Growth hormone therapy in high-risk pediatric populations: Integrated growth, metabolic, and safety outcomes in SGA, preterm, and Russell–silver syndrome

 Corresponding author: Ahmed Khalil Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution Liscense 4.0. Growth hormone therapy in high-risk pediatric populations: Integrated growth, metabolic, and safety outcomes in SGA, preterm, and Russell–silver syndrome Ashraf T. Soliman 1 , Fawzia Alyafei 1, Nada M. Alaaraj 1, Shayma M. Ahmed 1, Noora S. AlHumaidi 1, Noor Hamed 1, Ahmed S. Elawwa 1, 2 and Ahmed Khalil 3, * 1 Department of Pediatrics, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar. 2 Pediatric Endocrinology and Diabetology Unit, Faculty of Medicine, Alexandria University, Egypt. 3 Department of Pharmacy, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar. World Journal of Advanced Research and Reviews, 2025, 28(02), 1531–1548 Publication history: Received on 03 October 2025; revised on 15 November 2025; accepted on 18 November 2025 Article DOI: https://doi.org/10.30574/wjarr.2025.28.2.3819 Abstract Background: Growth hormone (GH) therapy is widely used to enhance growth outcomes in children with growth disorders, including those born small for gestational age (SGA), preterm infants, and individuals with Russell-Silver Syndrome (RSS). While GH therapy demonstrates consistent efficacy in improving height and metabolic parameters, variability in response and concerns about long-term safety require careful evaluation. Objective: This review aims to assess the effects of GH therapy on growth outcomes, metabolic health, and safety profiles in children born SGA, preterm, and those diagnosed with RSS, and to provide updated clinical recommendations for optimizing treatment strategies. Methods: A systematic review of 95 clinical studies published between 2000 and 2025 was conducted, analyzing outcomes in over 6,500 pediatric patients receiving GH therapy. Data were synthesized from randomized controlled trials, cohort studies, and observational research, focusing on changes in height standard deviation scores (SDS), growth velocity, IGF-1 levels, and metabolic safety outcomes. Results: In SGA children, GH therapy resulted in a mean height SDS improvement of +2.2 and a 36% increase in growth velocity, with the most favorable outcomes when treatment was initiated before 4 years of age. Mild insulin resistance and glucose intolerance were noted in a subset of patients. Preterm infants demonstrated an average height SDS gain of +1.9 and a 32% increase in growth velocity, particularly when GH therapy was combined with optimal nutritional strategies. Transient insulin resistance was occasionally observed but without significant long-term consequences. In RSS patients, GH therapy improved height SDS by +1.8 and growth velocity by 27%, although responses varied depending on the underlying genetic etiology. Metabolic benefits included improvements in IGF-1 levels and body composition, with minimal adverse effects. Weekly GH regimens were found to be comparable to daily injections in efficacy and safety across all populations. Conclusion: GH therapy significantly improves growth outcomes and metabolic profiles in children born SGA, preterm, and with RSS. Early initiation and individualized treatment approaches optimize height gains while minimizing metabolic risks. Although generally safe, GH therapy requires regular monitoring of glucose metabolism and metabolic parameters, particularly in SGA and preterm populations. Personalized protocols based on genetic and nutritional factors, along with long-term follow-up, are essential to maximizing the therapeutic benefits while ensuring safety. Future research should further explore genetic predictors of GH response and the long-term metabolic and cardiovascular outcomes of GH-treated children. World Journal of Advanced Research and Reviews, 2025, 28(02), 1531–1548 1532 Keywords: Growth Hormone Therapy; Small for Gestational Age (SGA); Preterm Infants; Russell-Silver Syndrome (RSS); Growth Velocity and Metabolic Outcomes 1. Introduction 1.1. Small-for-Gestational-Age (SGA) Infants Children born small for gestational age (SGA) are defined as having a birth weight or length below the 10th percentile for their gestational age. While some SGA infants experience spontaneous catch-up growth, approximately 10–15% fail to achieve normal height, leading to persistent short stature [1]. The underlying causes of growth failure in SGA children are multifactorial, involving placental insufficiency, fetal malnutrition, and genetic factors [2]. These children are at an increased risk of metabolic syndrome, insulin resistance, cardiovascular disease, and osteoporosis in adulthood due to fetal programming effects that persist postnatally [3,4]. GH therapy has been shown to effectively improve growth velocity and final height in SGA children, particularly when initiated early (before 4 years of age). Studies indicate that GH therapy can increase height SDS by 1.5–2.5 in childhood and lead to improved adult height outcomes [5]. However, concerns persist regarding the long-term metabolic effects of GH therapy, including insulin resistance, glucose intolerance, and potential cardiovascular risks [6]. 1.2. Preterm Infants and Growth Challenges Preterm birth, defined as delivery before 37 weeks of gestation, affects approximately 10% of live births worldwide [7]. Extremely preterm infants (<32 weeks gestation) are particularly vulnerable to postnatal growth failure, often due to suboptimal nutrition, medical complications, and hormonal imbalances [8]. Growth restriction in preterm infants is associated with reduced lean body mass, decreased bone mineral density, and increased cardiometabolic risk later in life [9]. GH therapy has been explored as a potential intervention to enhance growth outcomes and metabolic health in preterm infants who fail to show adequate catch-up growth. Studies suggest that GH therapy can improve growth velocity by 30–40%, increase IGF-1 levels, and enhance nutrient utilization and energy metabolism [10,11]. However, preterm infants have a higher predisposition to metabolic disturbances, and some studies have reported transient insulin resistance and altered glucose metabolism as potential side effects of GH therapy in this population [12]. 1.3. Russell-Silver Syndrome (RSS) and Growth Failure Russell-Silver Syndrome (RSS) is a rare genetic disorder characterized by severe intrauterine growth retardation, postnatal growth failure, body asymmetry, and feeding difficulties [13]. The condition is most associated with epigenetic abnormalities affecting the 11p15 imprinting region, leading to dysregulation of growth-related genes [14]. RSS patients often exhibit distinctive facial features, limb asymmetry, and a high incidence of early feeding difficulties, which further exacerbate their growth deficits [15]. GH therapy has become the standard of care for children with RSS, significantly improving height SDS (+1.5 to +3.0) and growth velocity (5–10 cm/year) when started at an early age [16]. However, the response to GH therapy in RSS is often variable, depending on the underlying genetic mutation, age at initiation, and nutritional status [17]. Additionally, RSS patients may be more susceptible to hypoglycemia and insulin resistance, requiring careful GH dosing and metabolic monitoring [18]. 1.4. Differences in GH Therapy Response Among These Populations The response to GH therapy varies significantly among SGA, preterm, and RSS children due to differences in underlying pathology, genetic determinants, and metabolic profiles. SGA children generally show robust height improvements, particularly when treatment is initiated early. In contrast, preterm infants may require additional nutritional interventions to optimize growth responses. RSS patients tend to have a slower initial response but can achieve comparable adult height outcomes with long-term therapy [19]. 1.5. Long-Term Benefits vs. Risks of GH Therapy While GH therapy is effective in promoting linear growth, increasing lean body mass, and enhancing metabolic health, concerns about long-term metabolic risks persist. Studies have suggested that SGA and preterm infants treated with GH therapy may exhibit alterations in insulin sensitivity, raising concerns about a potential increased risk of type 2 diabetes World Journal of Advanced Research and Reviews, 2025, 28(02), 1531–1548 1533 in adulthood [20]. However, these risks appear to be dose-dependent and may be mitigated through careful monitoring and individualized treatment protocols [21]. In RSS patients, GH therapy is generally well-tolerated, though some experience a delayed pubertal growth spurt or mild metabolic alterations [22]. 1.6. The Need for a Comprehensive Review Despite the widespread use of GH therapy in these populations, significant gaps remain in our understanding of its longterm efficacy and safety. Given the variability in treatment response and potential metabolic risks, an updated comprehensive review is essential to guide clinical decision-making. This review synthesizes current evidence on GH therapy in SGA, preterm, and RSS children, emphasizing growth outcomes, metabolic changes, and safety considerations. By integrating findings from clinical trials and observational studies, we aim to provide updated recommendations on optimal treatment strategies, patient selection criteria, and long-term safety monitoring. Objectives • To evaluate the effectiveness of growth hormone (GH) therapy in improving growth outcomes (height SDS, growth velocity) in children born small for gestational age (SGA), preterm, and those with Russell-Silver Syndrome (RSS). • To assess the metabolic effects of GH therapy, including changes in IGF-1 levels, insulin sensitivity, and body composition. • To determine the long-term safety profile of GH therapy, with a focus on potential adverse effects such as insulin resistance, glucose metabolism alterations, and cardiovascular risks. • To analyze the variability in response to GH therapy across these different populations and explore the genetic, nutritional, and environmental factors influencing treatment efficacy. • To provide updated clinical recommendations for optimizing GH therapy use in SGA, preterm, and RSS patients, including patient selection criteria and long-term monitoring strategies. 2. Methods 2.1. Study Selection A systematic review of clinical studies published between 2000–2025 was conducted using PubMed, Scopus, and clinical trial databases. The review included randomized controlled trials, cohort studies, and case reports evaluating growth hormone (GH) therapy in children born small for gestational age (SGA), preterm, or with Russell-Silver Syndrome (RSS). Studies were selected based on their relevance to growth outcomes, metabolic markers, and safety considerations. 2.2. Inclusion Criteria • Studies were included if they met the following criteria • Population: Children diagnosed with SGA, preterm birth (<37 weeks gestation), or genetically confirmed RSS. • Intervention: GH therapy, including daily or long-acting GH regimens. • Outcome Measures: Reported growth velocity, height SDS changes, metabolic markers (IGF-1 levels, insulin sensitivity), and safety outcomes. • Follow-up Duration: Studies with at least six months of GH therapy follow-up. • Study Design: Randomized controlled trials (RCTs), cohort studies, and observational studies. 2.3. Exclusion Criteria 2.3.1. Studies were excluded if they • Lacked growth or safety data on GH therapy. • Involved patients with syndromes affecting growth (e.g., Turner syndrome, Prader-Willi syndrome). • Were non-English publications without available translations. • Reported duplicate findings or lacking a clear methodology. 2.4. Statistical Methods 2.4.1. The statistical approaches used for data synthesis included • Descriptive statistics for baseline characteristics, height SDS changes, and IGF-1 levels. World Journal of Advanced Research and Reviews, 2025, 28(02), 1531–1548 1534 • Meta-analysis techniques (where applicable) to estimate pooled effects of GH therapy on growth and metabolic parameters. • Cohen’s d effect size calculation for assessing the impact magnitude of GH therapy on height SDS and IGF-1 levels. • Regression models to analyze the correlation between GH therapy duration, response variability, and metabolic risks. • Heterogeneity analysis (I² statistic) to assess differences in study populations and treatment effects. 2.4.2. Method for Calculating the Impact of GH Therapy • The impact of GH therapy on growth and metabolic parameters was calculated using 2.4.3. Height Standard Deviation Score (SDS) Changes • Height SDS = (Final Height SDS – Baseline Height SDS) • Significant improvement defined as Height SDS ≥ 1.5 2.4.4. Growth Velocity Improvement • Growth velocity (cm/year) = (Final height – Initial height) ÷ Duration of therapy • Improvement categorized as mild (+3–5 cm/year), moderate (+5–8 cm/year), or significant (>8 cm/year). 2.4.5. IGF-1 Level Changes IGF-1 SDS improvement of ≥1.0 SDS considered clinically meaningful. 2.4.6. Metabolic Safety Indicators • Insulin sensitivity assessed using HOMA-IR index changes. • Glucose tolerance monitored via oral glucose tolerance test (OGTT). • Bone mineral density (BMD) changes analyzed via dual-energy X-ray absorptiometry (DEXA). 2.4.7. Ethical Considerations • Patient Data Protection: All studies reviewed complied with data privacy regulations and ethical approval from respective institutions. • Informed Consent: Studies involving human participants followed ethical guidelines ensuring parental/legal guardian consent. • Conflict of Interest: Only studies with transparent disclosure of funding sources and conflict of interest statements were included. • Pediatric Safety Monitoring: Special attention was given to studies with long-term follow-up protocols to monitor adverse events related to GH therapy. World Journal of Advanced Research and Reviews, 2025, 28(02), 1531–1548 1535 Figure 1 Prisma flowchart The PRISMA flowchart outlines the systematic selection process, highlighting the exclusion of duplicate, irrelevant, and non-English studies, and culminating in 52 high-quality studies included for qualitative synthesis. World Journal of Advanced Research and Reviews, 2025, 28(02), 1531–1548 1536 3. Results 3.1. Growth Hormone Therapy in Small-for-Gestational-Age (SGA) Children Table 1 The Calculated Impacts of GH Therapy on Different Aspects in SGA Children Aspect Impact of GH Therapy Calculated Outcome/Key Results Risks References Height and Growth Velocity Significant increase in height SDS and growth velocity Height SDS improved by ~+2.5 (early initiation); growth velocity increased by ~+10 cm/year None noted specifically for growth outcomes [1],[2] Body Composition Improved lean mass and reduced fat mass Significant improvements in lean mass; fat mass reduced by ~10–15% Centripetal fat redistribution observed in some studies [3],[4] Metabolic Health Mildly increased insulin resistance in some cases; generally well-tolerated Insulin resistance observed in ~5–10% of cases Risk of type 2 diabetes in children with genetic predisposition [5],[6] Muscle Function Improved jump performance and fitness index Jump performance increased by ~15% after 1 year of therapy None noted specifically for muscle outcomes [7] Renal Function No direct adverse effects of GH therapy on kidney function Reductions in eGFR linked to low birth weight and prematurity, not GH use Monitoring recommended for children with preexisting kidney conditions [8] Safety Profile Generally favorable with rare adverse effects ~95% of cases showed positive outcomes with no significant side effects Risks include insulin resistance (~5%), centripetal fat redistribution, and local side effects [5],[6] Weekly vs. Daily GH Therapy Weekly GH therapy (somapacitan) matched daily GH therapy in efficacy and safety Weekly GH achieved similar height velocity improvement (~+10 cm/year) as daily GH therapy No additional risks observed for weekly GH therapy compared to daily [31] Table 1a highlights the significant benefits of growth hormone (GH) therapy in small-for-gestational-age (SGA) children, particularly in improving height, body composition, metabolic health, and muscle function. Height and growth velocity saw notable improvements, with height SDS increasing by ~+2.5 and growth velocity rising by ~+10 cm/year, especially with early GH initiation (Juul et al., 2022; Coutant et al., 2023). Body composition also improved, with lean mass increasing and fat mass decreasing by ~10–15%, though centripetal fat redistribution was observed in some cases (Carrascosa et al., 2008; De Schepper et al., 2008). Metabolic health impacts were mild, with insulin resistance appearing in ~5–10% of cases, and a potential risk of Type 2 diabetes in genetically predisposed children (Nomura et al., 2023; Savanelli et al., 2024). Muscle function benefited, as jump performance improved by ~15% after one year of therapy, without notable risks (Schweizer et al., 2023). Renal function remained stable, with reductions in eGFR linked to birth factors rather than GH therapy, though monitoring was recommended for preexisting kidney conditions (Koizumi et al., 2023). The overall safety profile was favorable, with 95% of cases showing positive outcomes, while rare side effects included insulin resistance (~5%) and centripetal fat redistribution (Savanelli et al., 2024; Nomura et al., 2023). Finally, weekly GH therapy (somapacitan) was found to be as effective and safe as daily GH therapy, achieving similar height velocity improvements (~+10 cm/year) without additional risks (Juul et al., 2024. World Journal of Advanced Research and Reviews, 2025, 28(02), 1531–1548 1537 Figure 2 Impacts of GH therapy on different aspects in SGA children Figure 2 illustrates the real impacts of growth hormone (GH) therapy in SGA children, highlighting key areas of improvement and associated risks. The most significant benefit is in height SDS and growth velocity, with an increase of ~+2.5 SDS and ~+10 cm/year, followed by enhanced muscle function (+15%) and improved body composition (increased lean mass and reduced fat). The safety profile remains highly favorable (~95% of cases), while mild insulin resistance (~5–10%) is a noted concern. The comparison of weekly vs. daily GH therapy shows similar efficacy, reinforcing GH therapy as a safe and effective intervention for growth enhancement in SGA children. 3.2. Summary of SGA Outcomes • Significant improvement in height SDS (+10 cm/year) especially with early GH initiation (Juul et al. [1], Coutant et al. [2]). • Lean mass increased and fat mass decreased (~10–15%), but centripetal fat redistribution occasionally noted (Carrascosa et al. [3], De Schepper et al. [4]). • Mild insulin resistance (~5–10%) seen, requiring monitoring for type 2 diabetes in susceptible children (Nomura et al. [5], Savan Elli et al. [6]). • Muscle strength improved (~15% increase in jump performance) (Schweizer et al. [7]). • Renal function remained stable, with no direct adverse effects from GH therapy (Koizumi et al. [8]). • Weekly GH therapy was found as effective and safe as daily GH (Juul et al. [31]). World Journal of Advanced Research and Reviews, 2025, 28(02), 1531–1548 1538 3.3. Growth Hormone Therapy in Preterm Infants Table 2a GH Therapy in Preterm Infants Author(s), Journal, Year Patients and Characteristics and GH Dose/Duration Main Findings (Response to GH Therapy) Positive or Negative Effect Boguszewski and Cardoso-DeMartini [9] Narrative review on short children born preterm GH therapy improves growth in pretermborn children, particularly during early years Positive Boguszewski et al. [10] 3,215 prepubertal children, varying gestational age and birth weight GH therapy significantly improved growth velocity and height SDS, particularly in preterm AGA and SGA groups Positive Garcia et al. [11] 25 preterm SGA children aged 2–4 years; GH dose: 0.066 mg/kg/day Height SDS improved by 1.3 and 2.1 in the first and second years; no adverse metabolic effects noted Positive Juul et al. [1] 3,318 children born SGA Early GH initiation improved growth outcomes significantly; no unexpected adverse effects Positive Mehta and Petrova [12] 70 preterm infants; urinary energy metabolism hormones measured IGF-1 and maternal milk intake as key contributors to improved growth velocity Positive Nitkin et al. [13] Retrospective study of preterm infants treated with VEGF therapy No significant adverse systemic effects Neutral Nomura et al. [5] Case report of SGA child treated with GH and family history of diabetes Transient insulin resistance progressing to Type 2 diabetes Negative (specific case) Table 2a summarizes the effects of growth hormone (GH) therapy in preterm infants, highlighting its generally positive impact on growth outcomes with minimal adverse effects in most cases. Studies consistently demonstrate that GH therapy significantly improves height SDS and growth velocity, particularly in preterm-born SGA and AGA children (Boguszewski and Cardoso-DeMartini, 2017; Boguszewski et al., 2011; Garcia et al., 2009). Notably, early GH initiation leads to better growth outcomes than delayed treatment (Juul et al., 2022). Additionally, factors like IGF-1 levels and maternal milk intake play a crucial role in optimizing growth velocity in preterm neonates (Mehta and Petrova, 2022). Importantly, systemic risks associated with GH therapy appear minimal, as no significant adverse effects on metabolic or pulmonary function were reported in most studies (Nitkin et al., 2022). However, caution is advised in high-risk populations, as one case study reported transient insulin resistance progressing to Type 2 diabetes in a child with a family history of diabetes, emphasizing the need for careful GH dosing in predisposed individuals (Nomura et al., 2023). Overall, GH therapy is a well-tolerated and effective intervention for preterm infants with growth deficits, provided careful monitoring is in place for metabolic risks in vulnerable populations. World Journal of Advanced Research and Reviews, 2025, 28(02), 1531–1548 1539 Table 2b Effectiveness and Safety of Growth Hormone Therapy in Preterm Infants: Key Outcomes and Considerations Aspect Impact of GH Therapy Percent Change/Improvement References Growth Velocity Significant increase in growth velocity in most cases, particularly with early GH initiation. 30 to 40% Garcia et al. [11]; Boguszewski et al. [10]; Juul et al. [1] Height SDS Improvement Height SDS improved by an average of 1.5–2.1 over the treatment duration. 1.5 to 2.1 SDS Garcia et al. [11]; Boguszewski et al. [10] Pubertal Development Limited data on pubertal effects; some evidence of improved markers in preterm cases treated early. Qualitative (insufficient data for %) Juul et al. [1] Metabolic Improvements Improved IGF-1 levels and energy metabolism, particularly when combined with maternal milk intake. 20 to 30% improvement in IGF-1 levels Hellstrom A et al [12] Safety Profile Generally well-tolerated; rare cases of transient insulin resistance in highrisk patients. ~90% safety with few adverse effects Nomura et al. [5]; Table 2b provides a comprehensive overview of the impact of GH therapy on key growth and metabolic parameters in preterm infants, reinforcing its effectiveness and safety. The most significant benefits include a 30–40% increase in growth velocity and an improvement of 1.5–2.1 SDS in height, particularly when GH therapy is initiated early (Garcia et al., 2009; Boguszewski et al., 2011; Juul et al., 2022). While data on pubertal development remain limited, some studies suggest potential benefits when GH is administered in early life (Juul et al., 2022). GH therapy also positively influences metabolic health, with 20–30% improvements in IGF-1 levels, especially when combined with maternal milk intake (Mehta and Petrova, 2022). Importantly, the safety profile remains favorable (~90% of cases well-tolerated), though transient insulin resistance has been observed in high-risk patients, emphasizing the need for careful monitoring in predisposed individuals (Nomura et al., 2023). Overall, GH therapy proves to be a highly effective intervention for growth promotion in preterm infants, with minimal but manageable risks when properly monitored. Figure 3 Impacts of GH therapy in Preterm infants World Journal of Advanced Research and Reviews, 2025, 28(02), 1531–1548 1546 Statement of ethical approval This review article is based exclusively on previously published studies and publicly available data. No new human subjects, patient interventions, or identifiable personal information were collected for this work. All included studies were conducted in accordance with the ethical standards of their respective institutional review boards (IRBs) and with the 1964 Helsinki Declaration and its later amendments. As this review does not involve direct patient participation or access to confidential patient records, institutional ethical approval and informed consent were not required. Funding No funding was received to support this study. Authors' Contributions A.T.S. provided substantial contributions to the study conception, design, and critical revision of the manuscript. F.A., N.M.A., S.M.A., N.S.A., and N.H. contributed to data acquisition, literature review, and drafting of the manuscript. A.S.E. performed statistical analysis and contributed to manuscript editing. A.K. assisted in manuscript refinement and reference verification. All authors reviewed and approved the final version of the manuscript for submission and publication. References [1] Juul A, Felton PM, Jørgensen J, et al. 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