetal growth and reduce perinatal mortality [15]. Khan et al. conducted a cluster randomized-controlled trial aimed to assess the effectiveness of wheat soya blend plus provided during pregnancy and lactation on weight gain during pregnancy, reduction of low birth weight, and improvement in nutritional status in infants at 6 months of age. This important study looked at maternal nutrition intervention in pregnancy as a mechanism for reducing fetal growth retardation and low birth weight in rural Pakistan. The study demonstrated that improving birth weight did improve early infant growth, reduce wasting and anemia. This study further supports the importance of improving nutrition in pregnancy as a mechanism to improve birth outcomes and growth in infancy [16] at national level [17]. Future studies should also assess better maternal outcomes of health, well-being, and longer-term benefits for mothers themselves and not just birth outcomes [15].

 

Impact of treatment with RUTF on plasma lipid profiles of severely malnourished Pakistani children

Comments: Little is known on impacts of ready-to-use therapeutic food (RUTF) treatment on lipid metabolism in children with severe acute malnutrition (SAM). Shokry et al. analyzed glycerophospholipid fatty acids and polar lipids in plasma of 41 Pakistani children with SAM before and after 3 months of RUTF treatment using gas chromatography and flow-injection analysis tandem mass spectrometry. This is an important and relatively rare study of the status of plasma fatty acids in a cohort of Pakistani infants with severe acute malnutrition undergoing nutritional rehabilitation with standard RUTF. The study documented very low concentrations of EFAs at baseline and improvements in and LC-PUFAs and AA/linoleic acid ratio after therapy. The study points to the need for nutritional rehabilitation regimen to include appropriate concentrations of lipid formulations including EFAs and studies correlating clinical outcomes with such biochemical markers. Indeed, preventive studies with lipid nutrient supplements have been associated with improved nutrition outcomes than standard rehabilitation protocols [18] and developmental outcomes [19]. This study by Shokry et al. points the way for future studies to relate clinical and developmental outcomes to metabolic and dietary studies.

 

Daily supplementation with egg, cow milk, and multiple micronutrients increases linear growth of young children with short stature

Comments: Stunting is the most common form of childhood malnutrition worldwide and is associated with impaired neurocognitive development and increased susceptibility to infection. A recent community-based study by Mahfuz et al. (which was a part of the ongoing Bangladesh Environmental Enteric Dysfunction [BEED] study), aimed to evaluate the effect of nutritional intervention on linear growth of 12- to 18-month stunted (length-for-age z-score [LAZ] <–2) and at risk for stunting (–1< LAZ <–2) Bangladeshi children (n = 472). The intervention included daily supplementation with an egg and 150 mL of milk for 90 days, and 1 sachet of multiple micronutrient powder for 60 days. This supplementation provided 33% of the required kcal of energy, and important growth-promoting nutrients (92% RDA high-quality proteins, 40% RDA of calcium, 188% RDA of iron, and 206% RDA of zinc). The comparison group included historical data on children from the same community of the same age and same baseline LAZ (n = 174), who were enrolled in an earlier non-interventional study. The results showed a small improvement of LAZ in the intervention group, while children in the comparison group exhibited gradually worsening LAZ scores, with an effect size of +0.23 SD in LAZ (p < 0.05) (the intervention group gained 0.09 SD in LAZ vs. –0.14 SD in the control group). The effect size of the intervention was more pronounced in stunted children (+0.27 SD [p < 0.05], the intervention group gained 0.14 SD in LAZ vs. –0.13 SD in the control group) as compared to children at risk of stunting (+0.19 SD [p < 0.05], the intervention group gained 0.04 SD in LAZ vs. –0.14 SD in the control group). No adverse events related to milk and egg consumption were observed during the study.

The main strength of this study is the low dropout rate, which resulted from the very good acceptance of the supplementation provided by the children and mothers. However, this study has several limitations. The main limitations include the study design, which was non-randomized with a historical control group. The absence of randomization and the use of historical comparison group (the data was collected 3 years before the current study) is prone to major biases such as overestimation of treatment effect. Another limitation is the short intervention of only 90 days, which may be too short to assess the full potential of the intervention on linear growth. In addition, the role of pathogen burden and its association with stunting were not addressed. Finally, the study design cannot enable to identify which of the three components of the nutritional intervention was the most effective, or whether all three are required.

Considering the cost and the complexity of this intervention, the effect size seems rather modest. Further investigation, using a randomized-controlled design and a longer duration, with an additional intervention to reduce pathogen burden, is needed to justify the nutritional intervention suggested in this study.

 

Micronutrient supplementation and fortification interventions on health and development outcomes among children under-five in low- and middle-income countries: A systematic review and meta-analysis

Comments: Children under-five, especially those living in low- and middle-income countries (LMICs), are prone to micronutrient deficiencies, as rapid growth and development demands for micronutrients are high in this age group. Micronutrient deficiencies during early childhood are associated with physical, developmental, and cognitive impairment, increased susceptibility to infections and higher morbidity and mortality.

This systematic review and meta-analysis by Tam et al. provide an extensive overview of the available evidence on strategies to prevent micronutrient malnutrition among children under-five in LMICs, including single and multiple micronutrient (MMN) supplementation, lipid-based nutrient supplementation (LNS), targeted and large-scale fortification, and point-of-use fortification with micronutrient powders (MNPs). The outcome parameters included both the efficacy and effectiveness of these interventions on improving child health and development, including mortality, nutritional indicators (wasting, underweight, stunting, anemia), morbidities, deficiencies, and mental and motor skill development. The systematic review included 197 studies which fulfilled the eligibility criteria. Of these studies, 136 studies contributed data to the meta-analyses. The main positive clinical outcomes resulted from the meta-analyses included the following:

1. Iron alone, iron-folic acid, MMN supplementation, MNPs, targeted fortification, and large-scale fortification reduced the risk of anemia.

2. Vitamin A supplementation was found to reduce the risk of all-cause mortality by 10%.

3. Zinc supplementation decreased the incidence of diarrhea.

4. LNS was the only effective intervention to improve stunting and underweight, though MMN supplementation also slightly increased length-for-age z-scores.

5. LNS also led to improvements in mental development scores for language and personal-social/socioemotional, improved motor development generally.

This updated review is important, as it deals with several major literature gaps, including the effects of individual micronutrient interventions, several relevant outcomes which remain inadequately studied (for example, the effects of vitamin A supplementation on morbidity and mortality) and effectiveness data for real-life benefits of micronutrient intervention programs. The results of this systemic review and meta-analysis further support the importance of the reviewed strategies for reducing the burden of micronutrient malnutrition in children. It is probable that several of these strategies should be used simultaneously, taking into consideration the cost-benefit, target population, and context.

 

Others

Cartilage-specific knockout of Sirt1 significantly reduces bone quality and catch-up growth efficiency

Comments: Using the phenomenon of catch-up growth (CUG), this group is trying to find novel targets for intervention in growth abnormalities. The current study is a follow-up work on a previous study wherein the authors showed in a nutrition-induced CUG model that the level of sirtuin-1 (Sirt1) was significantly increased in food-restricted animals and decreased during refeeding [20]. The current study sought to investigate the role of Sirt1 in modulating the growth response of the epiphyseal growth plate (EGP) to nutritional manipulation, using a collagen type II-specific Sirt1 knockout (CKO) transgenic mice.

The transgenic CKO mice had higher and less organized EGP, specifically at the resting and proliferative zones culminating in shorter bones in both young and older mice. These results support the previous data that Sirt1 inhibits chondrocyte proliferation. Interestingly, Sirt1 knockout led also to a significant reduction in bone mineralization even when animals were fed ad libitum and in spite of a small but consistent increase in animal weight. The apparently remarkable linkage between the EGP and bone structure and mineralization might be explained by trans-differentiation of EGP chondrocytes. The authors further investigated the role of Sirt1 in growth regulation by exposing the animals to food restriction and re-feeding in a model of CUG. Collagen II-specific Sirt1 k/o led to a less efficient CUG, indicated by weight, bone length, EGP height, and bone remodeling. The response of the CKO mice to food restriction and refeeding was less efficient and differed from that of the CTL mice. All remodeling activity in the CKO mice was lower, maybe because they were less efficient in utilizing their energy reserve, as also manifested by their increased weight. These effects may be explained by the multiple roles of Sirt1 during low and high energy conditions: during low-energy period, Sirt1 is localized to the nucleus; there, it binds PABP1 (shown by another group) and limits protein synthesis. This is important for keeping the reserve zone from exhausting its growth potential and keeping the proliferating cells from synthesizing proteins under restricted conditions. During refeeding, there is high demand for protein production, and Sirt1 is protecting the cells from ER stress. In the CKO mice, Sirt1 ablation leads to lower cell reserve during food restriction due to unregulated protein synthesis and to less efficient CU growth, due to the unsupported ER stress. To conclude, Sirt1 is important for normal regulation of the EGP and bone mineralization. In its absence, the EGP is less organized, and CUG is less efficient. These results suggest that SIRT1 may serve as a novel therapeutic target for short stature.

 

New approach to comprehensive growth and nutrition assessment in children

Comments: This article by Sentongo, presents a new etiology-based approach to growth and nutrition assessment from infancy to adolescence. This approach was constructed by a multidisciplinary team of healthcare providers based on an extensive literature review and includes five domains: (1) Anthropometry – including measurements of weight, length/height, length for height/BMI, head circumference, and the interpretation of these measurements to percentile or Z-score according to published growth charts (Fenton, WHO, and CDC). Additional assessment of body composition indices is also recommended in this domain, including mid-upper arm circumference and triceps skinfold thickness. (2) Dynamism of growth – this domain includes the evaluation of the changes in the growth outcomes Z-scores. (3) Duration of growth abnormalities – definition of acute growth abnormalities (<3 months) vs. chronic (>3 months). (4) The etiology of the nutritional imbalance – description of the mechanisms leading to malnutrition (i.e., underlying disease, inadequate dietary intake). (5) The impact of the nutritional state on functional outcomes (i.e., measuring hand grip strength which provides a dynamic indicator of muscle function, and the evaluation of delayed development of motor skills).

Implementation of such a new approach is important, especially in western countries, where the definition of undernutrition and malnutrition is inconsistent due to variations in the methodology used. Implementation of this approach by clinicians and researchers may help to standardize the screening, diagnosis, and the evaluation of the outcomes of therapy in pediatric malnutrition.

 

Pediatric sarcopenia: A paradigm in the overall definition of malnutrition in children?

Comments: Sarcopenia is characterized by reduced skeletal muscle mass which contributes to altered muscle functionality. In the pediatric population, sarcopenia is associated with adverse outcomes, including impaired growth, bone health, and cognitive development; increased cardiometabolic risk, increased length of hospital stay, infection, and postsurgical complications. Sarcopenia has been characterized in adults as a component of malnutrition; however, there has been very little research addressing the concept of sarcopenia in children. The review by Ooi et al. aimed to evaluate knowledge gaps in the assessment of childhood sarcopenia.

The review demonstrated that there are limited data on childhood sarcopenia, and many knowledge gaps in all aspects, including the etiology, definition, and diagnosis, prevalence, and treatment of pediatric sarcopenia. Research is also limited by a small number of studies, low study quality, and lack of longitudinal data assessing the evolution of sarcopenia in children. The mechanism specific to childhood sarcopenia is not well understood. Several potential mechanisms include inadequate nutrition intake, physical inactivity, and hypermetabolism. A better understanding of the mechanisms underlying pediatric sarcopenia may help develop effective rehabilitation strategies, including nutrition and physical activity.

Another major knowledge gap is the lack of clear definition for the diagnosis of childhood sarcopenia. In the existing literature, there is controversy upon the body composition measurement techniques, and lack of recommended tests for detecting muscle function deficit. In order to diminish these research gaps, a consensus, based on further study, is required. This consensus should include methodological approaches in pediatric sarcopenia diagnosis, body composition measurements and age-appropriate muscle function tests and effective multidisciplinary treatment strategies.

 

Bacteriophages isolated from stunted children can regulate gut bacterial communities in an age-specific manner

Comments: Although it has been shown that stunted children have an altered gut microbiome [21], much is still unknown on the relationship between the gut bacteria and children’s health and growth. This study takes us to another component of the complex gut ecosystem, the bacteriophages. Bacteriophages, bacterial viruses, are highly abundant in the human gut, and are known to influence bacterial ecosystems both in number and in function. However, it is unknown whether there is a role for bacterialphage interplay in children with early-life stunted growth. The authors of this study investigated the microbes isolated from fecal samples of 30 non-stunted and 30 stunted children aged 14–38 months. After characterizing the abundance and diversity of the phage and bacterial communities in the original fecal samples, the investigators performed in vitro cross-infections of bacteria from non-stunted children by phages from stunted children and vice versa. The observational phase revealed a unique microbial and phage profile in stunted compared to non-stunted children, in an age- and diet-specific manner. In the in vitro cross-infection study, phages from stunted children <23 months old allowed for Proteobacteria to grow in gut bacterial communities from non-stunted children, perhaps implying a role for phages in the pathophysiology of child stunting. This result was not found in children older than 23 months. Although these results need to be validated in vivo, this study raises important questions on the role of phages in childhood stunting and highlights the need for further studies in this field.