Comparison of the effectiveness of recombinant human growth hormone therapy in preterm and full-term children with short stature born small for gestational age
Article information
Abstract
Purpose
With improvements in the infant survival rates for high-risk pregnancies, the prevalence of short stature in children born prematurely and small for gestational age (SGA) has also increased. The aim of this study was to compare the effectiveness of recombinant human growth hormone (rhGH) therapy for preterm and full-term SGA children with short stature.
Methods
This study included 114 children born SGA (40 preterm and 74 term), who showed no catch-up growth by age 4 years and had undergone rhGH therapy for at least one year. The clinical parameters were reviewed retrospectively.
Results
The mean height standard deviation scores (SDSs) for preterm and full-term SGA children at the start of rhGH therapy were -2.97±0.85 and -2.46±0.54, respectively. The mean duration of treatment was 3.3±1.9 years for preterm SGA children and 3.3±1.6 years for full-term SGA children. The height SDS increased to -1.13±0.96 in preterm children and -0.77±0.59 in full-term children by the fourth year of treatment. Full-term SGA children responded better to rhGH therapy than preterm children in the first year of therapy (P=0.03). Serum insulin-like growth factor 1 and insulin-like growth factor binding protein 3 levels significantly increased after the start of rhGH therapy (P<0.001).
Conclusions
rhGH therapy significantly improved height SDS in both preterm and full-term SGA children, emphasizing the key role of this intervention for managing short stature in children born SGA, regardless of gestational age.
Highlights
· This study demonstrated that recombinant human growth hormone (rhGH) therapy was comparably effective in enhancing the growth of preterm and full-term small for gestational age (SGA) children.
· This study validated the usefulness of prediction models for estimating SGA children’s responses to rhGH therapy, highlighting the importance of investigating compliance or other contributing factors when responses are poorer than expected.
· No metabolic complications were observed during rhGH therapy in either preterm or full-term SGA children.
Introduction
The World Health Organization (WHO) and the Korean National Cohort Study reported progressive increases in the birth rates of premature and low birth weight infants [1,2]. Although advances in neonatal intensive care have improved the survival rates of premature babies, long-term issues related to growth and metabolic sequelae persist [3].
Approximately 10%–20% of children born preterm or small for gestational age (SGA) fail to achieve catch-up growth [4,5]. Although the degree of growth failure varies according to several factors, such as gestational age (GA), birth weight, birth length, and comorbidities, children born preterm and SGA are at increased risk of persistent short stature [4-6]. In addition, postnatal growth failure by 6–12 months of age results in short stature with inadequate weight gain and influences neurodevelopment outcomes [7,8].
Previous studies have demonstrated the efficacy of recombinant human growth hormone (rhGH) therapy for children born SGA with no catch-up growth [9,10]. rhGH therapy significantly increases height standard deviation scores (SDSs) in both full-term and preterm SGA children [11,12]. Additionally, it significantly increases serum insulin-like growth factor 1 (IGF-1) amd insulin-like growth factor binding protein 3 (IGFBP-3) levels and the IGF-1/IGFBP-3 ratios without bone age advancement or metabolic complications [9,10,13].
In 2001, the U.S. Food and Drug Administration (FDA) approved rhGH therapy for children with short stature who were born SGA. The European Agency for the Evaluation of Medicinal Products approved rhGH therapy for this purpose in 2003, and the Korean FDA did so in 2008 [10,14]. Factors that influence responses to rhGH therapy include age at initiation of therapy, height SDS, midparental height (MPH) SDS, and rhGH dosage [9]. A previous study in the Netherlands compared the effectiveness of rhGH therapy in preterm and full-term children with short stature born SGA and found no significant differences in the growth responses of the 2 groups [12].
However, no comparative study has investigated the efficacy of rhGH therapy in preterm and full-term children born SGA in Korea. Therefore, this study was performed to compare the effects of rhGH therapy in preterm and full-term SGA children who had not achieved catch-up growth by the age of 4 years.
Materials and methods
1. Subjects
The study included 114 children born SGA between January 1998 and December 2018 at the Department of Pediatrics, Asan Medical Center, Seoul, Korea. SGA was defined as a birth weight and/or birth length less than the third percentile for GA and sex [15]. GA was determined using either the dates of the mother’s last menstrual period or ultrasound measurements [16]. Based on the WHO classification, a birth at 37 weeks of gestation or later was classified as full-term, whereas a birth before 37 weeks was considered preterm [17]. Inclusion criteria were as follows: (1) children born SGA who had not achieved catch-up growth by the age of 4 years; (2) prepubertal children, defined as breast Tanner stage I in girls and testicular volume less than 4 mL in boys; and (3) children treated with rhGH therapy for at least 1 year. Exclusion criteria included children with chromosomal abnormalities, growth failure due to other genetic disorders (e.g., skeletal dysplasia or Silver-Russell syndrome), or those who were treated with corticosteroid therapy. However, patients with congenital hypothyroidism and congenital heart disease were included.
2. Methods
The patients were treated with subcutaneous rhGH injections at initial doses ranging from 0.033 mg/kg/day to 0.066 mg/kg/day for 6 days per week. The following parameters were retrospectively reviewed: sex, GA, birth weight, MPH, weight, height, body mass index (BMI), age at the start of rhGH therapy, bone age (BA), and serum levels of IGF-1, IGFBP-3, random glucose, thyroid-stimulating hormone (TSH), and free thyroxine (T4) levels. The clinical information was collected at baseline and annually thereafter.
Height, weight, and BMI were expressed as SDSs based on the 2017 Korean National Growth Charts [18]. BA was assessed according to the Greulich and Pyle method [19]. The SDSs for serum IGF-1 and IGFBP-3 levels were calculated using age- and sex-matched normative reference data from a Korean study [20].
We used an rhGH response prediction model that incorporated multiple factors, including weight SDS, MPH SDS, initial rhGH dosage, and age at therapy initiation (Supplementary Table 1) [21,22]. Using these factors, we compared the studentized residuals to represent the difference between the predicted growth velocity and the observed growth velocity in both preterm and full-term SGA children.
3. Statistical analysis
Continuous variables were expressed as means±standard deviations, and categorical variables were expressed as counts and percentages. A Student t-test was employed to compare the continuous variables between the 2 groups, and an unpaired t-test was used to assess differences in growth velocity before and after rhGH therapy. The annual changes in height SDS, weight SDS, and BMI SDS during rhGH therapy were analyzed using repeated measures analysis of variance. Statistical analyses were performed using IBM SPSS Statistics ver. 21.0 (IBM Co.). P-values less than 0.05 were considered statistically significant.
4. Ethical statement
The Institutional Review Board (IRB) of Asan Medical Center approved this study (IRB No. 2023-0566) and waived the need to obtain informed consent because the clinical data were obtained retrospectively.
Results
1. Baseline characteristics
This study included 40 patients (26 males and 14 females) in the preterm SGA group and 74 patients (52 males and 22 females) in the full-term SGA group. The mean GA was 32.8±4.0 weeks (range, 22.9–36.9 weeks) in the preterm SGA group and 38.6±1.3 weeks (range, 37.0–42.3 weeks) in the full-term SGA group. The mean birth weight was 1,235.8±588.2 g (range, 410–2,220 g) in the preterm SGA group and 2,272.1±356.9 g (range, 510–2,740 g) in the full-term SGA group. The mean MPH SDS was -0.40±0.74 in the preterm SGA group and -0.59±0.86 in the full-term SGA group (P=0.23) (Table 1).
Baseline characteristics
The comorbidities of the preterm SGA group included respiratory distress syndrome (n=17, 42.5%), bronchopulmonary dysplasia (n=7, 17.5%), inguinal hernia (n=8, 20%), cryptorchidism (n=8, 20%), retinopathy of prematurity (n=5, 12.5%), hypospadias (n=4, 10%), developmental delay (n=4, 10%), necrotizing enterocolitis (n=3, 7.5%), intraventricular hemorrhage (n=3, 7.5%), meconium plug syndrome (n=2, 5%), and congenital heart diseases, including patent ductus arteriosus (n=9, 22.5%), pulmonary atresia with intact ventricular septum (n=2, 5%), and atrial septal defect (n=1, 2.5%). In contrast, the comorbidities of the full-term SGA group included ventricular septal defect (n=2, 2.7%), pulmonary atresia with ventricular septal defect (n=1, 1.4%), and one congenital diaphragmatic hernia (n=1, 1.4%).
At 4 years of age, the mean height SDS was -2.96±0.78 in the preterm SGA group and -2.54±0.48 in the full-term SGA group. Age at the start of rhGH therapy was 5.1±1.0 years for the preterm SGA group and 6.1±1.8 years for the full-term SGA group, with initial mean doses of rhGH of 0.05±0.01 mg/kg/day and 0.04±0.01 mg/kg/day for the preterm and full-term SGA groups, respectively.
2. Effects of rhGH therapy on height, weight, and BMI
The durations of rhGH therapy were 3.3±1.9 years (range, 1.0–8.3 years) and 3.3±1.6 years (range, 1.0–10.0 years) for the preterm and full-term SGA groups, respectively. In the preterm group, the mean height SDS increased from -2.97±0.85 at baseline to -2.05±0.91, -1.67±0.89, -1.26±0.79, and -1.13±0.96 after 1, 2, 3, and 4 years of treatment, respectively (P<0.001) (Fig. 1A). In the full-term SGA group, the mean height SDS increased from -2.46±0.54 at baseline to -1.57±0.58, -1.13±0.58, -0.91±0.66, and -0.77±0.59 after 1, 2, 3, and 4 years of treatment, respectively (P<0.001) (Fig. 1A). At the final follow-up, the mean height SDS was -1.29±0.95 for the preterm SGA group and -0.95±0.66 for the full-term SGA group (P=0.03). The weight SDS in the preterm group increased from -3.29±1.53 at baseline to -1.26±1.54 after 4 years of treatment (P<0.001, Fig. 1B). The full-term SGA group exhibited a weight SDS increase from -2.20±0.87 at baseline to -0.73±0.75 after 4 years of treatment (P<0.001) (Fig. 1B). There were no statistically significant changes in BMI SDS during rhGH therapy for either group (P>0.05) (Fig. 1C).
Changes in the height (A), weight (B), and body mass index (BMI) (C) standard deviation scores (SDSs) during recombinant human growth hormone (rhGH) therapy. The horizontal axis represents the time after the initiation of rhGH therapy, and the vertical axis shows the mean SDS values. The dashed line (Δ) depicts the data for the preterm small for gestational age (SGA) children, and the solid line (●) shows the changes for full-term SGA children.
The annual observed versus predicted height velocities (HVs) and changes in height SDS during rhGH therapy are summarized in Table 2. In the preterm SGA group, the observed HV was significantly higher than predicted in the third year of treatment (P=0.013) and lower in the fourth year of treatment (P=0.025). In the full-term SGA group, the observed HV was significantly higher than predicted in the second year of treatment (P=0.002). At the other treatment time points, there were no significant differences between the observed and predicted HVs for either SGA group.
Growth responses during rhGH treatment and comparison between the observed versus predicted height velocity
The annual change in height SDS was greatest in the first year of treatment (0.93±0.42 for preterm, 0.89±0.34 for full-term), the preterm and full-term SGA groups, the annual change in height SDS significantly decreased over the 4-year treatment period (P<0.001).
To compare the preterm and full-term SGA groups’ responsiveness to rhGH therapy, studentized residuals were calculated using the difference between the observed and predicted HVs: (observed HV – predicted HV)/standard error (Supplementary Table 1). We described the relationship between the predicted HVs and the studentized residuals using scatter plots (Fig. 2). When we compared the preterm SGA and full-term SGA groups using studentized residuals over 4 years of rhGH therapy as an index of responsiveness, no significant differences were observed (Fig. 3). These findings suggest that the effectiveness of rhGH therapy in children born SGA was not influenced by GA.
Relationships between predicted height velocities (x-axis) and studentized residuals (y-axis). During first year (A), second year (B), third year (C), and fourth year (D). The x-axis shows the predicted height velocities (cm), and the y-axis shows the studentized residuals (cm). The black circles (●) depict the data from the preterm small for gestational age (SGA) children, and the white triangles (Δ) indicate the data from full-term SGA children. The horizontal lines at y=2 and y=-2 are marked. When studentized residuals were within this range, the observed height velocities matched the predicted effectiveness of rhGH therapy.
Analysis of studentized residuals to evaluate the rhGH therapy responses of preterm and full-term small for gestational age (SGA) groups during 4 years of treatment. Mean studentized residuals during 4 years of rhGH therapy for the preterm SGA children (black circles) and full-term SGA children (white triangles) are shown, with error bars indicating standard deviations. rhGH, recombinant human growth hormone.
3. Changes in serum IGF-1 and IGFBP-3 levels and BA during rhGH therapy
Serum IGF-1 and IGFBP-3 levels increased significantly in both the preterm and full-term SGA groups during rhGH therapy (P<0.001) (Fig. 4). However, there were no significant differences in serum IGF-1 and IGFBP-3 levels between the preterm and full-term SGA groups (P>0.05). During rhGH therapy, serum levels of TSH, free T4, and random glucose remained within the normal range in both the preterm and full-term SGA groups.
Changes in IGF-1 (A) and IGFBP-3 (B) standard deviation scores (SDSs) during rhGH therapy. Two box plots, one with black boxes for preterm small for gestational age (SGA) children and the other with gray boxes for full-term SGA children, depict the changes in IGF-1 and IGFBP-3 SDSs over 4 years of rhGH therapy. IGF-1, insulin-like growth factor 1; IGFBP-3, insulin-like growth factor binding protein 3; rhGH, recombinant human growth hormone.
Six of the 40 children (15%) in the preterm SGA group had previously been treated with levothyroxine due to congenital hypothyroidism. Thyroid function in these children remained stable during the rhGH therapy. One patient in the preterm SGA group was diagnosed with primary hypothyroidism at the age of 7.2 years during rhGH therapy and was treated with levothyroxine thereafter. rhGH therapy was discontinued in one patient in the full-term SGA group because of progressive scoliosis.
At the start of rhGH therapy, the mean difference between BA and chronological age (CA) was -1.65±0.80 years in the preterm SGA group and -1.71±1.01 years in the full-term SGA group (P=0.707). The difference between BA and CA significantly decreased to -0.76±1.02 years in the preterm SGA group and -0.65±1.16 years in the full-term SGA group after 4 years of treatment, respectively (P<0.001).
At the start of rhGH therapy, all patients were prepubertal. During rhGH therapy, 4 preterm children (1 male and 3 females) and in 12 full-term children (10 males and 2 females) reached pubertal age. One patient born full-term SGA was diagnosed with central precocious puberty at 7.5 years of age after 3.2 years of rhGH therapy and was treated with both rhGH therapy and a long-acting gonadotropin-releasing hormone analog.
Discussion
This study demonstrated that rhGH therapy effectively increased height SDS and serum IGF-1 and IGFBP-3 levels in both the preterm and full-term SGA groups. We compared responses to rhGH therapy between the preterm SGA and full-term SGA groups using a prediction model that incorporated variables such as weight SDS, MPH SDS, initial dose of rhGH, and age at the start of therapy. The use of studentized residuals as an index of responsiveness to rhGH therapy facilitated a detailed comparison of predicted and observed HV. However, there were no significant differences in the effectiveness of rhGH therapy between the 2 groups.
Premature birth, characterized by incomplete in utero growth, can lead to postnatal growth retardation due to increased neonatal morbidities, such as infections, poor nutritional status, chronic lung disease, developmental delay, and potential need for medications (e.g., corticosteroids) [23-25]. Consequently, we hypothesized that the preterm SGA group would encounter challenges in growth and respond unfavorably to rhGH therapy compared to the full-term SGA group. However, our study provides compelling evidence of the effectiveness of rhGH therapy for preterm SGA children with short stature.
This is the first study in Korea to compare the effectiveness of rhGH therapy in preterm SGA and full-term SGA children. The findings are consistent with those of a previous study [12] showing that, despite lower baseline height SDS of preterm SGA children than full-term SGA children, there were no significant differences in height SDS between the 2 groups after 3 years of rhGH therapy. Our results support those of previous studies demonstrating significant height improvement in preterm SGA children with rhGH therapy [12,26,27], including those born preterm (33–37 weeks of gestation) and very preterm (<33 weeks of gestation) SGA children [28].
When we compared long-term outcomes, the full-term SGA group displayed significantly greater height SDSs at their final follow-up than the preterm SGA group. However, these findings are limited by the absence of final adult height data, which could provide more definitive conclusions regarding the long-term effectiveness of rhGH therapy.
Factors such as age at the initiation of treatment, higher weight SDS, dose of rhGH, MPH SDS, and HV in the preceding year influence the effectiveness of rhGH therapy [20,21]. Analyzing studentized residuals can assist prediction of initial responses to therapy in patients with SGA. The studentized residual values observed in our study did not exhibit a consistent trend, reflecting individual variability in responses to rhGH therapy. Therefore, development of individualized rhGH treatment plans for SGA children is imperative.
IGF-1 plays a critical role in fetal development; low levels of serum IGF-1 impede normal growth. IGFBP-3, a major IGF-1-binding protein that transports IGF-1 in the bloodstream, preserves the stability of IGF-1 and regulates its effects [29,30]. The significant increase in serum IGF-1 and the relationship between this increase and the significant increase in height SDS during rhGH therapy in our study are consistent with findings of previous studies [29,30]. Serum IGF-1 and IGFBP-3 levels were monitored during rhGH therapy, and the rhGH dose was reduced when IGF-1 levels exceeded +2.0 SDS [31]. In our study, 1 patient in the preterm group and 3 patients in the full-term group experienced temporary elevation of IGF-1 levels that exceeded +2.0 SDS. However, in subsequent evaluations, IGF-1 levels returned to the normal range without any adjustment of the rhGH doses. In this study, we observed stable thyroid function and serum glucose levels during rhGH therapy; the therapy did not adversely affect these parameters, in agreement with previous studies [32,33].
In this study, there were no significant changes in the difference between CA and BA during treatment. However, by the fourth year of treatment, the difference between CA and BA significantly narrowed in both the preterm and full-term SGA groups even though BA continued to be delayed. BA did not progress according to the Pfizer International Growth Study Database in patients with GH deficiency, Turner syndrome, idiopathic short stature, or SGA following one year of rhGH therapy [34]. Although rhGH therapy reduced the BA–CA difference, the BA remained delayed compared to CA, even after 6 years of rhGH therapy [35]. The reduction in the BA–CA difference in the fourth year of treatment in our cohort may be attributed to multiple factors, such as the earlier onset and faster progression of puberty among children born SGA [36,37].
This study has several limitations. As a retrospective study conducted at a single academic center, it is subject to potential biases, including missing data and variability in the duration and dosage of rhGH therapy. Additionally, although all patients were prepubertal at the initiation of therapy, some entered puberty during the treatment period, which may have influenced height outcomes.
In conclusion, this study demonstrated the effectiveness and safety of rhGH therapy for both preterm and full-term SGA children, resulting in significant increases in height SDS, especially in the first year of treatment. Additionally, this study validated the usefulness of the prediction models for estimating the rhGH therapeutic responses of SGA children.
Supplementary material
Supplementary Table 1 is available at https://doi.org/10.6065/apem.2448128.064.
Equations for predicting height velocity considering variables for the responses to rhGH therapy in children born small for gestational age (SGA) with short stature
Notes
Conflicts of interest
The authors report no potential conflicts of interest relevant to this article.
Funding
This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (Ministry of Science and ICT) (No. NRF2021R1F1A104593011).
Data availability
The data supporting the findings of this study are available from the corresponding author upon reasonable request.
Author contribution
Conception and design: DK and JHC. Acquisition, analysis, and interpretation of data: DK, JHY, SH, JHK, HWY, and JHC. Drafting and revising the manuscript: DK and JHC. Final approval of the manuscript: DK, JHY, SH, JHK, HWY, and JHC.