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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 8 3095-3101
Copyright © 2007 by The Endocrine Society

Improvement in Growth after Two Years of Growth Hormone Therapy in Very Young Children Born Small for Gestational Age and without Spontaneous Catch-Up Growth: Results of a Multicenter, Controlled, Randomized, Open Clinical Trial

Jesús Argente, Ricardo Gracia, Lourdes Ibáñez, Antonio Oliver, Emilio Borrajo, Amaya Vela, Juan Pedro López-Siguero, M. Llanos Moreno, Francisco Rodríguez-Hierro on behalf of the Spanish SGA Working Group1

Hospital Infantil Universitario Niño Jesús (J.A.), Universidad Autónoma de Madrid and CIBER Fisiopatología Obesidad y Nutrición (CB06/03) Instituto de Salud Carlos III, 28009 Madrid, Spain; Hospital Infantil Universitario La Paz (R.G., A.O.), 28034 Madrid, Spain; Endocrinology Unit (L.I., F.R.-H.), Hospital Sant Joan de Déu, University of Barcelona, 08950 Esplugues, Barcelona, Spain; Department of Pediatrics (E.B.), Hospital Universitario Virgen de la Arrixaca, 30120 Murcia, Spain; Department of Paediatric Endocrinology (A.V.), Hospital de Cruces, 48903 Barakaldo, Spain; Department of Pediatrics (J.P.L.-S.), Hospital Materno Infantil de Málaga, 29011 Málaga, Spain; and Novo Nordisk Pharma S.A. (M.L.M.), 28033 Madrid, Spain

Address all correspondence and requests for reprints to: Jesús Argente, M.D., Ph.D., Professor and Chairman, Department of Endocrinology Hospital Infantil Universitario Niño Jesús, Avenida Menéndez Pelayo, 65 E28009 Madrid, Spain. E-mail: argentefen{at}terra.es.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: GH treatment is effective in children born small for gestational age (SGA); however, its effectiveness and safety in very young SGA children is unknown.

Objective: The aim was to analyze the outcome of very young SGA children treated with GH and followed for 2 yr. The results after 24 months of treatment, compared with a control group without treatment during 12 months followed by 12 months of treatment, are shown.

Design: We performed a multicenter, controlled, randomized, open trial.

Settings: The pediatric endocrinology departments of 14 public hospitals in Spain participated in the study.

Patients: Seventy-six children, aged 2–5 yr born SGA and without catch-up growth, were studied.

Intervention: Children received GH at 0.06 mg/kg·d for 2 yr (group I) or were followed for 12 months with no treatment and then treated for 12 months (group II).

Main Outcome Measures: Age, general health status, pubertal stage, bone age, height, weight, biochemical and hormonal analyses, and adverse side effects were determined at biannual check-ups.

Results: The mean height SD score gain for chronological age in children treated for 24 months (group I) was 2.10, whereas in those treated only during the last 12 months (group II) was 1.43. In both groups, children under 4 yr of age had the greatest gain in growth velocity. No significant acceleration of bone age or side effects related to treatment was seen.

Conclusion: Very young SGA children without spontaneous catch-up growth could benefit from GH treatment because growth was accelerated and no negative side effects were observed.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
NEARLY 3% OF INFANTS are born small for gestational age (SGA), defined as birth weight and/or length at least 2 SD below the mean for gestational age (1, 2). Independently of whether these children are born prematurely or at term, most SGA infants experience postnatal growth sufficient to normalize their height by 2 yr of age (2). This growth is referred to as catch-up growth. However, it is estimated that approximately 10% of SGA children remain short (height below –2 SD) throughout childhood (1, 3). Although most of these children do not exhibit GH deficiency (4), the International Small for Gestational Age Advisory Board has suggested that GH deficiency should be ruled out in these patients (5). A number of international studies have shown that the majority of these children could benefit from GH therapy to normalize height during childhood, to maintain a normal growth velocity during prepuberty and through puberty, and to attain a normal adult height (6, 7, 8, 9, 10, 11, 12, 13, 14). However, because these studies were conducted in older SGA children, the appropriate time as to when GH treatment should be started remains a matter of discussion. The objective of this study was to investigate the efficacy and safety of GH therapy in young children born SGA, when treatment is started between 2 and 5 yr of age.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

The study population was composed of short SGA children who had not experienced catch-up growth (as defined below) at the time of inclusion and who were recruited from 14 participating centers. Inclusion criteria for the study were as follows: 1) SGA as defined by length and/or weight at the time of birth below the lower limit (P < 10th centile) of the curves of Lubchenco for gestational age (15, 16); 2) chronological age (CA) between 2 and 5 yr; 3) absence of catch-up growth [height < 3rd centile for CA according to the growth curves of Hernández et al. (17)] and height growth velocity below the mean for CA; 4) height of parents at least –2 SD score (SDS) of the population mean; 5) normal response to a GH stimulation test (≥10 mg/liter); and 6) bone age (BA) according to the method of Greulich and Pyle (18) less than or equal to CA. Exclusion criteria included children born from multiple births, newborns with postischemic encephalopathy, malformative syndromes associated with short stature (including Silver-Russell syndrome), endocrine-metabolic abnormalities with the exception of thyroid disease with appropriate substitution therapy, and growth retardation associated with infections, embryopathies, severe chronic illnesses, nutritional disorders, or osteodystrophies. Patients that were receiving or had received any treatment that could interfere with the effects of GH (anabolic steroids, sex steroids, etc.) and children with karyotype anomalies (e.g. Turner’s syndrome), neoplasias, previous or current chemotherapy or radiotherapy, renal dysfunction, as defined by a serum creatinine of more than 1 mg/dl, and previous inclusion in other clinical trials (during the previous 3 months) were also excluded.

A total of 81 patients (40 boys and 41 girls) were recruited in 14 centers in Spain. Of these, 78 were included in the safety analysis and 76 in the intention-to-treat analysis (two patients were not compliant with the selection criteria).

Study design

The randomization of this multicenter, open clinical trial (number NCT00184691, assigned by Clinical Trials Database of the U.S. National Institutes of Health) was performed by blocks and was stratified according to gestational age (<37 wk is considered premature and ≥37 wk full term). The randomization process was centralized at Novo Nordisk A/S, Denmark, with a 1:1 distribution between groups. A parallel design was used to recruit a control group; these children did not receive GH treatment during the first 12 months but followed the same treatment protocol as the study group during the following 12 months.

Treatment

A dose of 0.06 mg/kg·d of liquid recombinant GH (Norditropin SimpleXx; Novo Nordisk A/S, Bagsvaerd, Denmark) with daily rotation of the site of injection was used. GH was administered sc at bedtime, with a pen injection system (Nordipen; Novo Nordisk). Total GH dose was adjusted to weight at each visit. During the first 12 months of the study, group I received GH at the above mentioned dose, whereas group II, the control group, remained untreated. After 12 months, group I continued with the same treatment for 12 additional months, whereas group II started treatment with GH at the same dose and also continued for 12 months.

Efficacy of treatment was assessed by determining the evolution of the height SDS and height velocity SDS for both CA and BA and the changes in serum IGF-I and IGF-binding protein 3 (IGFBP-3) levels. Safety was measured by determining the effects of treatment on bone maturation, blood count, liver and kidney functions, glycosylated hemoglobin (HbA1c), insulin and glucose levels, thyroid function, and the incidence of adverse local and systemic reactions. Although the study design was planned for 3 yr of GH treatment, the results of the first 24 months of follow-up are presented (24 months GH treatment in the study group and 12 months in the control group). Because the first year of therapy in SGA patients is a major predictor of the final response to GH, the prompt availability of these results can be regarded of interest for the international community.

Auxological and laboratory parameters

At the onset of the study and during biannual check-ups, the following assessments were performed: height, weight, general health status, pubertal stage according to Tanner (19), x-ray of the left hand and wrist for BA, biochemical analyses including glucose, insulin, HbA1c, creatinine, urea, liver function, (alanine/aspartate aminotransferase), lactate dehydrogenase, albumin, alkaline phosphatase, cholesterol, high-density lipoprotein, low-density lipoprotein, apolipoproteins A and B, triglycerides, thyroid function (free T4, TSH, and T3), IGF-I, and IGFBP-3. In addition, at the 6-month visit, information regarding compliance with the treatment and potential side effects was collected. All analytical determinations were performed in the laboratory of each participating center with the exception of IGF-I and IGFBP-3, which were centralized in the Department of Endocrinology of the Hospital Infantil Universitario Niño Jesús (Madrid, Spain). BA assessment according to the method of Greulich and Pyle (18) was also centralized in the same department and performed by two independent investigators blinded for the study.

Auxological data were normalized according to age and gender for the Spanish population (17) by using the Growth Vision program (Novo Nordisk). In all patients, the SDS according to CA and gender was calculated for height, height for BA, growth velocity during the preceding year, weight, and body mass index (BMI). Bone maturation was expressed as the ratio of the change in BA to the change in CA.

Biochemical measurements

Serum for IGF-I and IGFBP-3 assessment was frozen at –20 C, and sent to the central laboratory for analysis. Serum levels of IGF-I and IGFBP-3 were converted into SDS to adjust for pubertal stage and gender, using reference values for healthy Spanish children with normal stature (20).

Total IGF-I levels were determined by RIA (Nichols Laboratories, San Clemente, CA) after acid-ethanol extraction of serum. IGFBP-3 levels were measured by RIA (Nichols Laboratories) after dilution of serum. Intra- and interassay coefficients of variation were 4.9 and 8.9% for IGF-I and 3.6 and 6.1% for IGFBP-3, respectively.

Statistical analysis and ethics

Statistical analysis included baseline descriptive analysis of all data stratified by group and gender. The Kolmogorov-Smirnov test was used to check for normality in the continuous variables. Baseline quantitative variables were compared for homogeneity using a Student’s t test for independent groups (normal distribution) or by a Mann-Whitney U test (nonparametric distribution). The categorical variables were compared by means of the Fisher’s exact test or the {chi}2 test.

Principal and secondary efficacy variables were analyzed with an ANOVA model (minimum squares) with the treatment group, controlled by gender and center (grouped by number of patients recruited). All post hoc comparisons were performed using Student’s t tests with Bonferroni multiple comparisons adjustment both between groups and between treatment visits. An ANOVA with repeated measures was performed to compare results from the various study visits, and the cumulative gain in height SDS and weight were also compared by an analysis of covariance.

Pearson correlation analyses were performed between the cumulative weight gain in SDS for the CA at the last follow-up examination. They were also correlated with the baseline variables including weeks of gestation, parents’ height, auxological data, initial height SDS, and growth velocity during the first semester (initial catch-up). Categorical data were analyzed with the Fisher’s exact test or the Pearson’s {chi}2 test.

A two-sided {alpha}-error of 5% was considered for all comparison analyses.

The study was conducted in accordance with the guidelines of the Declaration of Helsinki. Each of the 14 participating centers received authorization of their corresponding Ethics Committee of Clinical Investigation. Before commencement of the trial, the Spanish Health Ministry approved the protocol and the informed consent form. The parents or guardians were informed of the characteristics and objectives of the study and gave their written consent for participation in the clinical trial before any study-related procedure was started.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Baseline characteristics

There were no significant differences between treatment groups at baseline (Table 1Go). Of the 76 patients in the efficacy analysis, 37 were male (49%) and 39 female (51%), and 45% were less than 4 yr old. The gender distribution by treatment groups did not show statistically significant differences (despite 59% of the patients in group I being males vs. 38% in group II). Mean gestational age was similar between treatment groups (37.4 wk in group I vs. 37.1 wk in group II), and BA was also similar (2.7 in group I vs. 2.5 in group II). Five children (6.6%) did not complete the 24 months of follow-up. They were equally distributed between groups, and no statistically significant differences were identified in the comparison of demographics and baseline characteristics with those that completed the study.


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  		TABLE 1. Baseline characteristics of patients in both groups

 
Auxological data

Height SDS for CA increased steadily throughout the study in group I (Fig. 1AGo), whereas in group II, a significant change was seen only after the first 12 months when these patients began GH treatment. The cumulative height increase in group I was 2.1 SDS [95% confidence interval (CI), 1.89–2.30], which was significantly greater than the increase seen in group II (1.4 SDS; 95% CI, 1.22–1.64; P < 0.001) (Fig. 1BGo).


Figure 1
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  		FIG. 1. A, Evolution of the SDS of height for CA (H SDS CA); B, cumulative H SDS CA gain; C, SDS of growth velocity (GV) for CA (GV SDS CA) during the first 24 months of study. *, P < 0.001 vs. baseline within group comparison; #, P < 0.001 between-groups comparison. Group I received GH from the beginning of the study. Group II received GH starting at the 12-month time point. Results are shown as mean and 95% CI.

 
Height SDS for BA was significantly different between the two groups only when group II did not receive GH treatment (0.6 SDS vs. –0.5 SDS at month 12, group I vs. II, respectively, P < 0.05, data not shown).

Growth velocity SDS for CA increased from –2.2 (95% CI, –2.5 to –1.8) at baseline in group I to 4.7 (95% CI, 4.1–5.3) at 12 months. In group II, growth velocity SDS for CA did not change significantly from baseline values until GH treatment started (month 12), reaching a mean value of 5.2 at month 24 (Fig. 1CGo).

Stratifying the analysis by CA, it was found that children under 4 yr had a significantly greater response to GH treatment compared with those aged 4 yr or older not only in SDS but also in absolute increase in centimeters [height increased 1.7 SDS in children < 4 yr (mean absolute increase of 12.5 cm) compared with 1.2 SDS in those ≥ 4 yr in group I at month 12 and increased 1.5 SDS in children < 4 yr (mean absolute increase of 10.3 cm) compared with 1.3 in those ≥ 4 yr in group II at month 24; Fig. 2Go]. The gain in height of the younger children was maintained throughout the study. However, because of the difference in age and gender of the children, data are presented in SDS instead of the absolute increases in centimeters.


Figure 2
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  		FIG. 2. Evolution of the SDS of height for CA (cumulative H SDS CA gain) in children less than or greater than 4 yr of age in each group. *, P < 0.05 group I (GI) less than 4 yr vs. group I 4 yr or older; ^, P < 0.05 group I 4 yr or older vs. group II (GII) 4 yr or older; #, P < 0.05 group I less than 4 yr vs. group II less than 4 yr and 4 yr or older; $, P < 0.05 group I 4 yr or older vs. group II less than 4 yr and 4 yr or older. Group I received GH from the beginning of the study. Group II received GH starting at the 12-month time point. Results are shown as mean and 95% CI.

 
Weight SDS increased following the same pattern described for height (mean weight SDS for CA increased from –2.0 at baseline to –1.3 at month 12 in group I and from –2.2 at baseline to –1.3 at month 24 in group II). BMI SDS did not change significantly during the study period, and the initial increase identified in group I was normalized after 12 months (Table 2Go).


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  		TABLE 2. Evolution of secondary auxological data during the 24 months of study

 
The correlation analysis of cumulative height SDS increase showed an inverse correlation with baseline CA and BA in group I, indicating a higher height SDS increase when the treatment starts at a younger age (data not shown).

Serum IGF-I and IGFBP-3

Serum IGF-I levels increased significantly after 6 months of treatment with GH (from –0.8 SDS at baseline to –0.3 SDS at month 6 in group I and from –0.8 SDS at baseline to 0.01 SDS at month 18 in group II) and remained so throughout the study (Fig. 3AGo). Similarly, serum IGFBP-3 levels increased significantly with GH treatment in both groups after 6 months (Fig. 3BGo). The stratified analysis by age (<4 vs. ≥4 yr) showed that both IGF-I and IGFBP-3 increased more after 12 months of treatment in the <4-yr stratum, although the initial response at 6 months was higher in the ≥4-yr stratum (data not shown).


Figure 3
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  		FIG. 3. A, Mean plasma IGF-I SDS; B, IGFBP-3 SDS during the 24 months of study. **, P < 0.001 between-group comparison; #, P < 0.001 vs. baseline within-group comparison. Group I received GH from the beginning of the study. Group II received GH starting at the 12-month time point. Results are shown as mean and 95% CI.

 
Safety

BA advanced at each clinical visit compared with baseline, but there were no differences between the treated (group I) and untreated (group II) subgroups. The BA/CA ratio increased progressively from baseline, with no significant differences between treatment groups and always remaining below one (Table 2Go).

Values of fasting blood glucose, HbA1c, insulin, T3, T4, and TSH remained within the normal range throughout the study (Table 3Go), again with no differences between the study subgroups (data not shown). No patient reported any intolerance to the daily treatment with sc GH.


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  		TABLE 3. Evolution of glucose metabolic parameters (fasting plasma insulin, blood glucose, and HbA1C) during the 24 months of study

 
The adverse event incidences were higher in group I (71%) than in group II (29%), but none of them was considered to have a possible relationship to the drug under study. The most frequent adverse event was infections of the upper respiratory tract (31%). There were two serious adverse events (hospitalizations due to fever and convulsions; one per group during the treatment period), but they were considered to not be related to the study drug.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
We present the results describing the effect of 2 yr of GH therapy in very young SGA children in a multicenter, randomized, controlled, open clinical trial. To our knowledge, this is the youngest population of SGA children described in which a positive effect of GH treatment has been shown. Although most children born SGA exhibit catch-up growth during the first 2 yr of life sufficient to obtain a normal height, up to 10% of these children remain below –2 SDS and attain a short adult stature (8, 9, 10, 11, 12). The available evidence indicates consistently that GH therapy is a valid growth-promoting treatment in these children, even in those who show a normal response to GH stimulation tests and in whom no detectable cause for the absence of catch-up growth can be identified (5, 13).

In this study, we have demonstrated that very young SGA children without spontaneous catch-up growth significantly increase their height under GH treatment (0.06 mg/kg·wk). In addition, although BA increased in both study groups, there was no abnormal acceleration of BA even after 24 months of therapy, with the BA/CA ratio remaining approximately one throughout the study. These data are in agreement with those observed by other authors in older children (10, 11).

The literature reports different and contradictory values of IGF-I and IGFBP-3 in short, untreated SGA children (21, 22). In contrast, GH administration is known to result in dose-dependent increases in IGF-I and IGFBP-3 (11) and thus has raised concerns regarding the potential harmful effects of continuously high plasma IGF-I and GH levels for years (14, 23). In our cohort, circulating IGF-I and IGFBP-3 levels were in the low-normal range for CA at baseline and were not modified in the control group during the first 12 months when they did not receive GH treatment. In treated children, plasma IGF-I and IGFBP-3 levels increased significantly after 6 months of therapy and remained at a similar level throughout the study, although they did not exceed in any case +2 SDS for CA. Along these lines, the use of even higher doses (up to 0.1 mg/kg·d) of exogenous GH early in childhood is followed by a decrease in IGF-I and IGFBP-3 to low-normal levels upon discontinuation (9) and has so far proven safe (13).

No change in any other endocrine-metabolic parameters was detected, including estimates of insulin sensitivity. Although similar and even higher doses of exogenous GH in non-GH-deficient older SGA children have been shown to be associated with reversible decreases in insulin sensitivity (24, 25), discontinuation of treatment is followed by normalization of the metabolic profile (26); moreover, in young SGA adults treated with exogenous GH, blood pressure, serum cholesterol, glucose, and insulin, among other parameters, were equivalent to those of untreated young SGA adults, suggesting that long-term GH treatment does not increase the risk for diabetes mellitus type 2 and metabolic syndrome (27). In contrast to what was previously reported (28), in this study where a larger study population was included in the analysis, no significant change in neutrophils was seen at any time throughout the study.

Although final height data in these children are necessary, the results reported here suggest that GH therapy is effective and safe in young children born SGA, as demonstrated by other authors in older SGA children. The increase in growth velocity was highest during the first 12 months of treatment, as described previously for other GH-treated subjects, including GH-deficient patients (29, 30). One of the most striking observations of this study is that the increase in height (SDS) in response to GH treatment was significantly greater in patients younger than 4 yr of age compared with those older than 4 yr of age. Long-term follow-up is required to ascertain whether an early start (before 4 yr of age) results in a significantly greater adult height (31).

In conclusion, although the underlying cause of growth retardation in this population of children remains unknown, they appear to require higher doses of GH compared with GH-deficient children to obtain a significant response. Because GH and IGF-I levels are normal in these subjects, a possible insensitivity at some point in this axis can be postulated. Here we have demonstrated that recombinant GH treatment at a dose of 0.06 mg/kg·d in a cohort of 76 very young SGA children without catch-up growth, is safe and effective, during at least the first 24 months of therapy. In addition, the younger the child, the greater the gain in height. Thus, it is conceivable that early implementation of relatively high-dose GH therapy may have long-term benefits in these children.


   Acknowledgments
 
Members of the Spanish SGA Working Group included V. Albiach, Hospital Infantil La Fé, Valencia, Spain; J. Bel, Hospital Germans Trias i Pujol, Barcelona, Spain; R. Cañete, Hospital Universitario Reina Sofía, Córdoba, Spain; A. Carrascosa, Hospital Infantil Universitario Vall d’Hebron, Barcelona, Spain; J. M. Fernández, Hospital Clínico Universitario San Cecilio, Granada, Spain; A. Gutiérrez, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain; V. Marcos, Hospital de Terrassa, Barcelona, Spain; M. J. Martínez-Aedo, Hospital Infantil Universitario Carlos Haya, Málaga, Spain; P. Martul, Hospital de Cruces, Bilbao, Spain; M. T. Muñoz and V. Barrios, Hospital Infantil Universitario Niño Jesús, Madrid, Spain; A. Rodríguez and M. D. Rodríguez-Arnao, Hospital Universitario Gregorio Marañón, Madrid, Spain; I. Rodríguez, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain; J. C. del Valle, Hospital Universitario Virgen del Rocío, Sevilla, Spain; and D. Yeste, Hospital Infantil Universitario Vall d’Hebron, Barcelona, Spain.

L.I. is a clinical investigator of REDIMET, R676D (FIS, Instituto de Salud Carlos III, Madrid, Spain.


   Footnotes
 
This study was supported by Novo Nordisk Pharma S.A. Spain.

Disclosure Statement: The authors have nothing to declare.

First Published Online May 29, 2007

1 See Acknowledgments for members of the Spanish SGA Working Group. Back

Abbreviations: BA, Bone age; BMI, body mass index; CA, chronological age; CI, confidence interval; HbA1c, glycosylated hemoglobin; IGFBP-3, IGF-binding protein 3; SDS, SD score; SGA, small for gestational age.

Received January 12, 2007.

Accepted May 22, 2007.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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