
==== Front
Eur J Pediatr
Eur J Pediatr
European Journal of Pediatrics
0340-6199
1432-1076
Springer Berlin Heidelberg Berlin/Heidelberg

39158594
5719
10.1007/s00431-024-05719-9
Research
Effect of long-acting PEGylated growth hormone for catch-up growth in children with idiopathic short stature: a 2-year real-world retrospective cohort study
Xie Liulu 1
Li Yanhong lyanh@mail.sysu.edu.cn

1
Zhang Jun 1
Guo Song 1
Chen Qiuli 1
Ma Huamei 1
Jiang Wenjun 2
1 https://ror.org/037p24858 grid.412615.5 0000 0004 1803 6239 Department of Pediatrics, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080 China
2 Medical Affairs Department, GeneScience Pharmaceuticals Co., Ltd., Changchun, 130012 China
Communicated by Gregorio Milani

19 8 2024
19 8 2024
2024
183 10 45314539
9 3 2024
8 7 2024
5 8 2024
© The Author(s) 2024
2024
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Several evidence gaps exist regarding the use of long-acting polyethylene glycol recombinant human growth hormone (PEG-rhGH) in children with idiopathic short stature (ISS), particularly studies conducted in real-world settings, with long-term follow-up, involving varied dosing regimens, and in comparison with daily rhGH. The study aimed to evaluate the effectiveness, safety, and adherence of once-weekly PEG-rhGH for catch-up growth in children with prepubertal ISS compared to daily rhGH. A real-world retrospective cohort study was conducted in prepubertal children with ISS in China. Children who voluntarily received once-weekly PEG-rhGH or daily rhGH were included and were followed up for 2 years. Ninety-five children were included, 47 received PEG-rhGH 0.2–0.3 mg/kg weekly and 48 received daily rhGH. Outcome measures included effectiveness in catch-up growth, adverse events, and treatment adherence. Height velocity increased significantly in both groups during rhGH therapy. In children who received PEG-rhGH treatment, height velocity was 10.59 ± 1.37 cm/year and 8.75 ± 0.86 cm/year in the first and second year, respectively, which were significantly more than those who received daily rhGH (9.80 ± 1.05 cm/year, P = 0.002, and 8.03 ± 0.89 cm/year, P < 0.001). The height standard deviation score improved at the end of the second year for all children (P < 0.001). However, children who received PEG-rhGH showed more excellent improvement than those with daily rhGH (1.65 ± 0.38 vs. 1.50 ± 0.36, P = 0.001). In children who received PEG-rhGH, lower missed doses were observed than those with daily rhGH (0.75 ± 1.06 vs. 4.4 ± 2.0, P < 0.001). No serious adverse events were observed. Conclusion: PEG-rhGH demonstrated superior effectiveness and adherence compared to daily rhGH in the treatment of children with ISS. The safety profiles were similar between the two treatments. What is Known:	
• Recombinant human growth hormone (rhGH) has been used to increase adult height in children with idiopathic short stature (ISS), and its safety profile is comparable to other indications for growth hormone treatment.	
• The use of long-acting rhGH in children with ISS is still an area of uncertainty.	
What is New:	
• This 2-year real-world study provides new evidence that PEGylated rhGH (PEG-rhGH) is more effective than daily rhGH in promoting catch-up growth in children with ISS.	
• PEG-rhGH also demonstrated superior treatment adherence compared to daily rhGH in children with ISS.	
• The safety profiles of PEG-rhGH and daily rhGH were found to be similar.	

Keywords

PEGylated recombinant human growth hormone
Long-acting growth hormone
Jintrolong
Idiopathic short stature
Catch-up growth
Treatment adherence
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pmcIntroduction

Idiopathic short stature (ISS) is a condition characterized by a height that falls more than two standard deviations (SD) below the average height for a given age and gender, with no identifiable cause [1]. It is the diagnosis label given after excluding other known conditions that can cause short stature in children [1]. Children with ISS typically exhibit normal birth size, proportional body growth, adequate food intake, the absence of psychiatric disorders, and no evidence of growth hormone deficiency (GHD) or chromosomal abnormalities [2, 3]. Previous research suggests that ISS accounts for approximately 80% of short children seen in pediatric clinics [1]. In China, the reported prevalence of ISS among children presenting with short stature is approximately 45% [4].

Recombinant human growth hormone (rhGH) was first introduced in 1985 as a treatment for children with GHD. Over time, it has also been approved for other pediatric conditions associated with short stature, such as Turner syndrome, small for gestational age, chronic renal insufficiency, Prader-Willi syndrome, and Noonan syndrome [5, 6]. In 2003, the US Food and Drug Administration (FDA) authorized the marketing of rhGH for ISS. According to a consensus statement on the diagnosis and treatment of children with ISS, rhGH contributes to an average increase in adult height of 3.5 to 7.5 cm, with a safety profile similar to that of other indications for GH treatment [7]. The efficacy and safety of daily subcutaneous injections of rhGH have also been proven in ISS children in China [8–10].

Though proven effective in clinical trials, the high frequency and long duration of treatment could be inconvenient and therefore result in increased non-compliance [11, 12], which may compromise the treatment effectiveness in real-world clinical settings. The adherence was even worse among children with ISS compared with GHD [12]. The development of long-acting growth hormone therapies has addressed this issue by reducing the injection frequency to once per week, thus alleviating the treatment burden. Polyethylene glycol rhGH (PEG-rhGH) is a long-acting form of growth hormone (GH) that was approved in China in 2014 for treating GHD in children. Previous phase I to IV studies have proven the efficacy and safety of weekly PEG-rhGH in children with GHD [13–18]. Furthermore, the efficacy and safety of PEG-rhGH have also been evaluated in Turner syndrome [19]. A study in 360 children with ISS found that weekly PEG-rhGH at a dosage of 0.2 mg/kg/week showed efficacy and safety comparable to untreated control patients [20]. Nonetheless, the evidence for PEG-rhGH in treating children with ISS is still lacking. No studies have been conducted on long-acting GH in ISS patients with a follow-up period longer than 1 year or in real-world settings. Existing research has not evaluated the effectiveness and safety of PEG-rhGH at doses other than 0.2 mg/kg/week. Moreover, there is a lack of direct comparative studies between once-weekly PEG-rhGH and daily rhGH. The potential improvements in treatment adherence associated with PEG-rhGH, as compared to daily rhGH, are currently based on hypothetical reasoning rather than direct comparisons in real-world scenarios. Our study is the first to comparatively evaluate the effectiveness, safety, and adherence of once-weekly PEG-rhGH versus daily rhGH in pediatric patients with ISS in a real-world clinical setting. We aimed to address gaps in the existing literature regarding the clinical evaluation of long-acting formulations, dosage comparisons, and treatment adherence.

Materials and methods

Population

This study is a real-world retrospective cohort study conducted in China. Prepubertal children who initiated GH treatment for ISS in the pediatric department of a tertiary hospital between 2014–01 and 2020–12 were retrospectively selected from hospital records. Short stature was defined as having a height below − 2 SD or the third percentile of the normal growth curve for children of the same age and gender [21]. The diagnosis of ISS made after excluding other causes of short stature includes (1) GHD, identified by a GH stimulation test; (2) Turner syndrome, confirmed by karyotyping in females; (3) Noonan syndrome, recognized by characteristic physical features and genetic testing for PTPN11 gene mutations; (4) Laron syndrome, confirmed using insulin-like growth factor 1 (IGF-1) generation test; (5) being small for gestational age, defined by birth height or weight below the tenth percentile or 2 SD with no catch-up growth by age 2; and (6) growth disorder caused by malnutrition or hypothyroidism. All patients whose rhGH treatment was Jintrolong (PEG-rhGH) or Jintropin (daily rhGH) and continued treatment for at least 1 year after initiation were included in the analysis.

Interventions

The patients independently chose their rhGH treatments and were divided into two groups based on their rhGH treatments. Patients in the PEG-rhGH group received subcutaneous injections of PEG-rhGH solution (Jintrolong) once a week. The initial dose was 0.2 mg/kg/week. Height and weight were measured every 3 months. The dose was adjusted based on weight gain and height velocity, with a maximum dose of 0.3 mg/kg/week. Patients in the daily rhGH group received daily injections of rhGH solution (Jintropin) administered subcutaneously before bedtime. The initial dose was 0.37 to 0.38 mg/kg/week. The maximum dose was 0.38 to 0.40 mg/kg/week.

Outcomes

Patients were observed for 2 years after treatment initiation. Outcome measures include effectiveness in catch-up growth, safety, and treatment adherence. Effectiveness outcomes include height velocity (cm/year), change in height standard deviation score (Ht SDS), change in body mass index (BMI) SDS, and change in IGF-1 SDS. Safety outcomes include fasting blood glucose (mmol/L), advancements in bone age (years), and the incidence of adverse events, including injection site reactions. Treatment adherence was evaluated through self-reports provided by patients and their parents, which included collecting the number of missed doses since the last visit. Adherence was quantified by the number and percentage of missed doses. The percentage of missed doses was calculated as (number of missed doses/total prescribed doses) × 100%. Following our local practice, height (cm) and weight (kg) were routinely measured every 3 months. IGF-1 levels (ng/mL) were evaluated every 3 to 6 months. Blood samples for IGF-1 analysis were collected 3 to 5 days after the last injection. Bone ages were assessed every 6 months using the Greulich-Pyle method.

Statistical analysis

For the first year of the study, data were available for all 47 patients in the PEG-rhGH group and all 48 patients in the daily rhGH group. For the second year of the study, data were available for 40 patients in the PEG-rhGH group and 42 patients in the daily rhGH group who continued treatment beyond the first year. No data were missing for specific variables. The analyses were conducted using the available data for each respective assessment time point. The normality of continuous variables was confirmed through the generation of normal Q-Q plots. Statistical analyses were performed using SPSS (version 26.0). Plots were generated using R (version 4.1.2). Continuous variables were presented as mean ± SD and compared using t-tests. Categorical variables were presented as count (%) and compared using χ2 tests. A P value of 0.05 was used as a statistically significant threshold.

Results

Study population

A total of 95 ISS children were included in the study, with 47 in the PEG-rhGH group and 48 in the daily rhGH group, respectively. The mean age was 6.9 ± 2.2 years, and 64 (67.3%) were male. Baseline characteristics of the two study groups are shown in Table 1, where no significant differences were observed between the two groups. Table 1 Baseline characteristics of the study population

Variable	PEG-rhGH (N = 47)	Daily rhGH (N = 48)	P value	
Age (years)	6.6 ± 2.6	7.3 ± 1.8	0.147	
Sex (male)	29 (61.7%)	35 (72.9%)	0.279	
Ht SDS	 − 2.38 ± 0.66	 − 2.56 ± 0.39	0.089	
BMI SDS	 − 0.77 ± 0.81	 − 0.75 ± 0.37	0.837	
IGF-1 SDS	 − 1.40 ± 0.51	 − 1.22 ± 0.82	0.194	
Bone age (years)	5.2 ± 2.6	5.4 ± 1.9	0.815	
Height velocity (cm/year)	5.21 ± 0.56	5.14 ± 0.42	0.46	
THSDS	 − 0.72 ± 0.70	 − 0.87 ± 0.70	0.31	
BMI body mass index, Ht height, IGF-1 insulin-like growth factor 1, rhGH recombinant human growth hormone, SDS standard deviation score, TH target height

Treatment adherence

Out of the 47 patients in the PEG-rhGH group, 40 received treatment for more than 2 years, while 7 discontinued after the first year. This is similar for the daily rhGH group, where 42 were treated for longer than 2 years and 6 discontinued after the first year. All treatment discontinuations were due to parent-related reasons. The average number of missed doses was 0.48 ± 0.82 (range 0 to 3) and 11.50 ± 7.83 (range 0 to 35) for PEG-rhGH and daily rhGH within the first year and 0.30 ± 0.61 (range 0 to 2) and 20.24 ± 14.84 (range 3 to 73) within the second year. The percentage of missed doses is shown in Fig. 1. Patients treated with PEG-rhGH had consistently better adherence, as evidenced by the significantly lower percentage of missed doses compared to patients treated with daily rhGH (P < 0.001 for both years).Fig. 1 Percentage of missed doses in PEG-rhGH and rhGH groups within the first and second years of treatment initiation

Effectiveness

In both groups, the height velocity significantly increased after receiving treatment (10.59 ± 1.37 vs. 5.21 ± 0.56 cm/year, P < 0.001, for the PEG-rhGH group, and 9.80 ± 1.05 vs. 5.14 ± 0.42 cm/year, P < 0.001, for the daily rhGH group). Height velocity was significantly higher in the PEG-rhGH group than in the daily rhGH group for both years (as shown in Table 2 and Fig. 2). Both groups showed a significant improvement in Ht SDS (P < 0.001). The mean change within 2 years of treatment initiation was 1.65 ± 0.38 for patients receiving PEG-rhGH and 1.50 ± 0.36 for patients receiving daily rhGH (P = 0.001, as shown in Table 2 and Fig. 2). Table 2 Comparison of effectiveness outcomes in two treatment groups

Outcome	Timeframe	PEG-rhGH	Daily rhGH	P value	
Height velocity (cm/year)	Month 0 ~ 6	11.03 ± 1.91	10.72 ± 1.53	0.38	
	Month 7 ~ 12	10.22 ± 1.67	8.92 ± 1.31	 < 0.001	
	Year 1	10.59 ± 1.37	9.80 ± 1.05	0.002	
	Year 2	8.75 ± 0.86	8.03 ± 0.89	 < 0.001	
Change in Ht SDS	Month 0 ~ 6	0.60 ± 0.30	0.56 ± 0.20	0.442	
	Month 7 ~ 12	0.54 ± 0.31	0.38 ± 0.18	0.006	
	Year 1	1.06 ± 0.30	0.94 ± 0.26	0.039	
	Year 2	0.66 ± 0.27	0.56 ± 0.17	0.046	
	2-year observation period	1.65 ± 0.38	1.50 ± 0.36	0.001	
Change in BMI SDS	Month 0 ~ 6	0.40 ± 0.39	0.04 ± 0.25	 < 0.001	
	Month 7 ~ 12	0.08 ± 0.42	0.07 ± 0.30	0.897	
	Year 1	0.47 ± 0.51	0.12 ± 0.35	 < 0.001	
	Year 2	 − 0.19 ± 0.45	0.07 ± 0.19	 < 0.001	
	2-year observation period	0.26 ± 0.53	0.19 ± 0.26	0.457	
Change in IGF-1 SDS	Month 0 ~ 6	1.40 ± 0.96	1.20 ± 0.89	0.29	
	Month 7 ~ 12	0.10 ± 0.92	0.74 ± 0.90	0.002	
	Year 1	1.50 ± 1.11	1.94 ± 0.90	0.035	
	Year 2	 − 0.01 ± 0.91	0.14 ± 0.71	 < 0.001	
	2-year observation period	1.51 ± 1.08	2.22 ± 0.92	0.002	
BMI body mass index, Ht height, IGF-1 insulin-like growth factor 1, rhGH recombinant human growth hormone, SDS standard deviation score

Fig. 2 Comparison of effectiveness outcomes between PEG-rhGH and rhGH groups: height velocity (a), change in Ht SDS (b), change in BMI SDS (c), and change in IGF-1 SDS (d). BMI, body mass index; Ht, height; IGF-1, insulin-like growth factor 1; SDS, standard deviation score

As shown in Table 2 and Fig. 2, patients receiving PEG-rhGH experienced a significantly greater increase in BMI SDS during the first 6 months compared to daily rhGH. However, this difference became insignificant during the second 6 months. Additionally, patients receiving PEG-rhGH experienced a decrease in BMI SDS during the second year. Overall, the change in BMI SDS was similar between the two groups during the 2-year observation period.

The mean change in IGF-1 SDS within 2 years after treatment initiation was significantly smaller for patients receiving PEG-rhGH compared to those receiving daily rhGH (1.51 ± 1.08 vs. 2.22 ± 0.92, P = 0.002, as shown in Table 2 and Fig. 2). We also evaluated the incidence of IGF-1 SDS increments exceeding + 2 SD. Five patients were identified in the PEG-rhGH group, including two in the first year and two in the second year. The other one had consistently exceeded this threshold since the first 6 months, with three tests exceeding the threshold within the 2-year period. Seven patients were identified in the daily rhGH group, including one in the first year and five in the second year. The other one had consistently exceeded this threshold since the first 6 months, with all tests exceeding + 2 SD throughout the 2-year period.

Safety profiles

As shown in Table 3, the PEG-rhGH group had significantly slower advancement in bone age than the daily rhGH group throughout the 2-year observation period (2.2 ± 0.7 vs. 2.5 ± 0.7, P = 0.041). We also compared the advance in bone age (△BA) with the advance in chronological age (△CA) for each year after treatment initiation (results shown in Fig. 3). In the PEG-rhGH group, 24 incidences of △BA > △CA were observed, 10 in the first year and 14 in the second year. Two patients had △BA > △CA for both years. In the daily rhGH group, 34 incidences of △BA > △CA were observed, 19 in the first year and 15 in the second year. Nine patients had △BA > △CA for both years. The maximum △BA/△CA was 2. At the end of the 2-year observation period, none of the patients had BA surpassing their CA, with some patients having BA matching their CA. Table 3 Comparison of bone age advancements in two treatment groups

Timeframe	PEG-rhGH	Daily rhGH	P value	
Year 1 (years)	0.9 ± 0.5	1.2 ± 0.5	0.01	
Year 2 (years)	1.3 ± 0.3	1.5 ± 0.4	0.523	
2-year observation period (years)	2.2 ± 0.7	2.5 ± 0.7	0.041	
rhGH recombinant human growth hormone

Fig. 3 Sankey plots depicting the advance in bone age with the advance in chronological age for each year after treatment initiation: comparison between PEG-rhGH and rhGH groups. △BA, advance in bone age; △CA, advance in chronological age

During the treatment, insulin and blood glucose levels remained within normal ranges for both groups. Four patients in the PEG-rhGH group and three in the daily rhGH group had one HOMA-IR value greater than 3. However, all had the value returned to normal within 3 months without relapse. No adverse events such as thyroid dysfunction, benign intracranial hypertension, or slipped capital femoral epiphysis were observed in either group. No cases of local injection site pain or subcutaneous fat atrophy were observed in the PEG-rhGH group.

Discussion

In this real-world study, we evaluated the 2-year effectiveness, safety, and adherence of once-weekly PEG-rhGH for catch-up growth in prepubertal children with ISS and compared it with daily rhGH. Analyses of the effectiveness outcomes demonstrated that once-weekly administration of PEG-rhGH improved the height velocity, enabling catch-up growth and achieving height improvement. The effectiveness was superior to daily injections of rhGH. Our study also demonstrated that patients who received PEG-rhGH had significantly better treatment adherence compared to those who received daily rhGH. Additionally, the safety profiles were similar, with no serious or unexpected adverse events. This study bridges the evidence gap regarding the direct comparison between PEG-rhGH and daily rhGH, especially in real-world settings.

The duration of GH treatment for children with ISS is typically long, lasting 4 to 7 years, as previously reported [7]. Daily injections can be difficult to adhere to due to the associated inconveniences, which may compromise treatment effectiveness. Our study provides direct evidence supporting the hypothesis that long-acting injections can improve treatment adherence and reduce treatment burden, thereby enhancing treatment effectiveness. During the 2-year treatment period, the percentage of missed doses for PEG-rhGH was less than 1%, while for daily rhGH, it was 4.4%. This can bring benefits to both the children and their caregivers.

In our study, PEG-rhGH demonstrated superior effectiveness compared to daily rhGH in the treatment of children with ISS. Our findings align with previous reports. A study of PEG-rhGH conducted in China reported height velocities of 11.05 cm/year for the first 6 months and 10.04 cm/year for the first year [20], which were 11.03 cm/year and 10.59 cm/year in our study. In that study, the changes in Ht SDS were 0.61 ± 0.30 for the first 6 months and 0.98 ± 0.35 for the first year. In another study of long-acting rhGH conducted in Korea, the change in Ht SDS was 0.58 during the first 6 months [22]. In our study, we observed changes of 0.60 ± 0.30 in the first 6 months and 1.06 ± 0.30 in the first year. Overall, our results were similar to the studies during the first 6 months, while the effectiveness appeared to be better in the first year, suggesting enhanced effectiveness in the latter half of the first year. This may be attributed to the flexible and personalized dosage adjustments implemented in our study. Initiating at a dose of 0.2 mg/kg/week, patients in our study adjusted the PEG-rhGH dose every 3 months based on their height and weight, which may facilitate the identification of the optimal dose for each individual. Our study proves the real-world effectiveness of PEG-rhGH for catch-up growth. Moreover, our study represents the first study with a follow-up period of longer than 1 year, showing that the effectiveness remained in the second year.

Patients in the PEG-rhGH group exhibited a fast increase in BMI during the initial stage of treatment. Within the first 6 months of treatment, BMI SDS increased by 0.54. After the initial 6 months, BMI SDS stabilized and even decreased. This observed trend is consistent with a previous study that investigated the use of rhGH in the treatment of ISS [9]. In that study, the rapid increase in BMI was suggested as a potential factor contributing to hyperglycemia. In our current study, insulin and blood glucose levels remained normal. Four patients in the PEG-rhGH group had one HOMA-IR value greater than 3, but these values soon returned to normal without relapse. Blood glucose should thus be monitored during treatment.

IGF-1 plays a crucial role in assessing the response to rhGH treatment [23]. Higher levels of IGF-1 are generally associated with improved growth outcomes [24, 25]. However, excessively elevated IGF-1 levels can increase the risk of atherosclerosis or cancer [26]. In our study, patients receiving PEG-rhGH had improvements in height, albeit significantly lower IGF-1 levels compared to those receiving daily rhGH. This can be attributed to the sustained release nature of long-acting rhGH, which offers a more consistent and prolonged exposure to growth hormone and may lead to improved height outcomes. This mechanism allows for gradual and steady growth stimulation over an extended period. From previous experience with daily rhGH, optimizing the dosage using IGF-1 level as a pharmacological indicator allows patients to achieve maximum benefits in terms of height, body composition, and metabolic outcomes while minimizing the occurrence of adverse events associated with rhGH treatment [24]. The current recommended dosage for PEG-rhGH, typically 0.2 mg/kg/week, is primarily based on studies involving GHD patients. For non-GHD short stature conditions such as ISS, the dosage extrapolated from GHD treatments may not be optimal. In real clinical practice, we have implemented individualized dosing titration, which led to a dosage up to 0.3 mg/kg/week as reported in our study, which was well tolerated. Our study suggests that this higher dosage could be more appropriate for the ISS population than the standard dose used for GHD to achieve effective catch-up growth and highlights the importance of timely dosage adjustments in real clinical practice. It is crucial for healthcare professionals to carefully evaluate and determine the optimal dosage of PEG-rhGH for ISS patients.

Previous studies have revealed significant benefits of long-acting rhGH across various patient categories, including those with GHD, ISS, Noonan syndrome, and Turner syndrome [27–29]. Long-acting rhGH can improve adherence due to the reduced frequency of injections, which is crucial since daily injections can be a barrier to treatment persistence. This reduced injection frequency may be as effective, or even superior, in promoting growth and improving body composition without increasing the risk of adverse events. The benefits extend beyond physical outcomes, as improved adherence can enhance quality of life for patients and their families by alleviating the burden of daily injections. However, long-term studies are needed to confirm the durability of these benefits and to assess any potential long-term safety concerns. Therefore, the transition towards long-acting rhGH therapy presents a promising development for enhancing treatment adherence and quality of life while maintaining therapeutic efficacy.

Our study has notable strengths. Firstly, we conducted a direct comparison between PEG-rhGH and daily rhGH. This design allows for a more robust assessment of the relative effectiveness of the two treatments. Secondly, our study has an observation period of 2 years, which is longer than previous studies. Thirdly, our study was conducted in a real-world setting, which enhances the generalizability of our findings to actual clinical practice. This setting provides a more accurate representation of real-life dosing, treatment effectiveness, and adherence compared to controlled clinical trials.

We acknowledge several limitations in our study. Firstly, in real-world settings, children diagnosed with ISS exhibit heterogeneity and have diverse underlying causes of short stature, which may lead to variations in their responses to PEG-rhGH. Due to the limited sample size, we were unable to evaluate the effectiveness of PEG-rhGH in more precise subcohorts. While adjusting for confounders would be ideal, it was not conducted because of the concern that adjustment approaches may not be stable due to the modest sample size. Additionally, unmeasured factors like socioeconomic status could have influenced treatment effectiveness, as PEG-rhGH is more expensive. These highlight the need for larger studies that can better address the heterogeneity of ISS and investigate potential confounding factors to provide a more nuanced understanding of treatment effectiveness. It is important to note that our cohort had a healthy BMI range. This demographic characteristic may affect the generalizability of our results to populations with higher BMIs. The rhGH treatment has not been approved for the treatment of ISS patients globally. There are differences across countries and regions in prescription criteria and approved indications. Therefore, the generalizability of our study results may be limited. When interpreting and applying the findings, consideration should be given to local regulatory policies and clinical practices.

Conclusions

In this 2-year real-world study, PEG-rhGH showed superior effectiveness and adherence compared to daily rhGH in treating children with ISS. Safety profiles were similar. Our findings support the use of long-acting injections to improve treatment adherence, reduce treatment burden, and enhance effectiveness. Future studies are required to evaluate the long-term efficacy and safety.

Abbreviations

BA Bone age

BMI Body mass index

CA Chronological age

FDA US Food and Drug Administration

GH Growth hormone

GHD Growth hormone deficiency

Ht Height

IGF-1 Insulin-like growth factor 1

ISS Idiopathic short stature

PEG Polyethylene glycol

rhGH Recombinant human growth hormone

SD Standard deviation

SDS Standard deviation score

TH Target height

Authors’ contributions

YL and LX conceived and designed the study. YL, JZ, QC, SG, HM, and HC collected the data. LX conducted the data analysis. JZ, QC, SG, HM, HC, and WJ contributed to the interpretation of the data. LX drafted the manuscript, while YL and WJ provided critical revisions. All authors gave final approval of the version to be published and agreed to be accountable for all aspects of the work.

Funding

The authors declare that no funds, grants, or other support was received during the preparation of this manuscript.

Data availability

The data used in this study is confidential and subject to data protection regulations. Due to the sensitive nature of the data, it is not publicly available.

Declarations

Ethics approval

The study was reviewed and approved by the First Affiliated Hospital of Sun Yat-Sen University Institutional Review (approval number [2020]360) and conducted in accordance with the principles outlined in the Declaration of Helsinki.

Competing interests

The authors declare no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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