High Caloric Density and Optimal Protein-to-Energy Ratio of Oral Nutritional Supplements: Impacts on Catch-Up Growth in Undernourished Indonesian Children

High Caloric Density and Optimal Protein-to-Energy Ratio of Oral Nutritional Supplements: Impacts on Catch-Up Growth in Undernourished Indonesian Children | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article High Caloric Density and Optimal Protein-to-Energy Ratio of Oral Nutritional Supplements: Impacts on Catch-Up Growth in Undernourished Indonesian Children Nur Aisiyah Widjaja, Meta Hanindita, Eva Ardianah, Febrina Santoso, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6668470/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract BACKGROUND: Pediatric oral nutritional supplements (ONS) are nutrient-dense foods that provide high calories in restricted volumes to meet nutritional requirement of undernourished children. Beyond providing high caloric content, ONS should maintain an optimal protein-to-energy ratio (PER). This study evaluated the efficacy of two ONS formulations, i.e., 1.0 kcal/mL with PER of 9.6% or 1.5 kcal/mL ONS with PER of 8.9%, to support catch-up growth among at-risk and undernourished pediatric outpatients in Surabaya, Indonesia. METHODS: A retrospective cohort study was conducted using electronic medical record of 150 eligible pediatric patients aged 1-5 years old with feeding difficulties and infection. The subjects were categorized into 2 groups: (i) who consumed 400 kcal of solid food and received 400 mL/day of 1.5 kcal/mL ONS, and (ii) who consumed 600 kcal of solid food and received 400 mL/day of 1 kcal/mL ONS. RESULTS: Interventions with both ONS for 90 days improved average weight and height of subjects. Nonetheless, the 1.5 kcal/mL ONS induced higher weight gains at Day 30 and higher height gains at Day 30, 60 and 90. In the sub-stratification analyses, the 1.5 kcal/mL ONS induced significant weight gain at Day 30 for severely underweight and wasted subjects as well as promoted significant height gain at Day 30 for severely stunted patients. CONCLUSION: The 1.5 kcal/mL ONS with PER of 8.9% demonstrated a better effectiveness in promoting catch-up growth among undernourished children. Health sciences/Diseases/Nutrition disorders/Malnutrition Health sciences/Health care/Paediatrics Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION A universal indicator of nutritional status among children is the growth assessment [ 1 ]. The World Health Organization (WHO) has developed several pediatric growth standards, including weight-for-age, height-for-age and weight-for-height that are commonly expressed in z-scores [ 1 ]. Those growth standards are important to uniformly identify children with undernutrition, as the prevalence of children with poor growth remains high worldwide [ 2 – 4 ]. Chronic undernutrition could contribute to mortalities among children under five years old as well as various long-term health consequences [ 1 , 5 , 6 ]. Vice versa, children contracting infectious diseases frequently suffered from undernutrition due to nutrient loss, reduced uptake, as well as increased energy requirements during inflammation [ 5 , 7 , 8 ]. Childhood undernutrition is closely associated with wealth-related inequality across various economic groups of nations worldwide [ 9 ]. Children from disadvantage communities in low- and middle-income countries have a higher risk to suffer from undernourishment [ 9 ]. The 2018 Indonesia Basic Health Research had indicated that the prevalence of wasted and stunted among Indonesian children under 5 years old were high, i.e., 7.2 and 19.7%, respectively [ 10 ]. Nutrient-dense foods are recommended for children aged 6–59 months with moderate acute undernutrition need to meet their nutritional requirements [ 11 , 12 ]. Pediatric oral nutritional supplements (ONS) are nutrient-dense foods designed for children, providing 1.0 or 1.5 kilocalorie per mL (kcal/mL) in restricted volumes. Several recommendations, including the WHO guideline, further emphasize in providing adequate protein (8.9–11.5% of total energy) alongside energy to support effective catch-up growth [ 13 ]. Those formulations could be used by undernourished children who have poor appetite or cannot tolerate higher intake of volume [ 14 ]. A positive correlation was observed with compliance in taking these formulas partly due to the readiness-to-drink and limited volume to be drunk [ 15 – 17 ]. This study thus investigated the usefulness of ONS energy-dense to support catch-up growth among Indonesian children with undernutrition, by comparing the efficacy of ONS using 1.0 (protein-to-energy ratio (PER) of 9.6%) or 1.5 kcal/mL (PER of 8.9%) to support catch-up growth among pediatric outpatients in Surabaya, East Java, Indonesia. SUBJECTS AND METHODS Study design and subjects This retrospective cohort study, conducted at Husada Utama Hospital in Surabaya, Indonesia, from September to December 2023, assessed the efficacy of high-calorie ONS with optimal PER in pediatric outpatients aged 1–5 years with feeding difficulties and undernutrition. Eligible patients had baseline (i) weight-for-age z-score (WAZ) <-2 SD; and/or (ii) height-for-age z-score (HAZ) <-2 SD; and/or (iii) weight-for-height z-score (WHZ) <-2 SD; as well as (iv) inadequate weight increment ( Supplementary Table 1 ). The exclusion criteria were patients having (i) fluid retention; (ii) organomegaly; (iii) tumor; (iv) congenital abnormality; (v) cerebral palsy, hormone disturbances and syndromes; and (vi) incomplete medical record. Participants were divided into two groups, receiving either 400 milliliter per day of 1.0 (PER of 9.6%) or 1.5 kcal/mL ONS (PER of 8.9%), combined with solid food to provide 1,000 kcal/day. The composition of both products provided by Danone Nutricia Indonesia were listed in Supplementary Table 2 . Parents were educated on complementary feeding, and micronutrient supplementation was provided as needed. Anthropometric data The electronic medical records of participants, included birthdate, sex, infection status, ONS compliance and adverse events, as well as weight and height measurements taken on Day 0, 14, 30, 60, and 90. Weight (in kilogram) was measured using baby scale SECA 354 or standing scale SECA 813 (Harmburg, Germany), Height (in centimeter) was measured using infantometer SECA 416 or stadiometer SECA 213 (Hamburg, Germany). At each timepoint, weight and height were measured twice, and if there was any discrepancy, a third measurement was taken. The average of the three measurements was recorded. The WAZ, HAZ and WHZ of each subject were calculated, based on the weight and height data, by using the WHO child growth standards. Based on the WAZ, a child was categorized as underweight if having z-score <-2 SD and ≥-3 SD of the median or as severely underweight if having z-score <-3 SD of the median. Based on the HAZ, a child was categorized as stunted if having z-score <-2 SD and ≥-3 SD of the median or as severely stunted if having z-score <-3 SD of the median. Based on the WHZ, a child was categorized as wasted if having z-score <-2 SD and ≥-3 SD of the median or as severely wasted if having z-score <-3 SD of the median. Statistical analyses Data were analyses using the SPSS ver. 24.0 (SPSS Inc., Chicago, IL, USA). Descriptive statistics were presented according to the type of data. Testing of normality and homogeneity of variation were performed on data of age, body weight, body height, WAZ, HAZ and WHZ before and after ONS provision. Difference between two groups was calculated using independent t-test or Mann-Whitney U test. For categorical data, either Pearson chi-squared or Fisher's exact test was used. A statistical significance was considered with p-value less than 0.05. Data visualization was performed using the GraphPad Prism version 10.4.1 (California, USA). RESULTS A total of 150 subjects were recruited into this study, which were equally divided between groups receiving the 1.0 (PER of 9.6%) and 1.5 kcal/mL (PER of 8.9%) ONS. Most demographic characteristics between two groups did not differ significantly, except age and status of infection (Table 1). Subjects within the 1.5 kcal/mL group were statistically younger and 73 out of 75 subjects (97.33%) contracted infections. Total caloric intake of 1,000 kcal/day for a duration of 90 days were prescribed for all subjects, i.e., while the group of 1.5 kcal/mL received 400 kcal from solid food and 600 kcal from ONS per day, the group of 1.0 kcal/mL received 600 kcal from solid food and 400 kcal for ONS per day. This implied that the calorie deficit was higher in the former group than the latter group. Hence, as expected, the average body weight and height at Day 0 in the 1.5 kcal/mL group were lower than the ones in the 1.0 kcal/mL group (Table 2). Despite birth weights and heights between two groups did not significantly differ (Table 1), the 1.5 kcal/mL group had more undernourished subjects than the 1.0 kcal/mL group, either based on WAZ, HAZ or WHZ. Of note, most subjects had gone to the hospital due to parental concerns of feeding difficulty-related no weight gain, in which majority of them were subsequently diagnosed with infections as well. Most subjects demonstrated good compliance in using the ONS products, in which the provisions of both products were observed to be safe (Table 1). Upon the ONS intervention for 90 days, the average body weight in both groups steadily increased during the study (Table 2 and Figure 1A). Interestingly, the average weight gain at Day 30 was significantly higher in the 1.5 kcal/mL group than in the 1.0 kcal/mL group (p=0.001), suggesting that the provision of 1.5 kcal/mL ONS induced a higher rate in weight gain during the first 30 days. At the end of the study, however, the average weight gain between both groups did not differ significantly (1.10±0.46 versus 1.00±0.54 kilograms (kg); p=0.240), suggesting that, upon 90-day of intervention, both ONS products eventually induced similar rates of weight gain. This notion was supported by improvements of WAZ scores observed across both groups during the study duration (Figure 1B). The ONS intervention for 90 days steadily improved the average body height in both groups as well (Table 2 and Figure 1C). Both groups were indeed observed to significantly improve their HAZ scores during the study duration (Figure 1D). Of note, the provision of 1.5 kcal/mL ONS induced better height gains than the provision of 1.0 kcal/mL ONS, as observed at Day 30, 60 and 90 (p=0.001), suggesting that the provision of 1.5 kcal/mL ONS steadily induced a higher rate in gaining height over time, contributing to an improvement of total body height within this group at the end of the study. Taken together, these findings reinforced the usefulness of high-calorie formula ONS products in managing children with calorie deficits, even for the ones with underlying infections, as reflected by the increment of body weight and height of study subjects at Day 90 based on the WHZ score (Supplementary Figure 1). The usefulness of 1.5 kcal/mL ONS to support catch-up growth among pediatric patients was also reinforced. The subsequent analyses were focused on undernourished subjects based on WAZ (underweight and severely underweight), HAZ (stunted and severely stunted), as well as WHZ criteria (wasted and severely wasted). Of note, one subject could be categorized into more than one category of undernutrition because of the utilization of three growth standards. There were 41 underweight and 20 severely underweight children included in this study (Supplementary Table 3). Forty-four stunted and 20 severely stunted children were found in this study cohort (Supplementary Table 4). Finally, 27 wasted and 9 severely wasted children were observed in this study (Supplementary Table 5). In agreement with the overall findings on all subjects, the undernourished subjects, on average, steadily gained weight and height during the study duration. It was of interest to note that for the categories of severe underweight and wasted, weight gains at Day 30 were significantly higher for the group of 1.5 kcal/mL (Supplementary Table 3 & 5). Height gains were also significantly higher for the group of 1.5 kcal/mL in the category of severely stunted at Day 30 (Supplementary Table 4). This suggests that the provision of 1.5 kcal/mL ONS also generated higher gaining rates in both weight and height for certain undernourished patients. The efficacy of providing either 1.0 or 1.5 kcal/mL ONS was subsequently evaluated by comparing proportions of undernourished subjects in various categories between Day 0 and Day 90. Figure 2 reported that while provision of 1.0 kcal/mL ONS decreased the proportion of underweight and severely underweight subjects as much as 8.0% (n=6) and 5.3% (n=4), respectively, the provision of 1.5 kcal/mL ONS achieved a greater reduction by decreasing the proportion of underweight and severely underweight subjects as much as 10.7% (n=8) and 14.6% (n=11), respectively. This finding was also observed among stunted and severely stunted children, in which the provision of 1.5 kcal/mL ONS reduced the proportion of stunted and severely stunted subjects as much as 5.3% (n=6) and 6.6% (n=5), respectively, but the provision of 1.0 kcal/mL ONS only decreased the proportion of stunted and severely stunted subjects as much as 2.6% (n=2) and 6.7% (n=5), respectively (Figure 3). Findings of wasted and severely wasted subjects were also in agreement with both findings (Figure 4). The provision of 1.0 kcal/mL ONS reduced the proportion of severely wasted subjects as much as 4.0% (n=3) but, intriguingly, did not reduce the proportion of wasted subjects. In contrast, the provision of 1.5 kcal/mL ONS was able to decrease the proportion of wasted subjects as much as 18.7% (n=14) and eliminated the proportion of severely wasted subjects (6.7%, n=5), respectively. Taken together, the administration of 1.5 kcal/mL ONS with PER of 8.9% appeared to be a better choice to improve both weight and height for undernourished children. DISCUSSION We hereby assessed a comparison between 1.0 and 1.5 kcal/mL ONS in supporting catch-up growth among undernourished children in Surabaya, Indonesia. High level of compliance and good safety profile were observed for the provision of both ONS products. While both high-calorie ONS products could support weight and height gains, the 1.5 kcal/mL ONS with PER of 8.9% was a better option for undernourished children. Our results can be summarized in four points. First, subjects receiving 1.5 kcal/mL ONS contracted more episodes of infection, particularly tuberculosis, than the ones receiving 1.0 kcal/mL ONS. This partly contributed to more severe cases of undernutrition observed in the former group, which also became the rationale to provide ONS product with higher calorie to these subjects. It is acknowledged that tuberculosis and undernutrition have a bi-directional relationship [18]. Undernutrition is the primary cause of immunodeficiency, creating a vulnerability among undernourished subjects to subsequently contract tuberculosis [8, 19]. Vice versa, tuberculosis can cause inflammation-related cachexia, anorexia, and malabsorption, resulting in undernutrition [20, 21]. Of note, subjects in the group of 1.5 kcal/mL were younger than the ones in the group of 1.0 kcal/mL at the beginning of the study, tempting us to speculate that an earlier treatment with a higher-calorie ONS product might be beneficial to improve growth among relevant pediatric patients, particularly during the first 1,000 days of life [22, 23]. In a previous study by using 1.0 kcal/mL ONS, however, the body weight and height increments did not substantially differ between subjects aged 12–24 months and aged >24–60 months [24], indicating more studies are required to address this issue. Second, while both ONS products could increase overall weight and height of study subjects at all time points, the provision of 1.5 kcal/mL ONS induced higher gains. The weight gains were indeed statistically different between groups at Day 30, suggesting that the 1.5 kcal/mL ONS facilitated a better increment of weight in the first 30 days. Of note, our finding was different from the previous study that had also compared 1.0 and 1.5 kcal/mL ONS products in Indonesia but did not observe any difference in weight gain between both groups [12]. The difference could be attributed to several methodological variation between both studies, including (i) age of subjects (~23.9 versus ~49.2 months); (ii) composition of tested ONS products; and (iii) duration of intervention (90 versus 28 days). Similarly, the provision of 1.5 kcal/mL ONS induced larger height gains than 1.0 kcal/mL ONS, in which significant differences were observed at Day 30, 60 and 90. Both ONS products were observed to be effective in reducing numbers of undernourished subjects, which were in agreement with the published meta-analysis [22]. Importantly, the 1.5 kcal/mL ONS provided a better improvement in various categories of undernutrition (based on WAZ, HAZ and WHZ) than the 1.0 kcal/mL ONS, suggesting that this product was better for catch-up growth among undernourished pediatric patients. The growth improvement was more pronounced based on the WHZ criterion. The WHZ score of 1.5 kcal/mL group at Day 90 was almost as high as the one of 1.0 kcal/mL group at Day 30. This improvement was striking, considering that the initial average body weight was substantially lower in the group of 1.5 kcal/mL and that total daily intake calorie was equal for both groups (i.e., 1,000 kcal/day). It was of interest to note that the growth improvement upon provision of 1.5 kcal/mL ONS in categories of severely underweight, severely stunted and wasted were significantly higher at Day 30, suggesting that the growth improvement was already noticeable as early as after 30 days of intervention. Third, the superiority of 1.5 kcal/mL ONS could be partly explained by its PER of 8.9%. It is known that increasing the energy content of a nutritional product without increasing the protein content is not recommended for undernourished children [25]. As the PER of 1.5 kcal/mL ONS was within the recommended range according to the WHO guideline, this formulation could support the optimal catch-up growth of lean and fat mass [13]. However, a higher PER does not equate to a more optimal product as the PER of 9.6% in 1.0 kcal/mL ONS did not support the latter formulation to become a better product in this study. In addition, ONS product with a too-high PER are associated with an unfavorable body composition [26]. Fourth, the provision of tested ONS could support catch-up growth among pediatric patients with underlying infections. This finding was encouraging because most subjects in this study had underlying infections (94%, n=141), in which 89% of whom (n=126) contracted tuberculosis. These patients were deemed to be more vulnerable because tuberculosis could worsen the state of undernutrition [20, 21]. Nonetheless, ONS could support catch-up growth among pediatric patients receiving proper medical treatments, including antibiotics [27]. Our findings reconfirmed this notion, in which the 1.5 kcal/mL ONS appeared to be a better choice for undernourished pediatric patients with underlying infections. Calorie-dense pediatric ONS with optimum PER is an effective method to support catch-up growth among children with issues in their nutritional statuses, because patients benefit of high calories from consuming products of limited volume [22]. However, it is important to understand that dietary counseling remains the first line of treatment to promote growth among at-risk children and that it should be still provided when ONS product is prescribed [22, 28]. This is because of the wide-spread, inappropriate usage of ONS, including over-prescription, under-prescription or mis-prescription, could result in non-improvement of patient’s nutritional status and/or cause injury to tissues [29–32]. Most ONS products cannot be used as the only source of nutrition because they are nutritionally incomplete [23]. Health education is therefore important to ensure the clinical appropriateness and benefits of providing ONS to patients [22, 23, 33]. In our study, the parents had been counselled and monitored to continuously provide family food, in conjunction to ready-to-drink, high calorie ONS products, to their children. This facilitated daily intake calorie of 1,000 kcal/day for all subjects to support their catch-up growth, but not causing excessive body weight gains during this study. Another important matter in prescribing ONS product is to decide when to stop prescribing ONS product [23]. This clinical judgement should be taken prudently. While other studies had assessed the impact of ONS interventions from 7 to 365 days [22], the length of ONS intervention in our study was 90 days. We observed that the average growth improvement of study subjects was still within the normal range, supporting a recommendation that ONS should be prescribed for at least 3 months to provide weight and height gains [23]. Our study had several limitations, including a single-center study design with limited number of subjects. In addition, the retrospective study design did not allow us to perform long-term assessment on subjects post-ONS prescription. In conclusion, administering 1.0 and 1.5 kcal/mL ONS for 90 days promoted catch-up growth in at-risk and undernourished children. Nonetheless, the 1.5 kcal/mL formulation with PER of 8.9% was more effective, even among those with infections. Declarations DATA AVAILABILITY Data will be available upon request to the corresponding author. ACKNOWLEDGEMENT Parts of the data were presented in the 57 th Annual Meeting of the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition in Helsinki, Finland. The authors thank Nova Sitorus for supporting this study administratively. AUTHORS’ CONTRIBUTION Conceptualization and methodology: N.A.W; Investigation: N.A.W., M.H.H., E.A., F.M.S. and J.J; Funding acquisition: N.A.W.; Data curation: M.H.H., E.A. and F.M.S.; Data analysis: N.A.W., M.H.H., E.A., F.M.S. and J.J.; Writing original draft: N.A.W. and J.J. All authors approved the final draft of manuscript. FUNDING The study was partially funded by Danone Specialized Nutrition Indonesia it was not involved in the study hypothesis/design, execution, analysis, or interpretation. ETHICAL APPROVAL The study was approved by the Ethics Committee of the Husada Utama Hospital (#17/KEP-RSHU/XI/2023) and was registered in ClinicalTrials.gov (NCT06160765). COMPETING INTEREST N. A. W. reports financial support from Danone Specialized Nutrition Indonesia. Other authors declare no competing interest. References World Health Organization (2024) The WHO Child Growth Standards. https://www.who.int/tools/child-growth-standards . 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Support Care Cancer 30:4149–4155. https://doi.org/10.1007/s00520-022-06837-6 Wan G ying, Yuan H, Xue H, et al (2021) Assessment of compliance with oral nutritional supplementation and exploration of barriers and facilitators for patients after gastrectomy: A mixed-methods study. J Adv Nurs 77:2845–2859. https://doi.org/10.1111/jan.14851 Tables Table 1 . Baseline characteristics of study subjects. Characteristic 1.5 kcal/mL group (n=75) 1.0 kcal/mL group (n=75) p-value Age (month)* 22.15 ± 10.33 25.72 ± 11.10 0.037 Birth weight (kilogram)* 2.99 ± 0.89 2.95 ± 0.59 0.756 Birth height (centimeter)* 48.10 ± 3.33 48.55 ± 3.13 0.912 Sex # Male Female 38 ( 50.67 ) 37 ( 49.33 ) 36 ( 48.00 ) 39 ( 52.00 ) 0.870 Reason visiting hospital $ Picky eater & unchanged weight No weight gain & no height gain No weight gain 18 ( 24.00 ) 3 ( 4.00 ) 54 ( 72.00 ) 27 ( 36.00 ) 1 ( 1.33 ) 47 ( 62.67 ) 0.193 Infection $ Urinary tract infection Urinary tract infection & Tuberculosis Tuberculosis none 1 ( 1.33 ) 34 ( 45.33 ) 38 ( 50.67 ) 2 ( 2.67 ) 14 ( 18.67 ) 22 ( 29.33 ) 32 ( 42.67 ) 7 ( 9.33 ) 0.005 Compliance $ Consumed >75% Consumed >50% Consumed <50% 72 3 0 73 2 0 0.649 Adverse events $ Diarrhea Nausea and/or Vomiting none 3 2 70 1 1 73 0.309 Weight-for-age $ Normal Underweight Severely underweight 38 ( 50.67 ) 24 ( 32.00 ) 13 ( 17.33 ) 51 ( 68.00 ) 17 ( 22.67 ) 7 ( 9.33 ) 0.087 Height-for-age # Normal Stunted Severely stunted 37 ( 49.33) 28 ( 37.33 ) 10 ( 13.33 ) 49 ( 65.34 ) 16 ( 21.33 ) 10 ( 13.33 ) 0.084 Weight-for-height $ Normal Wasted Severely wasted 52 ( 69.33 ) 18 ( 24.00 ) 5 ( 6.67 ) 62 ( 82.67 ) 9 ( 12 ) 4 ( 5.33 ) 0.136 Values were presented as mean ± standard deviation or number ( % ). *, Mann-Whitney U Test; # , Fischer’s exact test; $ , Pearson chi-square test. p-value <0.05 was highlighted as bold. kcal/mL, kilocalorie per milliliter. Table 2 . Effect of ONS intervention on body weight and height. Effect 1.5 kcal/mL group 1.0 kcal/mL group p-value Body weight at Day 0 (kg) 9.21 ± 1.92 10.33 ± 2.31 Weight gain at Day 14 (kg)* 0.24 ± 0.26 0.20 ± 0.15 0.184 Weight gain at Day 30 (kg) # 0.60 ± 0.33 0.43 ± 0.29 0.001 Weight gain at Day 60 (kg) # 0.85 ± 0.42 0.76 ± 0.44 0.250 Weight gain at Day 90 (kg) # 1.10 ± 0.46 1.00 ± 0.54 0.240 Body height at Day 0 (cm) 78.91 ± 8.07 82.86 ± 9.68 Height gain at Day 14 (cm)* 0.50 ± 0.36 0.42 ± 0.50 0.120 Height gain at Day 30 (cm)* 1.64 ± 0.77 1.10 ± 0.74 0.001 Height gain at Day 60 (cm)* 2.55 ± 1.00 1.92 ± 1.02 0.001 Height gain at Day 90 (cm)* 3.33 ± 1.00 2.71 ± 1.11 0.001 Weight gain was calculated by subtracting body weight at Day 14/30/60/90 with body weight at Day 0. Height gain was calculated by subtracting body height at day 14/30/60/90 with body height at day 0. *, Mann-Whitney U test; # , independent t-test. p-value <0.05 was highlighted as bold. kcal/mL, kilocalorie per milliliter; kg, kilogram; cm, centimeter. Additional Declarations There is NO conflict of interest to disclose. Supplementary Files SupplementaryfilesEJCNONS.pdf Supplementary Tables Cite Share Download PDF Status: Under Review Version 1 posted Review # 4 received at journal 29 Mar, 2026 Reviewer # 4 agreed at journal 26 Mar, 2026 Review # 3 received at journal 05 Feb, 2026 Reviewer # 3 agreed at journal 05 Feb, 2026 Reviewer # 2 agreed at journal 16 Jan, 2026 Reviewer # 1 agreed at journal 02 Jul, 2025 Reviewers invited by journal 25 Jun, 2025 Editor assigned by journal 16 May, 2025 Submission checks completed at journal 16 May, 2025 First submitted to journal 15 May, 2025 Unknown event 15 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6668470","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":476516361,"identity":"e78f513d-9a00-4d6f-8ea7-3765313264e9","order_by":0,"name":"Nur Aisiyah Widjaja","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAs0lEQVRIiWNgGAWjYJCCAw8MbOQYGHhI0ZJQkWZMmhaGhDOHExuI1mIukfvwQGJbWvqG42cPPvjAYCen20BAi+WMdAOgFpvcDWfykg1nMCQbmx0goMXgRhoDyJbcDQdyzKR5gOxtRGo5nG5w/g0pWoDeTzC4QbQtZ56BA9lw5o03xoYzDIjxy/E05g8fDGzk+c7nGD74UGEnR1ALHCiAVRoQqxwE5BtIUT0KRsEoGAUjCgAA0CJICNUI2XIAAAAASUVORK5CYII=","orcid":"","institution":"Universitas Airlangga","correspondingAuthor":true,"prefix":"","firstName":"Nur","middleName":"Aisiyah","lastName":"Widjaja","suffix":""},{"id":476516362,"identity":"f09539e7-d701-4170-8480-1217af394437","order_by":1,"name":"Meta Hanindita","email":"","orcid":"","institution":"Universitas Airlangga","correspondingAuthor":false,"prefix":"","firstName":"Meta","middleName":"","lastName":"Hanindita","suffix":""},{"id":476516363,"identity":"1eb6af41-09ec-4183-a53c-4cef38d6e17f","order_by":2,"name":"Eva Ardianah","email":"","orcid":"","institution":"Universitas Airlangga","correspondingAuthor":false,"prefix":"","firstName":"Eva","middleName":"","lastName":"Ardianah","suffix":""},{"id":476516364,"identity":"6570c341-e717-4c01-b0df-62d0ac73ced7","order_by":3,"name":"Febrina Santoso","email":"","orcid":"","institution":"Universitas Airlangga","correspondingAuthor":false,"prefix":"","firstName":"Febrina","middleName":"","lastName":"Santoso","suffix":""},{"id":476516365,"identity":"99b69a25-3ee0-4437-a2ff-57e86fd731ea","order_by":4,"name":"Juandy Jo","email":"","orcid":"https://orcid.org/0000-0002-5366-7605","institution":"University of Pelita Harapan","correspondingAuthor":false,"prefix":"","firstName":"Juandy","middleName":"","lastName":"Jo","suffix":""}],"badges":[],"createdAt":"2025-05-15 03:50:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6668470/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6668470/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":85827257,"identity":"056505dd-290b-4c1e-ab2e-8afb937ed3a2","added_by":"auto","created_at":"2025-07-02 07:23:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":780318,"visible":true,"origin":"","legend":"\u003cp\u003eAssessment of body weight and height upon intervention with ONS products. Two ONS products, i.e., 1.0 kcal/mL and 1.5 kcal/mL, were provided for study subjects (each group had 75 subjects) for a duration of 90 days. \u003cem\u003e(A)\u003c/em\u003e mean values of total body weight in both groups were presented at Day 0, 14, 30, 60 and 90. \u003cem\u003e(B)\u003c/em\u003eWeight-for-age z scores of both groups were presented as mean ± standard error at Day 0, 14, 30, 60 and 90. The statistical analyses were performed between values at Day 0 and each subsequent time point. Asterix sign refer to p-value \u0026lt;0.001. \u003cem\u003e(C)\u003c/em\u003emean values of total body height in both groups were presented at Day 0, 14, 30, 60 and 90. \u003cem\u003e(D)\u003c/em\u003e Height-for-age z scores of both groups were presented as mean ± standard error at Day 0, 14, 30, 60 and 90. The statistical analyses were performed between values at Day 0 and each subsequent time point. Asterix sign refers to p-value \u0026lt;0.001.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6668470/v1/34d8006b847c2071e8370e7a.png"},{"id":85828599,"identity":"78fa45c0-3527-483e-80f4-c4151bd4ae4c","added_by":"auto","created_at":"2025-07-02 07:31:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":216366,"visible":true,"origin":"","legend":"\u003cp\u003eProportions of at-risk, underweight and severely underweight subjects upon intervention with ONS products. The proportions of subjects with undernutrition based on weight-for-age z score (in percentage) were compared between Day 0 and Day 90 upon receiving 1.5 kcal/mL (left) or 1.0 kcal/mL (right) ONS product and depicted as pie charts.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6668470/v1/8eaf8f5b39da712560030cc5.png"},{"id":85827256,"identity":"5cc9ff82-13c7-4350-9e0e-5e5459e078fb","added_by":"auto","created_at":"2025-07-02 07:23:03","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":210449,"visible":true,"origin":"","legend":"\u003cp\u003eProportions of at-risk, stunted and severely stunted subjects upon intervention with ONS products. The proportions of subjects with undernutrition based on weight-for-age z score (in percentage) were compared between Day 0 and Day 90 upon receiving 1.5 kcal/mL (left) or 1.0 kcal/mL (right) ONS product and depicted as pie charts.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-6668470/v1/8fa2c537c09a50c96f625317.png"},{"id":85827258,"identity":"e1112edc-228f-4e74-a1d6-f49a6a723c5d","added_by":"auto","created_at":"2025-07-02 07:23:03","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":203845,"visible":true,"origin":"","legend":"\u003cp\u003eProportions of at-risk, wasted and severely wasted subjects upon intervention with ONS products. The proportions of subjects with undernutrition based on weight-for-age z score (in percentage) were compared between Day 0 and Day 90 upon receiving 1.5 kcal/mL (left) or 1.0 kcal/mL (right) ONS product and depicted as pie charts.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-6668470/v1/7655f5884f6c04769b65b25e.png"},{"id":85831079,"identity":"bcb77ace-4b1f-4df4-bea1-1eff8c698d7d","added_by":"auto","created_at":"2025-07-02 07:47:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2003123,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6668470/v1/e55298a2-469a-4d4f-9ffb-6b380097121a.pdf"},{"id":85828598,"identity":"dc80d100-b06b-4e86-b277-61d43de11f6f","added_by":"auto","created_at":"2025-07-02 07:31:03","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":118265,"visible":true,"origin":"","legend":"Supplementary Tables","description":"","filename":"SupplementaryfilesEJCNONS.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6668470/v1/9696f3582ca901063a059aa9.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"High Caloric Density and Optimal Protein-to-Energy Ratio of Oral Nutritional Supplements: Impacts on Catch-Up Growth in Undernourished Indonesian Children","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eA universal indicator of nutritional status among children is the growth assessment [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The World Health Organization (WHO) has developed several pediatric growth standards, including weight-for-age, height-for-age and weight-for-height that are commonly expressed in z-scores [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Those growth standards are important to uniformly identify children with undernutrition, as the prevalence of children with poor growth remains high worldwide [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eChronic undernutrition could contribute to mortalities among children under five years old as well as various long-term health consequences [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Vice versa, children contracting infectious diseases frequently suffered from undernutrition due to nutrient loss, reduced uptake, as well as increased energy requirements during inflammation [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Childhood undernutrition is closely associated with wealth-related inequality across various economic groups of nations worldwide [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Children from disadvantage communities in low- and middle-income countries have a higher risk to suffer from undernourishment [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The 2018 Indonesia Basic Health Research had indicated that the prevalence of wasted and stunted among Indonesian children under 5 years old were high, i.e., 7.2 and 19.7%, respectively [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003eNutrient-dense foods are recommended for children aged 6\u0026ndash;59 months with moderate acute undernutrition need to meet their nutritional requirements [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Pediatric oral nutritional supplements (ONS) are nutrient-dense foods designed for children, providing 1.0 or 1.5 kilocalorie per mL (kcal/mL) in restricted volumes. Several recommendations, including the WHO guideline, further emphasize in providing adequate protein (8.9\u0026ndash;11.5% of total energy) alongside energy to support effective catch-up growth [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Those formulations could be used by undernourished children who have poor appetite or cannot tolerate higher intake of volume [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. A positive correlation was observed with compliance in taking these formulas partly due to the readiness-to-drink and limited volume to be drunk [\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This study thus investigated the usefulness of ONS energy-dense to support catch-up growth among Indonesian children with undernutrition, by comparing the efficacy of ONS using 1.0 (protein-to-energy ratio (PER) of 9.6%) or 1.5 kcal/mL (PER of 8.9%) to support catch-up growth among pediatric outpatients in Surabaya, East Java, Indonesia.\u003c/p\u003e"},{"header":"SUBJECTS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and subjects\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThis retrospective cohort study, conducted at Husada Utama Hospital in Surabaya, Indonesia, from September to December 2023, assessed the efficacy of high-calorie ONS with optimal PER in pediatric outpatients aged 1\u0026ndash;5 years with feeding difficulties and undernutrition. Eligible patients had baseline (i) weight-for-age z-score (WAZ) \u0026lt;-2 SD; and/or (ii) height-for-age z-score (HAZ) \u0026lt;-2 SD; and/or (iii) weight-for-height z-score (WHZ) \u0026lt;-2 SD; as well as (iv) inadequate weight increment (\u003cb\u003eSupplementary Table\u0026nbsp;1\u003c/b\u003e). The exclusion criteria were patients having (i) fluid retention; (ii) organomegaly; (iii) tumor; (iv) congenital abnormality; (v) cerebral palsy, hormone disturbances and syndromes; and (vi) incomplete medical record. Participants were divided into two groups, receiving either 400 milliliter per day of 1.0 (PER of 9.6%) or 1.5 kcal/mL ONS (PER of 8.9%), combined with solid food to provide 1,000 kcal/day. The composition of both products provided by Danone Nutricia Indonesia were listed in \u003cb\u003eSupplementary Table\u0026nbsp;2\u003c/b\u003e. Parents were educated on complementary feeding, and micronutrient supplementation was provided as needed.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eAnthropometric data\u003c/h3\u003e\n\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe electronic medical records of participants, included birthdate, sex, infection status, ONS compliance and adverse events, as well as weight and height measurements taken on Day 0, 14, 30, 60, and 90. Weight (in kilogram) was measured using baby scale SECA 354 or standing scale SECA 813 (Harmburg, Germany), Height (in centimeter) was measured using infantometer SECA 416 or stadiometer SECA 213 (Hamburg, Germany). At each timepoint, weight and height were measured twice, and if there was any discrepancy, a third measurement was taken. The average of the three measurements was recorded. The WAZ, HAZ and WHZ of each subject were calculated, based on the weight and height data, by using the WHO child growth standards. Based on the WAZ, a child was categorized as underweight if having z-score \u0026lt;-2 SD and \u0026ge;-3 SD of the median or as severely underweight if having z-score \u0026lt;-3 SD of the median. Based on the HAZ, a child was categorized as stunted if having z-score \u0026lt;-2 SD and \u0026ge;-3 SD of the median or as severely stunted if having z-score \u0026lt;-3 SD of the median. Based on the WHZ, a child was categorized as wasted if having z-score \u0026lt;-2 SD and \u0026ge;-3 SD of the median or as severely wasted if having z-score \u0026lt;-3 SD of the median.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eData were analyses using the SPSS ver. 24.0 (SPSS Inc., Chicago, IL, USA). Descriptive statistics were presented according to the type of data. Testing of normality and homogeneity of variation were performed on data of age, body weight, body height, WAZ, HAZ and WHZ before and after ONS provision. Difference between two groups was calculated using independent t-test or Mann-Whitney U test. For categorical data, either Pearson chi-squared or Fisher's exact test was used. A statistical significance was considered with p-value less than 0.05. Data visualization was performed using the GraphPad Prism version 10.4.1 (California, USA).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA total of 150 subjects were recruited into this study, which were equally divided between groups receiving the 1.0 (PER of 9.6%) and 1.5 kcal/mL (PER of 8.9%) ONS. Most demographic characteristics between two groups did not differ significantly, except age and status of infection (Table 1). Subjects within the 1.5 kcal/mL group were statistically younger and 73 out of 75 subjects (97.33%) contracted infections. Total caloric intake of 1,000 kcal/day for a duration of 90 days were prescribed for all subjects, i.e., while the group of 1.5 kcal/mL received 400 kcal from solid food and 600 kcal from ONS per day, the group of 1.0 kcal/mL received 600 kcal from solid food and 400 kcal for ONS per day. This implied that the calorie deficit was higher in the former group than the latter group. Hence, as expected, the average body weight and height at Day 0 in the 1.5 kcal/mL group were lower than the ones in the 1.0 kcal/mL group (Table 2). Despite birth weights and heights between two groups did not significantly differ (Table 1), the 1.5 kcal/mL group had more undernourished subjects than the 1.0 kcal/mL group, either based on WAZ, HAZ or WHZ. Of note, most subjects had gone to the hospital due to parental concerns of feeding difficulty-related no weight gain, in which majority of them were subsequently diagnosed with infections as well.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMost subjects demonstrated good compliance in using the ONS products, in which the provisions of both products were observed to be safe (Table 1). Upon the ONS intervention for 90 days, the average body weight in both groups steadily increased during the study (Table 2\u0026nbsp;and\u0026nbsp;Figure 1A). Interestingly, the average weight gain at Day 30 was significantly higher in the 1.5 kcal/mL group than in the 1.0 kcal/mL group (p=0.001), suggesting that the provision of 1.5 kcal/mL ONS induced a higher rate in weight gain during the first 30 days. At the end of the study, however, the average weight gain between both groups did not differ significantly (1.10±0.46 versus 1.00±0.54 kilograms (kg); p=0.240), suggesting that, upon 90-day of intervention, both ONS products eventually induced similar rates of weight gain. This notion was supported by improvements of WAZ scores observed across both groups during the study duration (Figure 1B). The ONS intervention for 90 days steadily improved the average body height in both groups as well (Table 2\u0026nbsp;and\u0026nbsp;Figure 1C). Both groups were indeed observed to significantly improve their HAZ scores during the study duration (Figure 1D). Of note, the provision of 1.5 kcal/mL ONS induced better height gains than the provision of 1.0 kcal/mL ONS, as observed at Day 30, 60 and 90 (p=0.001), suggesting that the provision of 1.5 kcal/mL ONS steadily induced a higher rate in gaining height over time, contributing to an improvement of total body height within this group at the end of the study. Taken together, these findings reinforced the usefulness of high-calorie formula ONS products in managing children with calorie deficits, even for the ones with underlying infections, as reflected by the increment of body weight and height of study subjects at Day 90 based on the WHZ score (Supplementary Figure 1). The usefulness of 1.5 kcal/mL ONS to support catch-up growth among pediatric patients was also reinforced.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe subsequent analyses were focused on undernourished subjects based on WAZ (underweight and severely underweight), HAZ (stunted and severely stunted), as well as WHZ criteria (wasted and severely wasted). Of note, one subject could be categorized into more than one category of undernutrition because of the utilization of three growth standards. There were 41 underweight and 20 severely underweight children included in this study (Supplementary Table 3). Forty-four stunted and 20 severely stunted children were found in this study cohort (Supplementary Table 4). Finally, 27 wasted and 9 severely wasted children were observed in this study (Supplementary Table 5). In agreement with the overall findings on all subjects, the undernourished subjects, on average, steadily gained weight and height during the study duration. It was of interest to note that for the categories of severe underweight and wasted, weight gains at Day 30 were significantly higher for the group of 1.5 kcal/mL (Supplementary Table 3 \u0026amp; 5). Height gains were also significantly higher for the group of 1.5 kcal/mL in the category of severely stunted at Day 30 (Supplementary Table 4). This suggests that the provision of 1.5 kcal/mL ONS also generated higher gaining rates in both weight and height for certain undernourished patients.\u003c/p\u003e\n\u003cp\u003eThe efficacy of providing either 1.0 or 1.5 kcal/mL ONS was subsequently evaluated by comparing proportions of undernourished subjects in various categories between Day 0 and Day 90.\u0026nbsp;Figure 2\u0026nbsp;reported that while provision of 1.0 kcal/mL ONS decreased the proportion of underweight and severely underweight subjects as much as 8.0% (n=6) and 5.3% (n=4), respectively, the provision of 1.5 kcal/mL ONS achieved a greater reduction by decreasing the proportion of underweight and severely underweight subjects as much as 10.7% (n=8) and 14.6% (n=11), respectively. This finding was also observed among stunted and severely stunted children, in which the provision of 1.5 kcal/mL ONS reduced the proportion of stunted and severely stunted subjects as much as 5.3% (n=6) and 6.6% (n=5), respectively, but the provision of 1.0 kcal/mL ONS only decreased the proportion of stunted and severely stunted subjects as much as 2.6% (n=2) and 6.7% (n=5), respectively (Figure 3). Findings of wasted and severely wasted subjects were also in agreement with both findings (Figure 4). The provision of 1.0 kcal/mL ONS reduced the proportion of severely wasted subjects as much as 4.0% (n=3) but, intriguingly, did not reduce the proportion of wasted subjects. In contrast, the provision of 1.5 kcal/mL ONS was able to decrease the proportion of wasted subjects as much as 18.7% (n=14) and eliminated the proportion of severely wasted subjects (6.7%, n=5), respectively. Taken together, the administration of 1.5 kcal/mL ONS with PER of 8.9% appeared to be a better choice to improve both weight and height for undernourished children. \u0026nbsp;\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eWe hereby assessed a comparison between 1.0 and 1.5 kcal/mL ONS in supporting catch-up growth among undernourished children in Surabaya, Indonesia. High level of compliance and good safety profile were observed for the provision of both ONS products. While both high-calorie ONS products could support weight and height gains, the 1.5 kcal/mL ONS with PER of 8.9% was a better option for undernourished children. Our results can be summarized in four points. First, subjects receiving 1.5 kcal/mL ONS contracted more episodes of infection, particularly tuberculosis, than the ones receiving 1.0 kcal/mL ONS. This partly contributed to more severe cases of undernutrition observed in the former group, which also became the rationale to provide ONS product with higher calorie to these subjects. It is acknowledged that tuberculosis and undernutrition have a bi-directional relationship [18]. Undernutrition is the primary cause of immunodeficiency, creating a vulnerability among undernourished subjects to subsequently contract tuberculosis [8, 19]. Vice versa, tuberculosis can cause inflammation-related cachexia, anorexia, and malabsorption, resulting in undernutrition [20, 21]. Of note, subjects in the group of 1.5 kcal/mL were younger than the ones in the group of 1.0 kcal/mL at the beginning of the study, tempting us to speculate that an earlier treatment with a higher-calorie ONS product might be beneficial to improve growth among relevant pediatric patients, particularly during the first 1,000 days of life [22, 23]. In a previous study by using 1.0 kcal/mL ONS, however, the body weight and height increments did not substantially differ between subjects aged 12–24 months and aged \u0026gt;24–60 months [24], indicating more studies are required to address this issue.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSecond, while both ONS products could increase overall weight and height of study subjects at all time points, the provision of 1.5 kcal/mL ONS induced higher gains. The weight gains were indeed statistically different between groups at Day 30, suggesting that the 1.5 kcal/mL ONS facilitated a better increment of weight in the first 30 days. Of note, our finding was different from the previous study that had also compared 1.0 and 1.5 kcal/mL ONS products in Indonesia but did not observe any difference in weight gain between both groups [12]. The difference could be attributed to several methodological variation between both studies, including (i) age of subjects (~23.9 versus ~49.2 months); (ii) composition of tested ONS products; and (iii) duration of intervention (90 versus 28 days). Similarly, the provision of 1.5 kcal/mL ONS induced larger height gains than 1.0 kcal/mL ONS, in which significant differences were observed at Day 30, 60 and 90. Both ONS products were observed to be effective in reducing numbers of undernourished subjects, which were in agreement with the published meta-analysis [22]. Importantly, the 1.5 kcal/mL ONS provided a better improvement in various categories of undernutrition (based on WAZ, HAZ and WHZ) than the 1.0 kcal/mL ONS, suggesting that this product was better for catch-up growth among undernourished pediatric patients. The growth improvement was more pronounced based on the WHZ criterion. The WHZ score of 1.5 kcal/mL group at Day 90 was almost as high as the one of 1.0 kcal/mL group at Day 30. This improvement was striking, considering that the initial average body weight was substantially lower in the group of 1.5 kcal/mL and that total daily intake calorie was equal for both groups (i.e., 1,000 kcal/day). It was of interest to note that the growth improvement upon provision of 1.5 kcal/mL ONS in categories of severely underweight, severely stunted and wasted were significantly higher at Day 30, suggesting that the growth improvement was already noticeable as early as after 30 days of intervention.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThird, the superiority of 1.5 kcal/mL ONS could be partly explained by its PER of 8.9%. It is known that increasing the energy content of a nutritional product without increasing the protein content is not recommended for undernourished children [25]. As the PER of 1.5 kcal/mL ONS was within the recommended range according to the WHO guideline, this formulation could support the optimal catch-up growth of lean and fat mass [13]. However, a higher PER does not equate to a more optimal product as the PER of 9.6% in 1.0 kcal/mL ONS did not support the latter formulation to become a better product in this study. In addition, ONS product with a too-high PER are associated with an unfavorable body composition [26].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFourth, the provision of tested ONS could support catch-up growth among pediatric patients with underlying infections. This finding was encouraging because most subjects in this study had underlying infections (94%, n=141), in which 89% of whom (n=126) contracted tuberculosis. These patients were deemed to be more vulnerable because tuberculosis could worsen the state of undernutrition [20, 21]. Nonetheless, ONS could support catch-up growth among pediatric patients receiving proper medical treatments, including antibiotics [27]. Our findings reconfirmed this notion, in which the 1.5 kcal/mL ONS appeared to be a better choice for undernourished pediatric patients with underlying infections. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCalorie-dense pediatric ONS with optimum PER is an effective method to support catch-up growth among children with issues in their nutritional statuses, because patients benefit of high calories from consuming products of limited volume [22]. However, it is important to understand that dietary counseling remains the first line of treatment to promote growth among at-risk children and that it should be still provided when ONS product is prescribed [22, 28]. This is because of the wide-spread, inappropriate usage of ONS, including over-prescription, under-prescription or mis-prescription, could result in non-improvement of patient’s nutritional status and/or cause injury to tissues [29–32]. Most ONS products cannot be used as the only source of nutrition because they are nutritionally incomplete [23]. Health education is therefore important to ensure the clinical appropriateness and benefits of providing ONS to patients [22, 23, 33]. In our study, the parents had been counselled and monitored to continuously provide family food, in conjunction to ready-to-drink, high calorie ONS products, to their children. This facilitated daily intake calorie of 1,000 kcal/day for all subjects to support their catch-up growth, but not causing excessive body weight gains during this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAnother important matter in prescribing ONS product is to decide when to stop prescribing ONS product [23]. This clinical judgement should be taken prudently. While other studies had assessed the impact of ONS interventions from 7 to 365 days [22], the length of ONS intervention in our study was 90 days. We observed that the average growth improvement of study subjects was still within the normal range, supporting a recommendation that ONS should be prescribed for at least 3 months to provide weight and height gains [23]. Our study had several limitations, including a single-center study design with limited number of subjects. In addition, the retrospective study design did not allow us to perform long-term assessment on subjects post-ONS prescription.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn conclusion, administering 1.0 and 1.5 kcal/mL ONS for 90 days promoted catch-up growth in at-risk and undernourished children. Nonetheless, the 1.5 kcal/mL formulation with PER of 8.9% was more effective, even among those with infections.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData will be available upon request to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParts of the data were presented in the 57\u003csup\u003eth\u003c/sup\u003e Annual Meeting of the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition in Helsinki, Finland. The authors thank Nova Sitorus for supporting this study administratively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHORS’ CONTRIBUTION\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization and methodology: N.A.W; Investigation: N.A.W., M.H.H., E.A., F.M.S. and J.J; Funding acquisition: N.A.W.; Data curation: M.H.H., E.A. and F.M.S.; Data analysis: N.A.W., M.H.H., E.A., F.M.S. and J.J.; Writing original draft: N.A.W. and J.J. All authors approved the final draft of manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was partially funded by Danone Specialized Nutrition Indonesia it was not involved in the study hypothesis/design, execution, analysis, or interpretation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eETHICAL APPROVAL\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Ethics Committee of the Husada Utama Hospital (#17/KEP-RSHU/XI/2023) and was registered in ClinicalTrials.gov (NCT06160765).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOMPETING INTEREST\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eN. A. W. reports financial support from Danone Specialized Nutrition Indonesia. Other authors declare no competing interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWorld Health Organization (2024) The WHO Child Growth Standards. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.who.int/tools/child-growth-standards\u003c/span\u003e\u003cspan address=\"https://www.who.int/tools/child-growth-standards\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed 25 Feb 2024\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede Onis M, Branca F (2016) Childhood stunting: A global perspective. 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Nutr. 39:654\u0026ndash;663\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCoffey N, O\u0026rsquo; Leary F, Burke F, et al (2022) \u0026ldquo;Oral Nutritional Supplements: Sugar Content and Potential Dental Implications.\u0026rdquo; Gerodontology 39:354\u0026ndash;358. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/ger.12592\u003c/span\u003e\u003cspan address=\"10.1111/ger.12592\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHassanin IA, Salih RFM, Fathy MHM, et al (2022) Implications of inappropriate prescription of oral nutritional supplements on the quality of life of cancer outpatients: a cross-sectional comparative study. Support Care Cancer 30:4149\u0026ndash;4155. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00520-022-06837-6\u003c/span\u003e\u003cspan address=\"10.1007/s00520-022-06837-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWan G ying, Yuan H, Xue H, et al (2021) Assessment of compliance with oral nutritional supplementation and exploration of barriers and facilitators for patients after gastrectomy: A mixed-methods study. J Adv Nurs 77:2845\u0026ndash;2859. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/jan.14851\u003c/span\u003e\u003cspan address=\"10.1111/jan.14851\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e. Baseline characteristics of study subjects.\u0026nbsp;\u003c/p\u003e\n\u003cdiv align=\"Left\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.5 kcal/mL group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=75)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.0 kcal/mL group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=75)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003eAge (month)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e22.15\u0026nbsp;\u0026plusmn;\u0026nbsp;10.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e25.72\u0026nbsp;\u0026plusmn;\u0026nbsp;11.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.037\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003eBirth weight (kilogram)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e2.99\u0026nbsp;\u0026plusmn;\u0026nbsp;0.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.95\u0026nbsp;\u0026plusmn;\u0026nbsp;0.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.756\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003eBirth height (centimeter)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e48.10\u0026nbsp;\u0026plusmn;\u0026nbsp;3.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e48.55\u0026nbsp;\u0026plusmn;\u0026nbsp;3.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.912\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003eSex\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003eMale\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eFemale\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e38 (\u003cem\u003e50.67\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e37 (\u003cem\u003e49.33\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e36 (\u003cem\u003e48.00\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e39 (\u003cem\u003e52.00\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.870\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003eReason visiting hospital\u003csup\u003e$\u003c/sup\u003e\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003ePicky eater \u0026amp; unchanged weight\u003c/li\u003e\n \u003cli\u003eNo weight gain \u0026amp; no height gain\u003c/li\u003e\n \u003cli\u003eNo weight gain\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e18 (\u003cem\u003e24.00\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 (\u003cem\u003e4.00\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e54 (\u003cem\u003e72.00\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e27 (\u003cem\u003e36.00\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (\u003cem\u003e1.33\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e47 (\u003cem\u003e62.67\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.193\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003eInfection\u003csup\u003e$\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003eUrinary tract infection\u003c/li\u003e\n \u003cli\u003eUrinary tract infection \u0026amp; Tuberculosis\u003c/li\u003e\n \u003cli\u003eTuberculosis\u003c/li\u003e\n \u003cli\u003enone\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (\u003cem\u003e1.33\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e34 (\u003cem\u003e45.33\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e38 (\u003cem\u003e50.67\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e2 (\u003cem\u003e2.67\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e14 (\u003cem\u003e18.67\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e22 (\u003cem\u003e29.33\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e32 (\u003cem\u003e42.67\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e7 (\u003cem\u003e9.33\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.005\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003eCompliance\u003csup\u003e$\u003c/sup\u003e\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003eConsumed \u0026gt;75%\u003c/li\u003e\n \u003cli\u003eConsumed \u0026gt;50%\u003c/li\u003e\n \u003cli\u003eConsumed \u0026lt;50%\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.649\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003eAdverse events\u003csup\u003e$\u003c/sup\u003e\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003eDiarrhea\u003c/li\u003e\n \u003cli\u003eNausea and/or Vomiting\u003c/li\u003e\n \u003cli\u003enone\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.309\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003eWeight-for-age\u003csup\u003e$\u003c/sup\u003e\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003eNormal\u003c/li\u003e\n \u003cli\u003eUnderweight\u003c/li\u003e\n \u003cli\u003eSeverely underweight\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e38 (\u003cem\u003e50.67\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e24 (\u003cem\u003e32.00\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e13 (\u003cem\u003e17.33\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e51 (\u003cem\u003e68.00\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e17 (\u003cem\u003e22.67\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e7 (\u003cem\u003e9.33\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.087\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003eHeight-for-age\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003eNormal\u003c/li\u003e\n \u003cli\u003eStunted\u003c/li\u003e\n \u003cli\u003eSeverely stunted\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e37 (\u003cem\u003e49.33)\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e28 (\u003cem\u003e37.33\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e10 (\u003cem\u003e13.33\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e49 (\u003cem\u003e65.34\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e16 (\u003cem\u003e21.33\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e10 (\u003cem\u003e13.33\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.084\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003eWeight-for-height\u003csup\u003e$\u003c/sup\u003e\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003eNormal\u003c/li\u003e\n \u003cli\u003eWasted\u003c/li\u003e\n \u003cli\u003eSeverely wasted\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e52 (\u003cem\u003e69.33\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e18 (\u003cem\u003e24.00\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e5 (\u003cem\u003e6.67\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e62 (\u003cem\u003e82.67\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e9 (\u003cem\u003e12\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e4 (\u003cem\u003e5.33\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.136\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eValues were presented as mean\u0026nbsp;\u0026plusmn;\u0026nbsp;standard deviation or number (\u003cem\u003e%\u003c/em\u003e).\u003c/p\u003e\n\u003cp\u003e*, Mann-Whitney U Test; \u003csup\u003e#\u003c/sup\u003e, Fischer\u0026rsquo;s exact test; \u003csup\u003e$\u003c/sup\u003e, Pearson chi-square test.\u003c/p\u003e\n\u003cp\u003ep-value \u0026lt;0.05 was highlighted as bold.\u003c/p\u003e\n\u003cp\u003ekcal/mL, kilocalorie per milliliter.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e. Effect of ONS intervention on body weight and height.\u003c/p\u003e\n\u003cdiv align=\"Left\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"529\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEffect\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.5 kcal/mL group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.0 kcal/mL group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eBody weight at Day 0 (kg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e9.21\u0026nbsp;\u0026plusmn;\u0026nbsp;1.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e10.33\u0026nbsp;\u0026plusmn;\u0026nbsp;2.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eWeight gain at Day 14 (kg)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.24\u0026nbsp;\u0026plusmn;\u0026nbsp;0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.20\u0026nbsp;\u0026plusmn;\u0026nbsp;0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.184\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eWeight gain at Day 30 (kg)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.60\u0026nbsp;\u0026plusmn;\u0026nbsp;0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.43\u0026nbsp;\u0026plusmn;\u0026nbsp;0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eWeight gain at Day 60 (kg)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.85\u0026nbsp;\u0026plusmn;\u0026nbsp;0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.76\u0026nbsp;\u0026plusmn;\u0026nbsp;0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.250\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eWeight gain at Day 90 (kg)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e1.10\u0026nbsp;\u0026plusmn;\u0026nbsp;0.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.00\u0026nbsp;\u0026plusmn;\u0026nbsp;0.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.240\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eBody height at Day 0 (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e78.91\u0026nbsp;\u0026plusmn;\u0026nbsp;8.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e82.86\u0026nbsp;\u0026plusmn;\u0026nbsp;9.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eHeight gain at Day 14 (cm)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.50\u0026nbsp;\u0026plusmn;\u0026nbsp;0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.42\u0026nbsp;\u0026plusmn;\u0026nbsp;0.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.120\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eHeight gain at Day 30 (cm)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e1.64\u0026nbsp;\u0026plusmn;\u0026nbsp;0.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.10\u0026nbsp;\u0026plusmn;\u0026nbsp;0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eHeight gain at Day 60 (cm)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e2.55\u0026nbsp;\u0026plusmn;\u0026nbsp;1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.92\u0026nbsp;\u0026plusmn;\u0026nbsp;1.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eHeight gain at Day 90 (cm)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e3.33\u0026nbsp;\u0026plusmn;\u0026nbsp;1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.71\u0026nbsp;\u0026plusmn;\u0026nbsp;1.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eWeight gain was calculated by subtracting body weight at Day 14/30/60/90 with body weight at Day 0.\u003c/p\u003e\n\u003cp\u003eHeight gain was calculated by subtracting body height at day 14/30/60/90 with body height at day 0.\u003c/p\u003e\n\u003cp\u003e*, Mann-Whitney U test; \u003csup\u003e#\u003c/sup\u003e, independent t-test.\u003c/p\u003e\n\u003cp\u003ep-value \u0026lt;0.05 was highlighted as bold.\u003c/p\u003e\n\u003cp\u003ekcal/mL, kilocalorie per milliliter; kg, kilogram; cm, centimeter.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-clinical-nutrition","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"ejcn","sideBox":"Learn more about [European Journal of Clinical Nutrition](http://www.nature.com/ejcn/)","snPcode":"41430","submissionUrl":"https://mts-ejcn.nature.com/cgi-bin/main.plex","title":"European Journal of Clinical Nutrition","twitterHandle":"@ejcneditor","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6668470/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6668470/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBACKGROUND: Pediatric oral nutritional supplements (ONS) are nutrient-dense foods that provide high calories in restricted volumes to meet nutritional requirement of undernourished children. Beyond providing high caloric content, ONS should maintain an optimal protein-to-energy ratio (PER). This study evaluated the efficacy of two ONS formulations, i.e., 1.0 kcal/mL with PER of 9.6% or 1.5 kcal/mL ONS with PER of 8.9%, to support catch-up growth among at-risk and undernourished pediatric outpatients in Surabaya, Indonesia.\u003c/p\u003e\n\u003cp\u003eMETHODS: A retrospective cohort study was conducted using electronic medical record of 150 eligible pediatric patients aged 1-5 years old with feeding difficulties and infection. The subjects were categorized into 2 groups: (i) who consumed 400 kcal of solid food and received 400 mL/day of 1.5 kcal/mL ONS, and (ii) who consumed 600 kcal of solid food and received 400 mL/day of 1 kcal/mL ONS.\u003c/p\u003e\n\u003cp\u003eRESULTS: Interventions with both ONS for 90 days improved average weight and height of subjects. Nonetheless, the 1.5 kcal/mL ONS induced higher weight gains at Day 30 and higher height gains at Day 30, 60 and 90. In the sub-stratification analyses, the 1.5 kcal/mL ONS induced significant weight gain at Day 30 for severely underweight and wasted subjects as well as promoted significant height gain at Day 30 for severely stunted patients.\u003c/p\u003e\n\u003cp\u003eCONCLUSION: The 1.5 kcal/mL ONS with PER of 8.9% demonstrated a better effectiveness in promoting catch-up growth among undernourished children.\u003c/p\u003e","manuscriptTitle":"High Caloric Density and Optimal Protein-to-Energy Ratio of Oral Nutritional Supplements: Impacts on Catch-Up Growth in Undernourished Indonesian Children","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-02 07:22:58","doi":"10.21203/rs.3.rs-6668470/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-03-29T07:41:48+00:00","index":4,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-03-26T07:07:59+00:00","index":4,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-02-05T10:45:05+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-02-05T07:59:27+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-01-16T13:57:47+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-07-02T16:05:31+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-06-25T21:37:45+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-16T09:40:53+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-16T09:36:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Clinical Nutrition","date":"2025-05-16T01:49:20+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2025-05-15T09:37:02+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-clinical-nutrition","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"ejcn","sideBox":"Learn more about [European Journal of Clinical Nutrition](http://www.nature.com/ejcn/)","snPcode":"41430","submissionUrl":"https://mts-ejcn.nature.com/cgi-bin/main.plex","title":"European Journal of Clinical Nutrition","twitterHandle":"@ejcneditor","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"69c72f6f-0be7-4b55-8f85-66d544f22571","owner":[],"postedDate":"July 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":50601881,"name":"Health sciences/Diseases/Nutrition disorders/Malnutrition"},{"id":50601882,"name":"Health sciences/Health care/Paediatrics"}],"tags":[],"updatedAt":"2025-07-02T07:22:58+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-02 07:22:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6668470","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6668470","identity":"rs-6668470","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}