Effect of Oral Nutritional Supplementation on Health-Related Outcomes and Nutritional Biomarkers in Children and Adolescents with Undernutrition: A Systematic Review and Meta-Analysis

This systematic review aims to synthesize scientific evidence on the effects of oral nutritional supplementation (ONS) on health-related outcomes and nutritional biomarkers among children and adolescents with undernutrition. The review protocol was reported following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines. A comprehensive keyword and reference search was conducted in seven electronic bibliographic databases: PubMed, Academic Search Complete, Academic Search Premier, CINAHL, Global Health, Web of Science, and Scopus. We identified 14 peer-reviewed articles reporting results from 13 unique studies (eight randomized controlled trials, four pre-post studies, and one observational study). Study participants were recruited from 14 countries/regions, with ages ranging from 1 to 14 years. Outcomes of interest include health-related outcomes (acute diseases and infections) and nutritional biomarkers (e.g., serum iron and zinc). Six of the eight studies examining acute diseases/infections and five of the seven examining nutritional biomarkers reported statistically significant improvement in some, but not all, outcomes. A meta-analysis of three studies found that ONS interventions reduce the incidence of upper respiratory tract infection (URTI) by 39% (95% CI, 0.42–0.91) in children at nutritional risk when compared to dietary counseling (DC) alone. This systematic review suggests that ONS interventions can improve certain health-related outcomes and nutritional biomarkers in undernourished children and adolescents. Specifically, the use of ONS significantly reduces the risk of URTI, highlighting its potential to enhance immune function and break the cycle of undernutrition and infection.


Introduction
Undernutrition in children and adolescents, characterized by wasting, stunting, and being underweight, has been a global public health challenge with broad implications [1,2].In 2022, it was estimated that 148 million children under the age of five were stunted, and 45 million were wasted globally [3].Approximately half of the childhood deaths are attributed to undernutrition, according to UNICEF [4].The medical, developmental, and socioeconomic impacts of the global burden of undernutrition are profound and longlasting for children and adolescents, their families, local communities, and countries [5].
A two-way relationship, or a "vicious cycle" linking undernutrition to acute diseases/infections, has been extensively documented.Undernutrition elevates the suscepti-Nutrients 2024, 16, 2970 2 of 24 bility to acute diseases/infections, and acute diseases/infections aggravate undernutrition by suppressing appetite, inducing catabolism, and elevating demand for nutrients [6][7][8].The increased vulnerability to acute diseases/infections is thought to be partly caused by impaired immune function due to undernutrition [9].Undernutrition has significantly contributed to immunodeficiency, most pronounced among infants, children, adolescents, and older adults [10][11][12].Deficiencies in protein-energy and micronutrients are linked to impairments in cell-mediated immunity, antibody levels, phagocytic activity, the complement system, and cytokine production [13].
In the wake of the novel coronavirus disease 2019 (COVID-19), the relationship between undernutrition and infections has become more relevant than ever [14].Poor diet may compromise nutritional status, resulting in susceptibility to COVID-19 infections [15].The United Nations Children's Fund promotes three strategies for preventing and treating undernutrition in children and adolescents, including dietary diversification, food fortification, and micronutrient supplementation [16].
One of the key goals of nutrition intervention in treating undernourished children is to strengthen their resistance to infections [17].Micronutrients, including zinc, selenium, iron, copper, β-carotene, and vitamins A, C, and E, as well as folic acid, can affect various aspects of innate immunity [18].Nutrients also play a role in initiating and regulating adaptive immune responses by influencing the differentiation, proliferation, and activation of B and T lymphocytes, as well as antibody production [19].In addition, prebiotics and probiotics may promote a healthy microbial composition and help modulate the host immune system [20][21][22].
Oral nutritional supplements (ONS) are sterile formulations available in liquid, semisolid, or powdered forms, supplying both macronutrients and micronutrients [23].ONS are frequently utilized in both acute care and community health settings for individuals unable to fulfill their nutritional needs through a standard diet alone [23].ONS may benefit children and adolescents with growth faltering, selective diets, poor appetite, chronic diseases, and developmental disabilities [24].Standard ONS are formulated according to dietary recommendations to support children's growth.For example, the macronutrient distribution in ONS formulation usually follows the US Institute of Medicine's (or local) recommendations for typical diets for children and adolescents where the energy contributions of protein, fat, and carbohydrate are 10-15%, 30-35%, and 50-60%, respectively [25].In addition, the fatty acid composition and content of essential fatty acids in ONS are designed to meet the requirements for tissue incorporation and specific body functions in children and adolescents [26].ONS typically have an energy density between 1.0-1.5 kcal/mL with a high nutrient concentration, which helps support a balanced accretion of lean and fat tissues and regain normal growth [27].ONS are "nutritionally complete" because they contain all essential nutrients in proportions that make them suitable for use as a sole source of nutrition [28].
Zhang et al. conducted a systematic review and meta-analysis to assess the effectiveness of ONS interventions on growth outcomes among 9-month-to-12-year-old undernourished children [29].Eleven randomized controlled trials (RCTs) were included [29].ONS use was found to significantly improve various anthropometric measures (e.g., weight and height) compared to controls (e.g., under a usual diet, placebo, or dietary counseling alone) [29].Consistent with this finding, a newly published RCT again demonstrated that adding ONS to dietary counselling (DC) resulted in better weight and height gain and linear catch-up growth in children with or at risk of undernutrition, compared to DC alone [30] A recent systematic review synthesized research on the application of ONS for children 1-18 years with or at risk of faltering growth, focusing on subjects recruited from clinical settings [31].The review analyzed 10 RCTs involving 1116 children and found that the utilization of ONS resulted in significant enhancements in weight and height, likely a consequence of improved nutritional intake [31].
Considering the bi-directional relationship between nutrition and infections, we believe evaluating the effect of ONS intake on health-related outcomes is crucial.In the aforementioned systematic review, the researchers also investigated the effect of ONS on clinical outcomes and concluded that there is a possible association between ONS use and reduced infections [31].However, it is noteworthy that meta-analysis was not conducted for any clinical outcome, and the publication's search strategy only included studies up to November 2021.
Multiple nutrient deficiencies are common in children with or at risk of undernutrition.Therefore, the goals of nutrition interventions are to provide adequate nutrition to rectify these deficiencies and promote catch-up growth [17].Since the consumption of ONS has been shown to promote catch-up in height among children with or at risk of undernutrition, the use of nutrient-dense ONS is presumed to have enhanced the nutrition quality of the children's diet [17].It would therefore be of interest to determine whether ONS intake can address nutrient deficiencies, as assessed by biomarker status.
Complementing previous reviews [29,31] that have reported improvements in anthropometric measures, our study aimed to comprehensively identify and synthesize the scientific evidence concerning the effects of ONS on health-related outcomes among children and adolescents with or at risk of undernutrition.Changes in nutritional biomarkers and other relevant biochemical indices were also summarized.Review findings may address a critical gap in the scientific literature and inform evidence-based practices and policies to prevent detrimental health outcomes among undernourished minors.

Review Protocol and Registration
The review protocol was designed based on the methodological framework outlined in the Cochrane Handbook for Systematic Reviews of Interventions and reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) guidelines [32,33].The protocol was registered in the PROSPERO database (Registration No. CRD42022292035) [34].

Study Selection Criteria
We adopted the PICOS framework (Population, Intervention, Comparison, Outcome, Study design) to guide our data collection and synthesis process [35].Studies that fulfilled all of the following criteria were included in the review: (1) Study designs: human clinical trials (i.e., randomized, quasi-randomized, or non-randomized controlled trials, or single-arm trials with pre-vs.post-intervention comparisons) and observational studies; (2) Study participants: children or adolescents aged 1-19 years with mild, moderate, or severe undernutrition, who were either clinically healthy or had acute respiratory or gastrointestinal infections not requiring hospitalization; (3) Type of ONS: ONS containing at least one non-protein calorie source (carbohydrate or fat) and nitrogen (in the form of intact protein, hydrolyzed protein, or amino acids), along with a full spectrum of micronutrients; (4) Exposure: ONS administered orally, in any amount, and for a given period; (5) Healthrelated outcomes: number of sick days, rate of recurrent infections, acute health events (e.g., diarrhea, vomiting, nausea, constipation, and allergies), comorbidity, or mortality; (6) Nutritional biomarkers and relevant biochemical indices such as serum iron, zinc, albumin, total protein, hemoglobin, ferritin, calcium, and phosphorus; (7) Type of article: original, empirical studies published in peer-reviewed journals; (8) Search timeframe: from the database's inception to 1 February 2023; and (9) Language: articles published in English.
Studies meeting any of the following criteria were excluded from this review: (1) Animal or cell-culture studies; (2) Infant (younger than one-year-old) or adult (20 years and above) participants; (3) Children or adolescents without undernutrition; (4) Children or adolescents with pre-existing chronic diseases such as cystic fibrosis, HIV/AIDS, or cancer; (5) ONS that contain only, or predominantly, a single macronutrient (fat, carbohydrate, or protein), lipid-based supplements, or micronutrient-only (vitamins or minerals) supplements; (6) Therapeutic food products; (7) Semi-elemental formulations or fortified milk; (8) Studies of enteral tube feeding or parenteral nutrition; and (9) Letters, editorials, study or review protocols, case reports, or review articles.
The World Health Organization (WHO) has developed various childhood growth standards by age and sex [36].The three most widely adopted anthropometric measures are weight-for-age, height-for-age, and weight-for-height, which can be expressed as z-scores or percentiles [36].Other measures, including body mass index (BMI)-for-age and mid-arm circumference-for-age, are also used to assess growth [36].The risk of undernutrition can be classified as mild (−2 ≤ z-score < −1), moderate (−3 ≤ z-score < −2), and severe (z-score < −3) [37].Stunting is defined as a height-for-age z-score < −2, wasting as a weight-for-height z-score < −2, and underweight as a weight-for-age z-score < −2 [38].

Search Strategy
A keyword search was conducted across seven electronic bibliographic databases: PubMed/MEDLINE, Academic Search Complete, Academic Search Premier, CINAHL, Global Health, Web of Science (including Science Citation Index Expanded, Social Sciences Citation Index, and Emerging Sources Citation Index), and Scopus.The search algorithm includes keywords concerning ONS (e.g., "oral nutritional supplement", "protein-energy supplement"), children/adolescents, and undernutrition (e.g., "under-weight", "wasting", or "stunting").The search algorithm (Appendix A) was used to identify relevant titles and abstracts in the databases.Two co-authors independently screened the titles and abstracts found through the keyword search, retrieved articles that appeared eligible, and reviewed their full texts.Inter-rater agreement between the two co-authors was evaluated using Cohen's kappa (κ = 0.82).Any discrepancies were resolved through consultation with a third co-author.
A backward reference search and a forward citation search were performed using the full-text articles identified through the keyword search that satisfied the study selection criteria.Articles retrieved from both the backward and forward searches were subsequently screened and evaluated using the same selection criteria.This process was repeated for all newly identified articles until no further relevant articles were found.

Data Extraction and Synthesis
A standardized data extraction form was utilized to gather the following methodological and outcome variables from each included study: author(s), year of publication, country, participants' undernutrition status, participants' mean age and age range, participants' sex distribution, study design, sample size, intervention setting, intervention duration, arm-specific sample size, arm-specific intervention assignment, characteristics of the ONS product(s) used in the intervention, ONS daily dose, health-related outcomes, nutritional biomarkers, and intervention effectiveness (i.e., outcome-specific treatment effect estimates).

Meta-Analysis
The eligibility criterion for a meta-analysis is two or more studies of the same study design (e.g., RCT) assessing the same measure (e.g., number of sick days), with relevant treatment effect and standard error reported (or allowing the calculation of these two through the provision of relevant statistics, such as mean outcome measures in the treatment and control arms together with their respective standard deviations).All health-related outcomes and nutritional biomarkers reported in the included studies were assessed for their meta-analysis feasibility.The only eligible outcome identified is the incidence of upper respiratory tract infection (URTI).We used the I 2 index to assess heterogeneity across studies eligible for meta-analysis.The I 2 index indicates the proportion of variability in effect estimates among studies that is attributable to heterogeneity rather than random chance [32,39].An I 2 index greater than zero indicates the presence of heterogeneity, and an I 2 index over 50% indicates a high level of heterogeneity [32,39].A zero or low level of heterogeneity suggests a fixed-effect model, whereas a high level of heterogeneity supports a random-effect model [32,39].A fixed-effect model was estimated because the calculated I 2 index for the URTI outcome approximates zero.The meta-analysis was conducted using R version 4.2.

Study Quality Assessment
The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework is employed for creating and presenting evidence summaries and offers a systematic approach to formulating clinical practice recommendations [40].GRADE assesses each study and assigns it to one of four evidence levels: very low, low, moderate, or high.Randomized controlled trials (RCTs) begin with a high evidence rating, while observational studies typically start at a low evidence rating due to residual confounding [40].The quality of evidence for a study can be adjusted up or down during evaluation based on GRADE criteria, which consider factors such as risk of bias, imprecision, inconsistency, indirectness, and publication bias [40].

Identification of Studies
Figure 1 presents the PRISMA flow diagram.A total of 1534 articles were identified through keyword and reference searches.After duplicate removal, 832 unique articles were subjected to title and abstract screening, resulting in the exclusion of 773.The full texts of the remaining 60 articles were then assessed against the study selection criteria, leading to the exclusion of 46 articles.The reasons for exclusion were as follows: no health-related outcome and nutritional biomarker reported (n = 23), children or adolescents with preexisting chronic diseases besides undernutrition (n = 15), the inclusion of infants or adults only (n = 4), and exclusive tube feeding (n = 4).Therefore, 14 articles were included in the systematic review [41-54].Among them, three reporting URTI incidences were included in the meta-analysis [42,44,48].
Nutrients 2024, 16, x FOR PEER REVIEW 5 of 28 calculated I 2 index for the URTI outcome approximates zero.The meta-analysis was conducted using R version 4.2.

Study Quality Assessment
The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework is employed for creating and presenting evidence summaries and offers a systematic approach to formulating clinical practice recommendations [40].GRADE assesses each study and assigns it to one of four evidence levels: very low, low, moderate, or high.Randomized controlled trials (RCTs) begin with a high evidence rating, while observational studies typically start at a low evidence rating due to residual confounding [40].The quality of evidence for a study can be adjusted up or down during evaluation based on GRADE criteria, which consider factors such as risk of bias, imprecision, inconsistency, indirectness, and publication bias [40].

Identification of Studies
Figure 1 presents the PRISMA flow diagram.A total of 1534 articles were identified through keyword and reference searches.After duplicate removal, 832 unique articles were subjected to title and abstract screening, resulting in the exclusion of 773.The full texts of the remaining 60 articles were then assessed against the study selection criteria, leading to the exclusion of 46 articles.The reasons for exclusion were as follows: no healthrelated outcome and nutritional biomarker reported (n = 23), children or adolescents with pre-existing chronic diseases besides undernutrition (n = 15), the inclusion of infants or adults only (n = 4), and exclusive tube feeding (n = 4).Therefore, 14 articles were included in the systematic review [41-54].Among them, three reporting URTI incidences were included in the meta-analysis [42,44,48].

Characteristics of the Included Studies
The characteristics of the included studies are summarized in Table 2.Among the eight RCTs [42][43][44][45]48,[50][51][52][53], seven randomized participants to two arms-a treatment arm and a control arm [42][43][44][45]48,50,51], and the remaining intervention randomized participants to three arms-two treatment arms (one receiving ONS and the other receiving waterbased micronutrient supplement) and a control arm [52,53].Across trials, the treatment arms received ONS alone or in combination with other supplements (e.g., synbiotics) or therapies (e.g., growth hormone therapy, nutrition counseling).The control arms received nothing, therapy alone or ONS alone (when the corresponding treatment arm received ONS plus synbiotics) [42][43][44][45]48,[50][51][52][53].The four pre-post interventions measured and compared outcomes for all participants before and after ONS administration [41,46,49,54].The observational study provided high-fiber ONS to all participants [47].Nine studies were conducted in hospitals or clinics [41, [44][45][46][47][48]50,51,54], three in schools or daycare centers [43,49,52,53], and the remaining one was administered on their team's study site [42].The intervention duration had a mean and median of 7 and 6 months, respectively, ranging from 0.5 to 18 months [41-54].Eight of the 13 studies used PediaSure ® ONS product by Abbott Nutrition [41- 47,49]; one used S-26 PE Gold ® ONS product by Wyeth Nutrition (Singapore) Pte.Limited [50]; one used Pediapowder ® ONS product by MDwell (Seoul, Republic of Korea) [54]; and the remaining three did not specify the ONS brand used [48,[51][52][53].The daily dosage of ONS varied substantially across interventions and was quantified using a lower bound, a fixed amount, or an intake frequency.Two studies should be noted.Fisberg et al. (2002) compared ONS plus synbiotics (treatment arm) with ONS alone (control arm) [43].Because our review focuses on the effectiveness of ONS and it is common for ONS to be added with synbiotics, we made inferences from this study by comparing the pre-treatment and post-treatment outcomes in both arms.Soliman et al. (2021) compared energy-dense (1.5 kcal/mL) ONS (treatment arm) with standard (1 kcal/mL) ONS (control arm) [51].We made inferences from this study by comparing the relevant outcomes before and after consuming each ONS among both arms.
Two key findings emerged from the estimated intervention effects on health-related outcomes and nutritional biomarkers.First, six of the eight studies measuring health-related outcomes reported statistically significant improvement in some but not all outcomes.Specifically, Fisberg et al. (2002) found that the number of sick days per month decreased over four months among both ONS feeding groups with and without synbiotics added [43].Alarcon et al. (2003) and Ghosh et al. (2018) found that the ONS intervention reduced URTI incidence [42,44].Huynh et al. (2015) found that the number of sick days decreased following the ONS intervention [46].Kansu et al. (2018) found that the ONS intervention was associated with reduced vomiting, nausea, abdominal distension, and improved stool frequency [47].Vijayalakshmi et al. (2008) showed that compared to the control group, supplementation with ONS mixed in milk and ONS prepared using water both resulted in significant improvement in the degree of morbidity [53].On the other hand, Alarcon et al. (2003) identified no change in gastrointestinal symptoms (e.g., diarrhea, constipation) [42].Sheng et al. (2014) and Khadilkar et al. (2021) found no effect of the ONS intervention on the incidence of acute illnesses [48,50].Second, five of the seven studies evaluating nutritional biomarkers and other relevant biochemical indices reported statistically significant improvement in some but not all measures.Specifically, Akram et al. (2000) found the ONS intervention associated with improved serum sodium, potassium, BUN, creatinine, calcium, phosphorus, total protein, cholesterol, and triglyceride [41].Vijayalakshmi et al. (2008) found that the mean blood hemoglobin levels of children aged 7-12 years significantly increased after receiving a milk-based ONS when compared to the control group [52].Additionally, they observed a significant improvement in mean blood hemoglobin levels for children aged 7 and 10 years after using ONS prepared with water [52].However, there was no significant improvement in mean blood hemoglobin levels for children aged 8, 9, 11, and 12 years when using the water-based ONS [52].Pham et al. (2020) found that the ONS intervention improved blood hemoglobin, albumin, and zinc concentrations and reduced albumin and zinc deficiency [49].Soliman et al. (2021) found that ONS consumption improved IGF-1 among undernourished children [51].Shim et al. (2020) reported an increase in blood urea nitrogen concentration following ONS consumption over a 6-month intervention period [54].On the other hand, Alarcon et al. (2003) found no improvement in serum albumin, iron, ferritin, and zinc [42].Han et al. (2011) reported no improvement in IGF-1, IGFBP-3, transferrin, pre-albumin, ghrelin, and lipid concentrations [45].

Meta-Analysis
A fixed-effect meta-analysis was performed on the outcome of URTI incidence, which was reported by Alarcon et al. ( 2003 2021) [42,44,48].The ONS intervention was estimated to reduce URTI incidence by 39% (pooled risk ratio = 0.61; 95% confidence interval [CI] = 0.42, 0.91; p-value = 0.01; I 2 index = 0.00%) in undernourished children and adolescents.Figure 2 shows the forest plot of the metaanalysis estimate.No publication bias test was feasible due to the small sample size (n = 3).
Second, five of the seven studies evaluating nutritional biomarkers and other relevant biochemical indices reported statistically significant improvement in some but not all measures.Specifically, Akram et al. (2000) found the ONS intervention associated with improved serum sodium, potassium, BUN, creatinine, calcium, phosphorus, total protein, cholesterol, and triglyceride [41].Vijayalakshmi et al. (2008) found that the mean blood hemoglobin levels of children aged 7-12 years significantly increased after receiving a milk-based ONS when compared to the control group [52].Additionally, they observed a significant improvement in mean blood hemoglobin levels for children aged 7 and 10 years after using ONS prepared with water [52].However, there was no significant improvement in mean blood hemoglobin levels for children aged 8, 9, 11, and 12 years when using the water-based ONS [52].Pham et al. (2020) found that the ONS intervention improved blood hemoglobin, albumin, and zinc concentrations and reduced albumin and zinc deficiency [49].Soliman et al. (2021) found that ONS consumption improved IGF-1 among undernourished children [51].Shim et al. (2020) reported an increase in blood urea nitrogen concentration following ONS consumption over a 6-month intervention period [54].On the other hand, Alarcon et al. (2003) found no improvement in serum albumin, iron, ferritin, and zinc [42].Han et al. (2011) reported no improvement in IGF-1, IGFBP-3, transferrin, pre-albumin, ghrelin, and lipid concentrations [45].

Meta-Analysis
A fixed-effect meta-analysis was performed on the outcome of URTI incidence, which was reported by Alarcon et al. ( 2003 2021) [42,44,48].The ONS intervention was estimated to reduce URTI incidence by 39% (pooled risk ratio = 0.61; 95% confidence interval [CI] = 0.42, 0.91; p-value = 0.01; I 2 index = 0.00%) in undernourished children and adolescents.Figure 2 shows the forest plot of the metaanalysis estimate.No publication bias test was feasible due to the small sample size (n = 3).

Study Quality Assessment
We assessed the evidence/quality of the studies included in the review using the GRADE framework [40].As shown in Table 1, five studies were rated "high", two "moderate", and the remaining seven "low."The primary reason for a "low" rating concerns a non-randomized study design (observational or pre-post study).Other reasons include the risk of bias (i.e., potential confounders correlated with the treatment and outcomes) and imprecision (e.g., lacking quantitative estimates of the treatment effects concerning specific outcome measures).

Discussion
This study systematically reviewed the scientific evidence concerning the effects of ONS on health-related outcomes and nutritional biomarkers in children and adolescents with undernutrition.A comprehensive keyword and reference search in seven electronic bibliographic databases identified 14 peer-reviewed articles reporting results from 13

Study Quality Assessment
We assessed the evidence/quality of the studies included in the review using the GRADE framework [40].As shown in Table 1, five studies were rated "high", two "moderate", and the remaining seven "low."The primary reason for a "low" rating concerns a non-randomized study design (observational or pre-post study).Other reasons include the risk of bias (i.e., potential confounders correlated with the treatment and outcomes) and imprecision (e.g., lacking quantitative estimates of the treatment effects concerning specific outcome measures).
Adequate nutrition is essential in supporting immune response [55,56].Poor nutrition may impair host defenses by affecting both the innate and adaptive immune systems [8,57].Undernutrition has also been linked to intestinal dysbiosis [58][59][60], an undesirable alteration of the microbiota resulting in an imbalance between beneficial and harmful bacteria.It can impact the immune system since intestinal microbiota is essential in regulating systemic immunity and gut barrier function [59,61].
ONS are energy-and nutrient-dense formulations, containing both macro-and micronutrients and often added with prebiotics or probiotics [62].To our knowledge, this meta-analysis is the first to demonstrate that ONS usage decreased the risk of upper respiratory tract infections in undernourished children.Repeated infections can aggravate undernutrition due to appetite loss, nutrient malabsorption, increased demand for nutrients, and diversion of nutrients for immune response [6,13,63].Our finding suggests that ONS can improve the immunity of undernourished children, thus helping them escape the "vicious cycle" of undernutrition infection [6][7][8].This current result complements findings from an earlier systematic review, which showed the effectiveness of ONS intervention in enhancing better growth outcomes for children suffering from undernutrition compared to control treatments [29].

Nutritional Biomarkers
Nutritional biomarkers can generally be interpreted as the biological consequence of dietary intake [64].As the use of ONS should help restore nutrient deficiencies, it is expected that nutritional biomarkers of undernourished children will improve or regain normality.However, this is not universally seen based on the results of our systematic review.
It is recognized that a range of factors, including genetic variability, lifestyle, and analytical methodology, can influence biomarker measures of dietary intake [65,66].Furthermore, evidence suggests that specific biomarkers, such as total white blood cell and lymphocyte counts, are not affected by undernutrition [67].It is thus plausible that nutritional repletion may not always result in a change in biochemical parameters.The inconsistent findings observed could also be attributed to differences in the severity of nutritional deficiency, amount of ONS provided, and duration of nutrition intervention.These discrepancies highlight the need for standardized protocols and more rigorous studies to fully understand the impact of ONS on nutritional biomarkers.Nevertheless, robust evidence, including data from this review, has shown that ONS usage among undernourished children results in clinically meaningful endpoints, such as gains in weight and height and a reduced risk of infection.Hence, despite inconsistent findings on nutritional biomarkers due to various factors discussed above, the positive outcomes observed in growth and immunity can be indicative of an overall improvement of nutrient status following ONS supplementation.
A primary strength of this study is that it represents the first systematic review to assess the effectiveness of ONS on health-related outcomes and nutritional biomarkers in children and adolescents with undernutrition.We aimed to perform a rigorous review by adhering to established guidelines for such analyses, which were in line with the Cochrane Collaboration's recommendations for intervention studies [32].However, it is important to acknowledge several limitations related to both the review and the studies included.The literature examining relevant outcomes for undernourished children and adolescents undertaking an ONS intervention remains small and heterogeneous.Participants resided in 14 countries or regions with a wide age range.The interventions differed substantially in design, duration, ONS product used, and daily dosage administered.Pertinent measures were extensive and diverse, preventing meta-analysis and robust conclusions on the treatment effect on a specific outcome.Some studies failed to report the quantitative estimates of the treatment effect for the full range of outcomes assessed, and select reporting could be prone to publication bias.The review scope was limited to energy-dense, oral ONS products (≥ 1 kcal/mL); other nutrient-rich products, such as fortified milk and functional food, and enteral tube feeding of ONS were not considered.We excluded undernourished children and adolescents hospitalized or with pre-existing chronic conditions, as they may need medical treatment and health care besides nutrition intervention to restore health and normal growth.The meta-analysis estimate was based on only three studies and may lack generalizability.Moreover, their study samples were recruited from diverse geographical regions (Philippines and Taiwan vs. India), and interventions were performed in different settings (daycare center vs. hospital/clinic).Finally, children and adolescents participating in the studies included in the review could differ in their malnutrition (e.g., mild, moderate, or severe undernutrition) and health status, leading to differential responses to the ONS treatment.

Conclusions
This systematic review and meta-analysis demonstrate the potential benefit of ONS for undernourished children and adolescents in terms of improving certain health-related outcomes and nutritional biomarkers.Notably, the use of ONS was found to reduce the incidence of URTI by 39%, emphasizing its role in enhancing immune function among children with or at risk of undernutrition.This may have a significant impact on optimizing the growth and development of these children, considering URTI is a very common infection during childhood [68].While some improvements in nutritional biomarkers were observed, the results were inconsistent across all studies, suggesting variability due to genetic differences, lifestyle, and methodological variations.

Platform
Databases Search Algorithm Scopus Scopus AND (child* or schoolchild* or "school child*" or kid or kids or toddler* or adoles* or preadolescen* or pre-adolescen* or preteen* or teen* or boy* or girl* or minors or underage* or "under ag*" or juvenile* or youth* or kindergar* or puber* or pubescen* or prepubescent* or prepuberty* or pediatric* or paediatric* or peadiatric* or schools or "nursery school*" or preschool* or "pre school*" or "primary school*" or "secondary school*" or "elementary school*" or "high school*" or highschool* or "school age" or schoolage or "school age*" or schoolage* or student* or youngster*) AND (stunted or stunting or underweight or "under-weight" or wasting or wasted or "failure to thrive" or "growth retardation" or "growth faltering" or "growth failure" or "failure to grow" or "delayed growth*" or "restricted growth*" or "suboptimal growth*" or "sub-optimal growth*" or "catch-up growth*" or "catch-up growth*" or malnutrition or malnourishment or malnourished or "mal-nourished" or "under-nourished" or undernourishment or undernutrition or "under-nutrition" or undernourished or "picky eating" or "picky eater*" or "fussy eater*" or "feeding disorder*" or "infantile anorexia") * denotes a wildcard.

Figure 2 .
Figure 2. Forest plot of the meta-analysis on the incidence of upper respiratory tract infection [42,44,48].

Figure 2 .
Figure 2. Forest plot of the meta-analysis on the incidence of upper respiratory tract infection [42,44,48].

Table 1 .
Characteristics of the studies included in the review.
Notes: RCT-randomized controlled trial; BMI-body mass index; N/A-not available.

(
AB (child* or schoolchild* or "school child*" or kid or kids or toddler* or adoles* or preadolescen* or pre-adolescen* or preteen* or teen* or boy* or girl* or minors or underage* or "under ag*" or juvenile* or youth* or kindergar* or puber* or pubescen* or prepubescent* or * or "pre school*" or "primary school*" or "secondary school*" or "elementary school*" or "high school*" or highschool* or "school age" or schoolage or "school age*" or schoolage* or student* or youngster*) ) child* or schoolchild* or "school child*" or kid or kids or toddler* or adoles* or preadolescen* or pre-adolescen* or preteen* or teen* or boy* or girl* or minors or underage* or "under ag*" or juvenile* or youth* or kindergar* or puber* or pubescen* or prepubescent* or prepuberty* or pediatric* or paediatric* or peadiatric* or schools or "nursery school*" or preschool* or "pre school*" or "primary school*" or "secondary school*" or "elementary school*" or "high school*" or highschool* or "school age" or schoolage or "school age*" or schoolage* or student* or youngster*) OR TI = (child* or schoolchild* or "school child*" or kid or kids or toddler* or adoles* or preadolescen* or pre-adolescen* or preteen* or teen* or boy* or girl* or minors or underage* or "under ag*" or juvenile* or youth* or kindergar* or puber* or pubescen* or prepubescent* or prepuberty* or pediatric* or paediatric* or peadiatric* or schools or "nursery school*" or preschool* or "pre school*" or "primary school*" or "secondary school*" or "elementary school*" or "high school*" or highschool* or "school age" or schoolage or "school age*" or schoolage* or student* or youngster*) )