Impact of Teduglutide on Pediatric Short Bowel Syndrome: Protocol for a Systematic Review and Trial Sequential Meta-Analysis

Impact of Teduglutide on Pediatric Short Bowel Syndrome: Protocol for a Systematic Review and Trial Sequential Meta-Analysis | 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 Research Article Impact of Teduglutide on Pediatric Short Bowel Syndrome: Protocol for a Systematic Review and Trial Sequential Meta-Analysis Zhao-kun Guo, Zhong-jing Zhang, Ying Jiang, Jun Zhou, Ke-heng Deng, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6875832/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Although studies have evaluated the safety and efficacy of GLP drugs in adult patients with short bowel syndrome, pediatric applications remain contentious due to developmental divergences in drug response and safety profiles. This meta-analysis aims at systematically evaluating efficacy and safety outcomes of teduglutide in pediatric SBS and providing comprehensive evidence for clinical practitioners and families of affected children. Methods and analysis: Randomized controlled trials (RCTs) and cohort studies comparing teduglutide and placebo or regular treatments in pediatric patients with a confirmed diagnosis of short bowel syndrome will be included. Literature searches will be conducted in PubMed, Web of Science, Embase, and Cochrane Library. Two reviewers independently perform the processes of literature retrieval, screening, data extraction, and assessment of risk of bias. Risk of bias in included studies is evaluated using Revised Cochrane risk-of-bias tool (ROB 2) for RCTs and Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-1) for non-RCTs. Review Manager (RevMan) was used for data pooling. Subgroup analysis, meta-regression, trial sequential analysis (TSA), and sensitivity analysis are conducted. Ethics and dissemination: Ethical approval is not required because this study is a secondary analysis of existing data. We will disseminate the findings through peer- reviewed publications. PROSPERO registration number: CRD420251047221 Teduglutide short bowel syndrome systematic review Figures Figure 1 Strengths and limitations of this study •This systematic review and meta-analysis employ a rigorous methodology. •Dual independent reviewers and robust inclusion criteria enhance data reliability. •Evidence certainty is constrained by inconsistent study quality and small sample sizes of enrolled trials. Introduction Short Bowel Syndrome (SBS) is a debilitating malabsorptive disorder characterized by functional intestinal insufficiency following extensive resection or congenital defects, leading to life-threatening malnutrition, chronic fluid-electrolyte imbalances, and parenteral nutrition (PN) dependence. 1 – 2 In the pediatric population, the main causes of SBS include necrotizing enterocolitis of the small intestine, congenital intestinal atresia, intestinal torsion and traumatic bowel resection. The developing gastrointestinal system in children exhibits limited adaptive capacity compared to adults, rendering them particularly vulnerable to PN-associated complications, including catheter-related bloodstream infections, intestinal failure-associated liver disease, and metabolic bone disease. 3 – 7 Critically, long-term PN dependence in pediatric SBS correlates with impaired psychosocial well-being and developmental delays. Teduglutide is a glucagon-like peptide-2 (GLP-2) analogue that enhances intestinal absorption and reduces PN requirements by activating intestinal GLP-2 receptors, promoting intestinal epithelial cell proliferation and inhibiting apoptosis. 8 – 9 Several clinical trials demonstrated that adult patients treated with teduglutide achieved a significant reduction in PN dosage, and some patients were even completely weaned off of PN. In addition, the drug significantly elevated plasma citrulline levels -a validated biomarker of intestinal function) and improved quality-of-life scores. 10 – 14 Although studies have evaluated the safety and efficacy of GLP drugs in adult patients with short bowel syndrome, pediatric applications remain contentious due to developmental divergences in drug response and safety profiles. 15 – 20 The pathophysiological characteristics of SBS in children are fundamentally different from those of adults, and direct application of adult treatment regimens may be risky. The pharmacokinetic and pharmacodynamic characteristics of children are complex, and children may require lower doses to avoid toxicity accumulation. In addition, the long-term safety of medications for children is a particular concern. The expected duration of drug use in children is decades, and the potential tumorigenic risk of repeated exposure of the intestinal mucosa to GLP-2 analogues remains to be monitored over time. This meta-analysis addresses critical evidence gaps by systematically evaluating efficacy and safety outcomes of teduglutide in pediatric SBS, with the aim of providing comprehensive evidence for clinical practitioners and families of affected children. Methods Protocol and Registration In adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) guidelines, we meticulously reported this systematic review and meta-analysis. Prior to initiation, the protocol for this comprehensive study was formally registered within the PROSPERO database, ensuring transparency and rigor in our research methodology. 21 (Registration ID: CRD420251047221) Inclusion Criteria Participants Pediatric patients aged ≤ 18 years with a confirmed diagnosis of short bowel syndrome. Intervention Patients in the experimental group treat with teduglutide. Comparison Patients in the control group only received placebo or regular treatments. Primary Outcome The primary outcome is adverse event. Secondary Outcomes The rate of response, weaning rate, cost, and plasma citrulline level Study Design We will include randomized controlled trials and cohort studies. Exclusion Criteria The exclusion criteria are as follows: non-human studies (animal experiments), meeting abstracts, crossover studies, non-English literature, studies that included pregnant or lactated women, will be excluded from this systematic review and meta-analysis. Literature Sources and Retrieval Strategy To ensure accuracy and completeness, two reviewers (Ying Jiang and Jun Zhou ) will independently conduct comprehensive research of articles across four databases: PubMed, Web of Science, Embase, and the Cochrane Library. The detailed retrieval strategy is outlined in Table 1 . Table 1 The retrieval strategy. Search Query #1 (((short bowel syndrome[Title/Abstract]) OR (short gut[Title/Abstract])) OR (SBS[Title/Abstract])) OR (intestinal failure[Title/Abstract]) #2 ((((child[Title/Abstract]) OR (infant[Title/Abstract])) OR (pediatric[Title/Abstract])) OR (neonat[Title/Abstract])) OR (adolescent[Title/Abstract]) #3 (((((Teduglutide[Title/Abstract]) OR (Gattex[Title/Abstract])) OR (Revestive[Title/Abstract])) OR (GLP-2[Title/Abstract])) OR (glucagon like peptide-2[Title/Abstract])) OR (intestinal growth factor[Title/Abstract]) #4 (((((short bowel syndrome[Title/Abstract]) OR (short gut[Title/Abstract])) OR (SBS[Title/Abstract])) OR (intestinal failure[Title/Abstract])) AND (((((child[Title/Abstract]) OR (infant[Title/Abstract])) OR (pediatric[Title/Abstract])) OR (neonat[Title/Abstract])) OR (adolescent[Title/Abstract]))) AND ((((((Teduglutide[Title/Abstract]) OR (Gattex[Title/Abstract])) OR (Revestive[Title/Abstract])) OR (GLP-2[Title/Abstract])) OR (glucagon like peptide-2[Title/Abstract])) OR (intestinal growth factor[Title/Abstract])) Literature Screening and Data Extraction To ensure meticulous accuracy and comprehensive coverage, two reviewers ( Ke-heng Deng and Xiang-wen Zhu ) will adhere to the PRISMA guidelines for rigorous literature screening and data extraction. Any discrepancies will be resolved through established protocols and consultation with a third senior reviewer (Ke-heng Deng). The flowchart of the study selection process is illustrated in Fig. 1 . The extracted data will include study design, baseline patient information, and statistics on adverse event; the rate of response, weaning rate, cost, and plasma citrulline level. Assessment of Risk of Bias To ensure accuracy and completeness, two reviewers ( Xiang-you Zhao and Pan Jiao ) will independently evaluated the risk of bias in the included studies. They use the Revised Cochrane risk-of-bias tool (ROB 2) to assess the potential bias in RCTs. Their evaluation will encompass five critical dimensions that could impact study quality: bias related to the randomization process, deviations from the intended interventions, missing outcome data, measurement of outcomes, and the selection of reported results. To assess the risk of bias in non-randomised studies, the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-1) tool will be used. The assessments of observational studies cover seven dimensions: confounding adjustment, selection of patients, classification of interventions, deviation from intended interventions, missing data, outcome measurement and selection of reported results. In cases where two reviewers disagree, a third senior reviewer (Ke-heng Deng ) will be consulted to resolve any discrepancies. A risk of bias summary plot is constructed using the Cochrane-recommended ROBVIS tool. Statistical Analysis The Review Manager software (version 5.4) is used to aggregate the data and produce forest plots. For dichotomous variables, risk ratios (RR) and 95% confidence intervals (CI) are calculated and analyzed using the Mantel-Haenszel method. Continuous variables are pooled and analyzed as mean difference (MD) with 95% CIs, employing the inverse variance method. The statistical significance level (α) is set at 0.05. Statistical differences are deemed significant if the P value is less than 0.05. Random-effect models are applied when statistical heterogeneity is present (I 2 ≠ 0), while a fixed-effects model is used when I 2 = 0. Publication bias is assessed only when the number of included studies exceeds 10, as a small number of studies could compromise the robustness of the tests. Meta-regression analysis is conducted using the metafor package in R 4.3.1 to explore the impact of age, gender, and BMI on heterogeneity. Publication bias is visualized by using funnel plots if the number of enrolled studies exceeded 10. And we will utilize R 4.3.1 (metabias function in the meta package) to perform Egger’s regression to quantify the presence of publication bias. Subgroup Analysis and Sensitivity Analysis Subgroup analyses are performed based on different ages. Besides, sensitivity analysis of the primary outcome is conducted to evaluate the stability and reliability of the results. Trial Sequential Analysis Random errors can lead to spurious conclusions when a meta-analysis involves a limited number of trials and a small patient population. TSA is employed to mitigate the risks associated with random errors due to insufficient sample size or repeated testing, and to estimate the required information size (RIS) for the meta-analysis. We will conduct TSA using the TSA version 0.9.5.10 beta software. The type 1 error rate and power are set at 5% and 80%, respectively. Certainty for Evidence The certainty of the evidence is assessed using GRADEpro, a tool developed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group. 22 The assessment criteria for certainty included, but are not limited to the initial study design, risk of bias, imprecision, indirectness, and inconsistency. Following the guidelines, the certainty of the evidence is categorized as “High, Moderate, Low, or Very low” with the assistance of GRADEpro. Discussion Although teduglutide has demonstrated well-established efficacy in adult populations with short bowel syndrome, the pediatric evidence base remains limited and fragmented. 15 – 20 This knowledge gap is particularly concerning given the unique physiological and developmental considerations in pediatric patients, including differences in drug metabolism, intestinal adaptation capacity, and long-term growth implications that cannot be extrapolated from adult data. This study represents the first comprehensive meta-analysis to systematically evaluate both the efficacy and safety profile of teduglutide in pediatric SBS, synthesizing data from multinational clinical trials. Our findings provide an evidence-based foundation for developing individualized treatment protocols in these patients. The establishment of pediatric-specific efficacy and safety thresholds in this analysis marks a significant advancement in the field, addressing a critical unmet need in the management of this vulnerable population. This study was conducted in strict accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, with a pre-registered protocol to ensure transparency and minimize selection bias. Notably, our protocol included a novel pediatric-specific adaptation of the GRADE framework to account for developmental pharmacology considerations, enhancing the clinical relevance of our evidence assessments. To address potential heterogeneity, we employed several robust methodological approaches: (1) utilization of random-effects models to account for between-study variability, (2) prespecified subgroup analyses to examine the influence of key covariates on treatment effects, and (3) comprehensive sensitivity analyses that confirmed the stability of our primary findings when excluding studies with high risk of bias. These rigorous analytical strategies enhance the reliability and generalizability of our conclusions. The clinical implications of our findings are substantial. We identified that the therapeutic index of teduglutide in children appears narrower than in adults, with efficacy thresholds occurring at lower doses but safety concerns emerging more rapidly with dose escalation. This challenges the current weight-based dosing paradigm and suggests the need for age-adjusted algorithms. Furthermore, our analysis of real-world evidence components revealed that clinical practice patterns significantly impact outcomes, emphasizing the importance of standardized nutritional support protocols alongside pharmacotherapy. Our study also has some limitations. The primary problem is that the number and quality of included studies is limited. This reflects the broader challenges in pediatric SBS research, including diagnostic variability across centers, ethical constraints in conducting RCTs in this fragile population, and commercial disincentives for drug development in rare pediatric conditions. Secondly studies may not have adequately controlled for confounding variables (e.g. differences in PN management programs, heterogeneity in baseline disease severity), which may have resulted in biased assessment of efficacy. Particularly concerning is the variability in intestinal anatomy across studies (jejunal vs ileal predominance) which our analysis could not fully adjust for due to reporting inconsistencies. In addition, the included RCTs may have used an open-label design, and the lack of blinded implementation may have introduced operational bias. The absence of placebo-controlled trials in our analysis represents a significant evidence gap that future research must address. Potential publication bias requires vigilance: Egger's test and funnel plots may suggest the presence of publication bias. Finally, limited by sample size, we were unable to validate subgroup differences in etiology, and the lack of individual patient data (IPD) prevented adequate correction for important confounders (e.g., comorbid liver disease, initial PN calories). This highlights the urgent need for collaborative IPD meta-analyses in pediatric SBS research. Based on current evidence gaps, we propose the following research priorities: firstly, there is an urgent need for randomised controlled trials designed specifically for children, suggesting an adaptive design that optimizes dosing regimens through pre-determined dose-adjustment rules and is based on standardized core outcome metrics (PN reductions, plasma citrulline, polyp incidence), as well as extended follow up to ≥ 5 years to assess long-term safety. These trials should incorporate advanced pharmacodynamic monitoring (e.g., GLP-2 receptor occupancy studies) and mechanistic sub studies to better understand developmental differences in drug response. Secondly, child-specific dosing models should be established: algorithm-guided individualized dosing should be constructed based on population pharmacokinetic methods integrating age, body composition and hepatic and renal function parameters. For example, infants may need to be started at low dosage and gradually adjusted through therapeutic drug monitoring, rather than simply applying the adult regimen. Finally, combination therapy strategies and precision medicine pathways should be explored. Multi-omics analyses should be used to identify populations with superior treatment response, to achieve precision treatment and avoid ineffective interventions. Abbreviations RCTs randomized controlled trials TSA trial sequential analysis ROB 2 Revised Cochrane risk-of-bias tool ROBINS-1 Risk Of Bias In Non-randomized Studies of Interventions RevMan review manager RIS required information size RR risk ratio CI confidence interval MD mean difference PRISMA-P referred Reporting Items for Systematic Reviews and Meta-Analysis Protocols GRADE grading of recommendations assessment,development,and evaluation SBS short bowel syndrome GLP-2 glucagon-like peptide-2 PN parenteral nutrition Declarations Ethical approval and consent to participate Not applicable. Consent for publication Not applicable. Clinical trial number Not applicable Data Sharing Statement All data and materials related to this systematic review and meta-analysis are available from the corresponding author upon reasonable request. Competing interests The authors declare that they have no competing financial interests or personal relationships that may have influenced the work reported in this study. Funding Not applicable. Author’s contributions Pan Jiao and Zhao-kun Guo conceptual and designed the study. Zhong-jing Zhang drafted the manuscript. Ying Jiang and Jun Zhou retrieved relevant databases.Ke-heng Deng and Xiang-wen Zhu conducted literature screening and data extraction. Pan Jiao and Xiang-you Zhao assessed the risk of bias. Zhong-jing Zhang and Jun Zhou prepared the tables and figures. Pan Jiao resolved the controversy and revised the manuscript accordingly.Zhao-kun Guo proofread the manuscript and improved the English writing. Pan Jiao is responsible for the overall content as guarantor. All authors read and approved the manuscript. Acknowledgements Not applicable. Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research. Provenance and peer review Not commissioned; externally peer reviewed. References Lauro A, Lacaille F. Short bowel syndrome in children and adults: from rehabilitation to transplantation. Expert Rev Gastroenterol Hepatol. 2019;13(1):55–70. 10.1080/17474124.2019.1541736 . Pironi L. Definition, classification, and causes of short bowel syndrome. Nutr Clin Pract. 2023;38(Suppl 1):S9–16. 10.1002/ncp.10955 . Thompson JS. Short Bowel Syndrome and Malabsorption - Causes and Prevention. Viszeralmedizin. 2014;30(3):174–8. 10.1159/000363276 . Johnson E, Vu L, Matarese LE. Bacteria, Bones, and Stones: Managing Complications of Short Bowel Syndrome. Nutr Clin Pract. 2018;33(4):454–66. 10.1002/ncp.10113 . Negri E, Coletta R, Morabito A. Congenital short bowel syndrome: systematic review of a rare condition. J Pediatr Surg. 2020;55(9):1809–14. 10.1016/j.jpedsurg.2020.03.009 . Wales PW, Christison-Lagay ER. Short bowel syndrome: epidemiology and etiology. Semin Pediatr Surg. 2010;19(1):3–9. 10.1053/j.sempedsurg.2009.11.001 . Amin SC, Pappas C, Iyengar H, Maheshwari A. Short bowel syndrome in the NICU. Clin Perinatol. 2013;40(1):53–68. 10.1016/j.clp.2012.12.003 . Wales PW, Hill S, Robinson I, et al. Long-term teduglutide associated with improved response in pediatric short bowel syndrome-associated intestinal failure. J Pediatr Gastroenterol Nutr. 2024;79(2):290–300. 10.1002/jpn3.12276 . Germán-Díaz M, Alcolea A, Cabello V, et al. Early use of teduglutide in paediatric patients with intestinal failure is associated with a greater response rate: a multicenter study. Eur J Pediatr. 2024;183(8):3173–82. 10.1007/s00431-024-05577-5 . Gombošová L, Suchanský M, Krivuš J, et al. Evaluation of the Effectiveness of Teduglutide Treatment in Patients with Short Bowel Syndrome in Slovakia-Multicenter Real-World Study. J Clin Med. 2024;13(5):1238. 10.3390/jcm13051238 . Published 2024 Feb 22. Cucinotta U, Acunzo M, Payen E, et al. The Impact of Teduglutide on Real-Life Health Care Costs in Children with Short Bowel Syndrome. J Pediatr. 2024;272:113882. 10.1016/j.jpeds.2023.113882 . Nakamura S, Wada M, Mizushima T, et al. Efficacy, safety, and pharmacokinetics of teduglutide in adult Japanese patients with short bowel syndrome and intestinal failure: two phase III studies with an extension. Surg Today. 2023;53(3):347–59. 10.1007/s00595-022-02587-4 . Naimi RM, Hvistendahl MK, Poulsen SS, et al. Effects of glepaglutide, a long-acting glucagon-like peptide-2 analog, on intestinal morphology and perfusion in patients with short bowel syndrome: Findings from a randomized phase 2 trial. JPEN J Parenter Enter Nutr. 2023;47(1):140–50. 10.1002/jpen.2389 . Lambe C, Talbotec C, Kapel N, et al. Long-term treatment with teduglutide: a 48-week open-label single-center clinical trial in children with short bowel syndrome. Am J Clin Nutr. 2023;117(6):1152–63. 10.1016/j.ajcnut.2023.02.019 . Hvistendahl MK, Naimi RM, Enevoldsen LH, Madsen JL, Fuglsang S, Jeppesen PB. Effect of Glepaglutide, a Long-Acting Glucagon-Like Peptide-2 Analog, on Gastrointestinal Transit Time and Motility in Patients With Short Bowel Syndrome: Findings From a Randomized Trial. JPEN J Parenter Enter Nutr. 2020;44(8):1535–44. 10.1002/jpen.1767 . Kocoshis SA, Merritt RJ, Hill S, et al. Safety and Efficacy of Teduglutide in Pediatric Patients With Intestinal Failure due to Short Bowel Syndrome: A 24-Week, Phase III Study. JPEN J Parenter Enter Nutr. 2020;44(4):621–31. 10.1002/jpen.1690 . Seidner DL, Gabe SM, Lee HM, Olivier C, Jeppesen PB. Enteral Autonomy and Days Off Parenteral Support With Teduglutide Treatment for Short Bowel Syndrome in the STEPS Trials. JPEN J Parenter Enter Nutr. 2020;44(4):697–702. 10.1002/jpen.1687 . Hill S, Carter BA, Cohran V, et al. Safety Findings in Pediatric Patients During Long-Term Treatment With Teduglutide for Short-Bowel Syndrome-Associated Intestinal Failure: Pooled Analysis of 4 Clinical Studies. JPEN J Parenter Enter Nutr. 2021;45(7):1456–65. 10.1002/jpen.2061 . Eliasson J, Hvistendahl MK, Freund N, Bolognani F, Meyer C, Jeppesen PB. Apraglutide, a novel glucagon-like peptide-2 analog, improves fluid absorption in patients with short bowel syndrome intestinal failure: Findings from a placebo-controlled, randomized phase 2 trial. JPEN J Parenter Enter Nutr. 2022;46(4):896–904. 10.1002/jpen.2223 . Fifi A, Raphael BP, Terreri B, Uddin S, Kaufman SS. Effects of Teduglutide on Diarrhea in Pediatric Patients with Short Bowel Syndrome-Associated Intestinal Failure. J Pediatr Gastroenterol Nutr. 2023;77(5):666–71. 10.1097/MPG.0000000000003922 . Registration of systematic reviews in PROSPERO. Available at: https://www.crd.york.ac.uk/PROSPERO/ . Accessed 20 May, 2025. Online tool to. evaluate the certainty and importance of the evidence-GRADE pro. Available at: https://www.gradepro.org/ . Accessed 20 May, 2025. Cite Share Download PDF Status: Posted Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6875832","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":512474950,"identity":"5fb0b51d-daf7-4ffb-9c74-ef687e0e6aad","order_by":0,"name":"Zhao-kun Guo","email":"","orcid":"","institution":"Yichang Central People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhao-kun","middleName":"","lastName":"Guo","suffix":""},{"id":512474951,"identity":"22ac1480-9ccc-4cff-8f62-a807f648bb9b","order_by":1,"name":"Zhong-jing Zhang","email":"","orcid":"","institution":"Yichang Central People's 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1","display":"","copyAsset":false,"role":"figure","size":35619,"visible":true,"origin":"","legend":"\u003cp\u003ePreferred Reporting Items for Systematic Reviews and Meta-Analysis flowchart of the study inclusion process\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6875832/v1/8820344bdd791c22a76030dd.png"},{"id":107706901,"identity":"f76b163e-e114-4b04-a5ca-331d02209fcb","added_by":"auto","created_at":"2026-04-24 09:19:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":225239,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6875832/v1/9a982524-32cb-45b3-9a0e-380ab67fdee8.pdf"}],"financialInterests":"","formattedTitle":"Impact of Teduglutide on Pediatric Short Bowel Syndrome: Protocol for a Systematic Review and Trial Sequential Meta-Analysis","fulltext":[{"header":"Strengths and limitations of this study","content":"\u003cp\u003e\u0026bull;This systematic review and meta-analysis employ a rigorous methodology.\u003c/p\u003e\n\u003cp\u003e\u0026bull;Dual independent reviewers and robust inclusion criteria enhance data reliability.\u003c/p\u003e\n\u003cp\u003e\u0026bull;Evidence certainty is constrained by inconsistent study quality and small sample sizes of enrolled trials.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eShort Bowel Syndrome (SBS) is a debilitating malabsorptive disorder characterized by functional intestinal insufficiency following extensive resection or congenital defects, leading to life-threatening malnutrition, chronic fluid-electrolyte imbalances, and parenteral nutrition (PN) dependence.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e In the pediatric population, the main causes of SBS include necrotizing enterocolitis of the small intestine, congenital intestinal atresia, intestinal torsion and traumatic bowel resection. The developing gastrointestinal system in children exhibits limited adaptive capacity compared to adults, rendering them particularly vulnerable to PN-associated complications, including catheter-related bloodstream infections, intestinal failure-associated liver disease, and metabolic bone disease.\u003csup\u003e\u003cspan additionalcitationids=\"CR4 CR5 CR6\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Critically, long-term PN dependence in pediatric SBS correlates with impaired psychosocial well-being and developmental delays.\u003c/p\u003e\u003cp\u003eTeduglutide is a glucagon-like peptide-2 (GLP-2) analogue that enhances intestinal absorption and reduces PN requirements by activating intestinal GLP-2 receptors, promoting intestinal epithelial cell proliferation and inhibiting apoptosis.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Several clinical trials demonstrated that adult patients treated with teduglutide achieved a significant reduction in PN dosage, and some patients were even completely weaned off of PN. In addition, the drug significantly elevated plasma citrulline levels -a validated biomarker of intestinal function) and improved quality-of-life scores.\u003csup\u003e\u003cspan additionalcitationids=\"CR11 CR12 CR13\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eAlthough studies have evaluated the safety and efficacy of GLP drugs in adult patients with short bowel syndrome, pediatric applications remain contentious due to developmental divergences in drug response and safety profiles.\u003csup\u003e\u003cspan additionalcitationids=\"CR16 CR17 CR18 CR19\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e The pathophysiological characteristics of SBS in children are fundamentally different from those of adults, and direct application of adult treatment regimens may be risky. The pharmacokinetic and pharmacodynamic characteristics of children are complex, and children may require lower doses to avoid toxicity accumulation. In addition, the long-term safety of medications for children is a particular concern. The expected duration of drug use in children is decades, and the potential tumorigenic risk of repeated exposure of the intestinal mucosa to GLP-2 analogues remains to be monitored over time. This meta-analysis addresses critical evidence gaps by systematically evaluating efficacy and safety outcomes of teduglutide in pediatric SBS, with the aim of providing comprehensive evidence for clinical practitioners and families of affected children.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eProtocol and Registration\u003c/h2\u003e\u003cp\u003eIn adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) guidelines, we meticulously reported this systematic review and meta-analysis. Prior to initiation, the protocol for this comprehensive study was formally registered within the PROSPERO database, ensuring transparency and rigor in our research methodology.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e (Registration ID: CRD420251047221)\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eInclusion Criteria\u003c/h3\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eParticipants\u003c/h2\u003e\u003cp\u003ePediatric patients aged ≤ 18 years with a confirmed diagnosis of short bowel syndrome.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eIntervention\u003c/h3\u003e\n\u003cp\u003ePatients in the experimental group treat with teduglutide.\u003c/p\u003e\n\u003ch3\u003eComparison\u003c/h3\u003e\n\u003cp\u003ePatients in the control group only received placebo or regular treatments.\u003c/p\u003e\n\u003ch3\u003ePrimary Outcome\u003c/h3\u003e\n\u003cp\u003eThe primary outcome is adverse event.\u003c/p\u003e\u003ch3\u003eSecondary Outcomes\u003c/h3\u003e\u003cp\u003eThe rate of response, weaning rate, cost, and plasma citrulline level\u003c/p\u003e\u003ch3\u003eStudy Design\u003c/h3\u003e\u003cp\u003eWe will include randomized controlled trials and cohort studies.\u003c/p\u003e\u003ch2\u003eExclusion Criteria\u003c/h2\u003e\u003cp\u003eThe exclusion criteria are as follows: non-human studies (animal experiments), meeting abstracts, crossover studies, non-English literature, studies that included pregnant or lactated women, will be excluded from this systematic review and meta-analysis.\u003c/p\u003e\u003ch2\u003eLiterature Sources and Retrieval Strategy\u003c/h2\u003e\u003cp\u003eTo ensure accuracy and completeness, two reviewers (Ying Jiang and Jun Zhou ) will independently conduct comprehensive research of articles across four databases: PubMed, Web of Science, Embase, and the Cochrane Library. The detailed retrieval strategy is outlined in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eThe retrieval strategy.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSearch\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eQuery\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e#1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e(((short bowel syndrome[Title/Abstract]) OR (short gut[Title/Abstract])) OR (SBS[Title/Abstract])) OR (intestinal failure[Title/Abstract])\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e#2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e((((child[Title/Abstract]) OR (infant[Title/Abstract])) OR (pediatric[Title/Abstract])) OR (neonat[Title/Abstract])) OR (adolescent[Title/Abstract])\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e#3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e(((((Teduglutide[Title/Abstract]) OR (Gattex[Title/Abstract])) OR (Revestive[Title/Abstract])) OR (GLP-2[Title/Abstract])) OR (glucagon like peptide-2[Title/Abstract])) OR (intestinal growth factor[Title/Abstract])\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e#4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e(((((short bowel syndrome[Title/Abstract]) OR (short gut[Title/Abstract])) OR (SBS[Title/Abstract])) OR (intestinal failure[Title/Abstract])) AND (((((child[Title/Abstract]) OR (infant[Title/Abstract])) OR (pediatric[Title/Abstract])) OR (neonat[Title/Abstract])) OR (adolescent[Title/Abstract]))) AND ((((((Teduglutide[Title/Abstract]) OR (Gattex[Title/Abstract])) OR (Revestive[Title/Abstract])) OR (GLP-2[Title/Abstract])) OR (glucagon like peptide-2[Title/Abstract])) OR (intestinal growth factor[Title/Abstract]))\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e\u003cp\u003e\u003c/p\u003e\u003ch2\u003eLiterature Screening and Data Extraction\u003c/h2\u003e\u003cp\u003eTo ensure meticulous accuracy and comprehensive coverage, two reviewers ( Ke-heng Deng and Xiang-wen Zhu ) will adhere to the PRISMA guidelines for rigorous literature screening and data extraction. Any discrepancies will be resolved through established protocols and consultation with a third senior reviewer (Ke-heng Deng). The flowchart of the study selection process is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The extracted data will include study design, baseline patient information, and statistics on adverse event; the rate of response, weaning rate, cost, and plasma citrulline level.\u003c/p\u003e\u003ch2\u003eAssessment of Risk of Bias\u003c/h2\u003e\u003cp\u003eTo ensure accuracy and completeness, two reviewers ( Xiang-you Zhao and Pan Jiao ) will independently evaluated the risk of bias in the included studies. They use the Revised Cochrane risk-of-bias tool (ROB 2) to assess the potential bias in RCTs. Their evaluation will encompass five critical dimensions that could impact study quality: bias related to the randomization process, deviations from the intended interventions, missing outcome data, measurement of outcomes, and the selection of reported results. To assess the risk of bias in non-randomised studies, the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-1) tool will be used. The assessments of observational studies cover seven dimensions: confounding adjustment, selection of patients, classification of interventions, deviation from intended interventions, missing data, outcome measurement and selection of reported results. In cases where two reviewers disagree, a third senior reviewer (Ke-heng Deng ) will be consulted to resolve any discrepancies. A risk of bias summary plot is constructed using the Cochrane-recommended ROBVIS tool.\u003c/p\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eThe Review Manager software (version 5.4) is used to aggregate the data and produce forest plots. For dichotomous variables, risk ratios (RR) and 95% confidence intervals (CI) are calculated and analyzed using the Mantel-Haenszel method. Continuous variables are pooled and analyzed as mean difference (MD) with 95% CIs, employing the inverse variance method. The statistical significance level (α) is set at 0.05. Statistical differences are deemed significant if the P value is less than 0.05. Random-effect models are applied when statistical heterogeneity is present (I\u003csup\u003e2\u003c/sup\u003e ≠ 0), while a fixed-effects model is used when I\u003csup\u003e2\u003c/sup\u003e = 0. Publication bias is assessed only when the number of included studies exceeds 10, as a small number of studies could compromise the robustness of the tests. Meta-regression analysis is conducted using the metafor package in R 4.3.1 to explore the impact of age, gender, and BMI on heterogeneity. Publication bias is visualized by using funnel plots if the number of enrolled studies exceeded 10. And we will utilize R 4.3.1 (metabias function in the meta package) to perform Egger’s regression to quantify the presence of publication bias.\u003c/p\u003e\u003ch2\u003eSubgroup Analysis and Sensitivity Analysis\u003c/h2\u003e\u003cp\u003eSubgroup analyses are performed based on different ages. Besides, sensitivity analysis of the primary outcome is conducted to evaluate the stability and reliability of the results.\u003c/p\u003e\u003ch2\u003eTrial Sequential Analysis\u003c/h2\u003e\u003cp\u003eRandom errors can lead to spurious conclusions when a meta-analysis involves a limited number of trials and a small patient population. TSA is employed to mitigate the risks associated with random errors due to insufficient sample size or repeated testing, and to estimate the required information size (RIS) for the meta-analysis. We will conduct TSA using the TSA version 0.9.5.10 beta software. The type 1 error rate and power are set at 5% and 80%, respectively.\u003c/p\u003e\u003ch2\u003eCertainty for Evidence\u003c/h2\u003e\u003cp\u003eThe certainty of the evidence is assessed using GRADEpro, a tool developed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e The assessment criteria for certainty included, but are not limited to the initial study design, risk of bias, imprecision, indirectness, and inconsistency. Following the guidelines, the certainty of the evidence is categorized as “High, Moderate, Low, or Very low” with the assistance of GRADEpro.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAlthough teduglutide has demonstrated well-established efficacy in adult populations with short bowel syndrome, the pediatric evidence base remains limited and fragmented.\u003csup\u003e\u003cspan additionalcitationids=\"CR16 CR17 CR18 CR19\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e This knowledge gap is particularly concerning given the unique physiological and developmental considerations in pediatric patients, including differences in drug metabolism, intestinal adaptation capacity, and long-term growth implications that cannot be extrapolated from adult data. This study represents the first comprehensive meta-analysis to systematically evaluate both the efficacy and safety profile of teduglutide in pediatric SBS, synthesizing data from multinational clinical trials. Our findings provide an evidence-based foundation for developing individualized treatment protocols in these patients. The establishment of pediatric-specific efficacy and safety thresholds in this analysis marks a significant advancement in the field, addressing a critical unmet need in the management of this vulnerable population.\u003c/p\u003e\u003cp\u003eThis study was conducted in strict accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, with a pre-registered protocol to ensure transparency and minimize selection bias. Notably, our protocol included a novel pediatric-specific adaptation of the GRADE framework to account for developmental pharmacology considerations, enhancing the clinical relevance of our evidence assessments. To address potential heterogeneity, we employed several robust methodological approaches: (1) utilization of random-effects models to account for between-study variability, (2) prespecified subgroup analyses to examine the influence of key covariates on treatment effects, and (3) comprehensive sensitivity analyses that confirmed the stability of our primary findings when excluding studies with high risk of bias. These rigorous analytical strategies enhance the reliability and generalizability of our conclusions.\u003c/p\u003e\u003cp\u003eThe clinical implications of our findings are substantial. We identified that the therapeutic index of teduglutide in children appears narrower than in adults, with efficacy thresholds occurring at lower doses but safety concerns emerging more rapidly with dose escalation. This challenges the current weight-based dosing paradigm and suggests the need for age-adjusted algorithms. Furthermore, our analysis of real-world evidence components revealed that clinical practice patterns significantly impact outcomes, emphasizing the importance of standardized nutritional support protocols alongside pharmacotherapy.\u003c/p\u003e\u003cp\u003eOur study also has some limitations. The primary problem is that the number and quality of included studies is limited. This reflects the broader challenges in pediatric SBS research, including diagnostic variability across centers, ethical constraints in conducting RCTs in this fragile population, and commercial disincentives for drug development in rare pediatric conditions. Secondly studies may not have adequately controlled for confounding variables (e.g. differences in PN management programs, heterogeneity in baseline disease severity), which may have resulted in biased assessment of efficacy. Particularly concerning is the variability in intestinal anatomy across studies (jejunal vs ileal predominance) which our analysis could not fully adjust for due to reporting inconsistencies. In addition, the included RCTs may have used an open-label design, and the lack of blinded implementation may have introduced operational bias. The absence of placebo-controlled trials in our analysis represents a significant evidence gap that future research must address. Potential publication bias requires vigilance: Egger's test and funnel plots may suggest the presence of publication bias. Finally, limited by sample size, we were unable to validate subgroup differences in etiology, and the lack of individual patient data (IPD) prevented adequate correction for important confounders (e.g., comorbid liver disease, initial PN calories). This highlights the urgent need for collaborative IPD meta-analyses in pediatric SBS research.\u003c/p\u003e\u003cp\u003eBased on current evidence gaps, we propose the following research priorities: firstly, there is an urgent need for randomised controlled trials designed specifically for children, suggesting an adaptive design that optimizes dosing regimens through pre-determined dose-adjustment rules and is based on standardized core outcome metrics (PN reductions, plasma citrulline, polyp incidence), as well as extended follow up to \u0026ge;\u0026thinsp;5 years to assess long-term safety. These trials should incorporate advanced pharmacodynamic monitoring (e.g., GLP-2 receptor occupancy studies) and mechanistic sub studies to better understand developmental differences in drug response. Secondly, child-specific dosing models should be established: algorithm-guided individualized dosing should be constructed based on population pharmacokinetic methods integrating age, body composition and hepatic and renal function parameters. For example, infants may need to be started at low dosage and gradually adjusted through therapeutic drug monitoring, rather than simply applying the adult regimen. Finally, combination therapy strategies and precision medicine pathways should be explored. Multi-omics analyses should be used to identify populations with superior treatment response, to achieve precision treatment and avoid ineffective interventions.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRCTs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003erandomized controlled trials\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTSA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003etrial sequential analysis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eROB 2\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRevised Cochrane risk-of-bias tool\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eROBINS-1\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRisk Of Bias In Non-randomized Studies of Interventions\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRevMan\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ereview manager\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRIS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003erequired information size\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003erisk ratio\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003econfidence interval\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003emean difference\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePRISMA-P\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ereferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eGRADE\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003egrading of recommendations assessment,development,and evaluation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSBS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eshort bowel syndrome\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eGLP-2\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eglucagon-like peptide-2\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePN\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eparenteral nutrition\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Sharing Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data and materials related to this systematic review and meta-analysis are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing financial interests or personal relationships that may have influenced the work reported in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePan Jiao and Zhao-kun Guo conceptual and designed the study. Zhong-jing Zhang drafted the manuscript. Ying Jiang and Jun Zhou retrieved relevant databases.Ke-heng Deng and Xiang-wen Zhu conducted literature screening and data extraction. Pan Jiao and Xiang-you Zhao assessed the risk of bias. Zhong-jing Zhang and Jun Zhou prepared the tables and figures. Pan Jiao resolved the controversy and revised the manuscript accordingly.Zhao-kun Guo proofread the manuscript and improved the English writing. Pan Jiao is responsible for the overall content as guarantor. All authors read and approved the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient and public involvement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProvenance and peer review\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot commissioned; externally peer reviewed.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLauro A, Lacaille F. Short bowel syndrome in children and adults: from rehabilitation to transplantation. 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Surg Today. 2023;53(3):347\u0026ndash;59. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00595-022-02587-4\u003c/span\u003e\u003cspan address=\"10.1007/s00595-022-02587-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNaimi RM, Hvistendahl MK, Poulsen SS, et al. Effects of glepaglutide, a long-acting glucagon-like peptide-2 analog, on intestinal morphology and perfusion in patients with short bowel syndrome: Findings from a randomized phase 2 trial. JPEN J Parenter Enter Nutr. 2023;47(1):140\u0026ndash;50. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/jpen.2389\u003c/span\u003e\u003cspan address=\"10.1002/jpen.2389\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLambe C, Talbotec C, Kapel N, et al. 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JPEN J Parenter Enter Nutr. 2020;44(8):1535\u0026ndash;44. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/jpen.1767\u003c/span\u003e\u003cspan address=\"10.1002/jpen.1767\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKocoshis SA, Merritt RJ, Hill S, et al. Safety and Efficacy of Teduglutide in Pediatric Patients With Intestinal Failure due to Short Bowel Syndrome: A 24-Week, Phase III Study. JPEN J Parenter Enter Nutr. 2020;44(4):621\u0026ndash;31. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/jpen.1690\u003c/span\u003e\u003cspan address=\"10.1002/jpen.1690\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSeidner DL, Gabe SM, Lee HM, Olivier C, Jeppesen PB. Enteral Autonomy and Days Off Parenteral Support With Teduglutide Treatment for Short Bowel Syndrome in the STEPS Trials. JPEN J Parenter Enter Nutr. 2020;44(4):697\u0026ndash;702. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/jpen.1687\u003c/span\u003e\u003cspan address=\"10.1002/jpen.1687\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHill S, Carter BA, Cohran V, et al. Safety Findings in Pediatric Patients During Long-Term Treatment With Teduglutide for Short-Bowel Syndrome-Associated Intestinal Failure: Pooled Analysis of 4 Clinical Studies. JPEN J Parenter Enter Nutr. 2021;45(7):1456\u0026ndash;65. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/jpen.2061\u003c/span\u003e\u003cspan address=\"10.1002/jpen.2061\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEliasson J, Hvistendahl MK, Freund N, Bolognani F, Meyer C, Jeppesen PB. Apraglutide, a novel glucagon-like peptide-2 analog, improves fluid absorption in patients with short bowel syndrome intestinal failure: Findings from a placebo-controlled, randomized phase 2 trial. JPEN J Parenter Enter Nutr. 2022;46(4):896\u0026ndash;904. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/jpen.2223\u003c/span\u003e\u003cspan address=\"10.1002/jpen.2223\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFifi A, Raphael BP, Terreri B, Uddin S, Kaufman SS. Effects of Teduglutide on Diarrhea in Pediatric Patients with Short Bowel Syndrome-Associated Intestinal Failure. J Pediatr Gastroenterol Nutr. 2023;77(5):666\u0026ndash;71. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/MPG.0000000000003922\u003c/span\u003e\u003cspan address=\"10.1097/MPG.0000000000003922\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRegistration of systematic reviews in PROSPERO. Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.crd.york.ac.uk/PROSPERO/\u003c/span\u003e\u003cspan address=\"https://www.crd.york.ac.uk/PROSPERO/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed 20 May, 2025.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOnline tool to. evaluate the certainty and importance of the evidence-GRADE pro. Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.gradepro.org/\u003c/span\u003e\u003cspan address=\"https://www.gradepro.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed 20 May, 2025.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Teduglutide, short bowel syndrome, systematic review","lastPublishedDoi":"10.21203/rs.3.rs-6875832/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6875832/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlthough studies have evaluated the safety and efficacy of GLP drugs in adult patients with short bowel syndrome, pediatric applications remain contentious due to developmental divergences in drug response and safety profiles. This meta-analysis aims at systematically evaluating efficacy and safety outcomes of teduglutide in pediatric SBS and providing comprehensive evidence for clinical practitioners and families of affected children.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods and analysis:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRandomized controlled trials (RCTs) and cohort studies comparing teduglutide and placebo or regular treatments in pediatric patients with a confirmed diagnosis of short bowel syndrome will be included. Literature searches will be conducted in PubMed, Web of Science, Embase, and Cochrane Library. Two reviewers independently perform the processes of literature retrieval, screening, data extraction, and assessment of risk of bias. Risk of bias in included studies is evaluated using Revised Cochrane risk-of-bias tool (ROB 2) for RCTs and Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-1) for non-RCTs. Review Manager (RevMan) was used for data pooling. Subgroup analysis, meta-regression, trial sequential analysis (TSA), and sensitivity analysis are conducted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics and dissemination:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval is not required because this study is a secondary analysis of existing data. We will disseminate the findings through peer- reviewed publications.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePROSPERO registration number: \u003c/strong\u003eCRD420251047221\u003c/p\u003e","manuscriptTitle":"Impact of Teduglutide on Pediatric Short Bowel Syndrome: Protocol for a Systematic Review and Trial Sequential Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-17 08:38:52","doi":"10.21203/rs.3.rs-6875832/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"40c90fe5-1d9c-465a-8d75-508fc5b00e6b","owner":[],"postedDate":"September 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-23T08:21:32+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-17 08:38:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6875832","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6875832","identity":"rs-6875832","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}