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Early, Discontinuous, High Dose Growth Hormone Treatment to Normalize Height and Weight of Short Children Born Small for Gestational Age: Results Over 6 Years

The Belgian Study Group for Pediatric Endocrinology and the Departments of Pediatrics, Universities of Leuven (F.d.Z., K.V.), Antwerp (M.V.L.D.C.), Bruxelles (C.H.), Louvain (M.M., P.M.), Brussels (J.D.S.), and Ghent (M.C.), Belgium; and the Department of Pediatrics, Oregon Health Sciences University (R.G.R.), Portland, Oregon 97201

Address all correspondence and requests for reprints to: Francis de Zegher, M.D., Ph.D., Department of Pediatrics, University Hospital Gasthuisberg, 3000 Leuven, Belgium.

	Abstract

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Most children born small for gestational age (SGA) normalize their size through spontaneous catch-up growth within the first 2 yr after birth. Some SGA children fail to do so and maintain an abnormally short stature throughout childhood. We have previously reported that high dose GH treatment (66 or 100 µg/kg·day sc over 2 yr; age at start, 2–8 yr; n = 38) induces pronounced catch-up growth in short children born SGA, thereby normalizing their height and weight in childhood. Here, we report on the further prepubertal growth course of these children over the first 4 yr after withdrawal of early, high dose GH treatment.

Of the 38 treated children, none developed precocious puberty, and 22 remained prepubertal. Mean age of the latter at start of GH was 4.4 yr, height was -3.7 SD score, and height after adjustment for midparental height was -2.9 SD score. Height increased by an average of 2.5 SD during the 2 yr of GH treatment and decreased by 0.4 and 0.3 SD, respectively, during the first and second year after GH withdrawal. Subsequently, when stature was not extremely short at the start (mean adjusted height SD score, -2.7; n = 13), no further GH treatment was given, and the adjusted height was stabilized around -1.0 SD score; when stature was very short at the start (mean adjusted height, -3.3 SD score; n = 9), a second course of GH treatment (66 µg/kg·day sc) was initiated either 2 yr (n = 5) or 3 yr (n = 4) after initial GH withdrawal. This second course was associated with renewed catch-up growth and also resulted in a mean adjusted height of -1.0 SD score. In each subgroup, the pattern of the weight course paralleled that of the height course; GH treatment was well tolerated.

In conclusion, early, discontinuous, high dose GH treatment appears to be a safe and efficient option to normalize prepubertal height and weight in the majority of short SGA children. It remains to be examined whether the normalized stature will be maintained during pubertal development, either with or without further GH treatment.

	Introduction

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BY DEFINITION, approximately 3% of human infants are born small for gestational age (SGA). The majority of SGA children experience sufficient catch-up growth during infancy to normalize their stature (1). Approximately 10% of SGA children maintain a height below -2 SD throughout childhood (2, 3).

A series of independent, randomized, controlled, multicenter studies recently documented that GH treatment of short, prepubertal, non-GH-deficient, SGA children for 2 yr results in a dose-dependent acceleration of statural growth and weight gain (reviewed in Refs. 4, 5, 6, 7). These studies confirmed earlier dose-response observations that led investigators to prefer relatively high GH doses for the treatment of short stature in SGA children (8, 9, 10).

We previously reported the 2-yr results of a randomized, controlled, multicenter trial documenting the marked catch-up growth and weight gain induced by high dose GH treatment in short SGA children; we also mentioned that, as a consequence of the pronounced growth response over 2 yr, GH treatment was electively interrupted in this study population (11). Here we report on the growth course of those children who remained prepubertal over the first 4 yr after withdrawal of early, high dose GH treatment.

	Materials and Methods

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This follow-up paper reports on SGA children who were originally randomized to be treated with high dose GH (Genotropin, Pharmacia & Upjohn, Inc., Stockholm, Sweden; 66 or 100 µg/kg·day, sc) over 2 yr within an open labeled, controlled, multicenter trial (11). Specifically, we report on those children who were still prepubertal 4 yr after termination of the initial GH course. The inclusion criteria for the original 2-yr treatment phase were 1) birth weight and/or length below -2 SD for gestational age (12); 2) height SD score for age below -2.5 (13); 3) height velocity SD score for age below +1 (13) to exclude children presenting spontaneous catch-up growth; 4) chronological age between 2–8 yr at study start; 5) serum GH concentration above 10 µg/L spontaneously or after exercise, glucagon, or insulin tolerance test; 6) available growth data concerning the period preceding study start (preferentially 9–15 months); and 7) written informed consent. The exclusion criteria were endocrine disorders, Turner’s (lymphocyte karyotype) or Down’s syndrome, previous or concomitant irradiation or anabolic steroid therapy, and severe chronic disease or mental retardation.

At the end of the original 2-yr phase, none of the children received further GH treatment for 2 yr, i.e. during the third and fourth years of the study. At the beginning of the fifth and sixth years, prepubertal children were offered the possibility to restart GH treatment (66 µg/kg·day, sc) if height was below -2.0 SD score for chronological age (13).

Study visits, including history and auxological evaluation (and adjustment of GH dose when appropriate), were scheduled every 6 months; biochemical examinations and bone age determinations were performed yearly. All bone ages were read according to the Tanner-Whitehouse II 20-bone method by a single radiologist, who was blinded for chronological age and GH treatment.

The growth pattern was assessed according to the course of weight SD score and height SD score (adjusted for midparental height SD score), as derived from standardized weight and height measurements (13).

Measurements of serum insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) concentrations were performed in samples that had been collected at yearly intervals and had been kept frozen until assay. After acid size-exclusion chromatography, serum IGF-I was measured by RIA, as previously described (14). The minimal detectable concentration was 0.1 µg/L for IGF-I. The intra- and interassay coefficients of variation for IGF-I were 5% and 13%, respectively. Serum IGFBP-3 concentrations were measured using immunoradiometric assay kits supplied by Diagnostics Systems Laboratories, Inc. (Webster, TX). Results are expressed as the mean ± SEM.

The protocols for the sequential study phases were approved by the ethics committee of the Medical School, University of Leuven (Leuven, Belgium). Before initiation of each study phase, written informed consent was obtained from at least one of the parents or legal representatives of the participating child.

	Results

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Study population and treatment regimens

Of the 38 children who were treated with high dose GH over 2 yr, none developed precocious puberty, and 22 remained prepubertal during the first 4 yr after termination of the initial GH treatment. Of the latter children, 12 received a GH dose of 66 µg/kg·day, and 10 received 100 µg/kg/day. Growth results obtained with these two high doses were pooled; the average dose amounting to 77 µg/kg·day after linear correction for weight gain between study visits (11).

The 22 children had no dysmorphic syndrome (n = 15), Silver-Russell syndrome (n = 4), Dubowitz syndrome (n = 2), or 4p- syndrome (n = 1). Characteristics at birth and at the start of the 6-yr follow-up were as follows: birth weight, 1913 ± 133 g; birth length, 41.9 ± 1.0 cm; gestational age, 37.8 ± 0.7 weeks; chronological age, 4.4 ± 0.4 yr; bone age, 3.0 ± 0.4 yr; weight, 11.3 ± 0.6 kg; weight SD score, -3.0 ± 0.2; height SD score, -3.7 ± 0.2 (midparental height SD score, -0.8 ± 0.2); height velocity SD score, -1.0 ± 0.7; and BMI SD score, -2.0 ± 0.2. Of the 22 children, 13 remained off GH treatment during the entire follow-up, and 9 children restarted GH treatment, 5 of whom did so at the beginning of the fifth year and 4 of whom did so at the beginning of the sixth year.

Height and weight

Figure 1 (open squares) summarizes the height and weight courses of the 13 children who remained off treatment for 4 yr. GH withdrawal was first followed by a slow-down phenomenon and then by spontaneous stabilization at height and weight levels higher than those at baseline. After 6 yr, the mean adjusted height SD score was -1.0 compared to a baseline of -2.7. Figure 1 (closed squares) depicts the height and weight courses of 5 children who reinitiated GH treatment 2 yr after termination of the first GH course, as their height was below -2 SD score for chronological age (without adjustment for parental height). This group had, at the start, a shorter stature than the group that remained off treatment. The second phase of GH treatment resulted in renewed catch-up growth for both height and weight.

View larger version (18K): [in this window] [in a new window]   Figure 1. Prepubertal height (upper panel) and weight (lower panel; mean ± SEM) over 6 yr in SGA children who received high dose GH treatment, either in a single course (n = 13; mean GH dose, 77 µg/kg·day; open bar and squares) or in a double course (n = 5; mean GH dose, first 77 µg/kg·day and then 66 µg/kg·day; closed bars and squares). Height SD scores have been adjusted for parental height.

Bone maturation, hematology, biochemistry, and thyroid axis

After 6 yr of follow-up, the mean bone age of the 22 children was 9.8 ± 0.4 yr, with a mean chronological age of 10.4 ± 0.4 yr; there was no difference in bone maturation between children who did receive a second course of GH treatment and those who did not. Mean hemoglobin, hematocrit, erythrocyte, leukocyte, and thrombocyte counts and glucose in peripheral blood; serum T₄, TSH, creatinine, and urea; as well as urinary glucose, protein, and microscopic examination remained within normal limits.

IGF-I and IGFBP-3

Figure 2 depicts the yearly serum IGF-I and IGFBP-3 concentrations in children who received GH over the first 2 yr. At the start, circulating IGF-1 and IGFBP-3 levels were in the low normal range for chronological age. The pronounced IGF-I and IGFBP-3 responses during the first treatment phase have previously been described (11). After GH withdrawal, circulating IGF-I and IGFBP-3 levels decreased again into the normal range.

View larger version (13K): [in this window] [in a new window]   Figure 2. Prepubertal serum IGF-I (upper panel) and IGFBP-3 (lower panel) concentrations (mean ± SEM) over 6 yr in the SGA children whose growth course is depicted in Fig. 1 and who received GH only during the first 2 yr (n = 18 from 0–4 yr; n = 13 from 4–6 yr; see Results for values of children receiving GH after 4 or 5 yr).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Most children who are abnormally small at birth are thought to be growth retarded because of an adverse prenatal environment (15) and experience catch-up growth as soon as the postnatal environment provides sufficient nutritional support. Spontaneous catch-up growth usually starts early after birth, proceeds over 2 yr or less, and ends at a growth level that subsequently remains stable throughout the childhood years (1, 2, 3). The mechanisms of spontaneous catch-up growth after prenatal growth restriction remain poorly understood (reviewed in Ref. 16); there is some evidence pointing toward GH hypersecretion as one of the possible mechanisms driving the early catch-up phase (reviewed in Ref. 5). In the minority of SGA children who fail to normalize their stature by 2 yr of age despite sufficient GH secretion, pronounced catch-up growth can be induced by a course of high dose GH treatment (reviewed in Refs. 6, 7). Here, we report that the so-induced normalization of prepubertal height and weight can be maintained over at least 4 yr in the majority of non-GH-deficient SGA children. In other words, the early administration of high dose GH appears to have the capacity to reprogram the growth trajectory of short SGA children, so that the ensuing prepubertal height and weight pattern evolves at a level that is either within or closer to the genetic target range.

The average growth pattern after GH withdrawal appears to be biphasic; there is some slow-down during the first years and a stabilization at the higher height and weight levels during the following years. The mechanisms underlying this biphasic pattern are currently unknown. It remains to be studied whether this pattern is primarily governed at the neuroendocrine level, for example through modulation of GH secretion, at the level of peripheral IGF and/or IGFBP generation, or at the level of the growth plate.

The presented evidence indicates that the prepubertal body size of short SGA children can be normalized without excessive bone maturation by a single or a double course of high dose GH treatment. The available data, however, do not permit making general recommendations on GH treatment regimens for this indication; especially the impact of early treatment on adult height is still uncertain. Nevertheless, for the design of future studies, the following points may be taken into account. First, it seems reasonable to aim for a parental-adjusted height within the lower normal range (around -1 SD) during the prepubertal phase. Second, in the case of GH deficiency in SGA children, there is at present no pathophysiological basis for preference of an intermittent to a continuous GH treatment regimen (7). Third, the amplitude of the initial growth response to treatment depends on the GH dose, the age of the child (the younger, the more responsive), and the parental-adjusted height (the lower the parental-adjusted height SD score, the more responsive) in that order (4, 8, 9, 17, 18). Fourth, the amplitude of the slow-down during the first years after GH withdrawal appears to be independent of the previously administered GH dose (6, 10). Fifth, short SGA children appear to be capable of mounting marked IGF-I and IGFBP-3 responses to exogenous GH and to have levels in the low normal range before and after a prepubertal phase of GH treatment, thus confirming that the growth failure in short SGA children does not seem to be primarily attributable to a severe form of GH resistance (5, 7, 19, 20).

The safety profile of an early single or double phase of high dose GH treatment for short SGA children continues to be reassuring. Until now, we have failed to detect any major clinical or biochemical side-effect. Beneficial effects of high dose GH treatment have now also been documented for craniofacial growth in short SGA children (reviewed in Ref. 21). Further follow-up of these children is needed, in particular to assess the long term effects of early GH treatment on other pediatric endocrinopathies that have been related to reduced fetal growth (22, 23, 24, 25, 26, 27, 28).

In conclusion, these observations over 6 yr support an early, single or double course of high dose GH treatment as an effective and safe option to normalize the prepubertal height and weight of short, non-GH-deficient SGA children. It remains to be verified whether the normalized stature will be maintained during pubertal development, either with or without further GH treatment.

	Acknowledgments

 
Recombinant human GH was a generous gift from Pharmacia & Upjohn, Inc. (Stockholm, Sweden). The authors thank the Members of the Belgian Study Group for Pediatric Endocrinology for helpful discussions.

	Footnotes

 
¹ F. de Zegher is a Clinical Research Investigator of the Fund for Scientific Research, Flanders, Belgium.

Received October 14, 1998.

Revised January 28, 1999.

Accepted February 10, 1999.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by de Zegher, F. Articles by Rosenfeld, R. G. Search for Related Content PubMed PubMed Citation Articles by de Zegher, F. Articles by Rosenfeld, R. G.