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Growth Hormone Treatment of Short Children Born Small for Gestational Age: Growth Responses with Continuous and Discontinuous Regimens Over 6 Years¹

Department of Pediatrics, University of Leuven (F.d.Z.), 3000 Leuven, Belgium; Department of Pediatrics, University of Göteborg (K.A.-W.), 41685 Göteborg, Sweden; Department of Pediatrics, University of Tübingen (H.A.W.), 72070 Tübingen, Germany; Department of Pediatrics, University of Lyon (P.C.), 69322 Lyon, France; and Department of Pediatrics, University of Paris (J.-L.C.), 75014 Paris, France; Pharmacia, Inc. (A.L.), 11287 Stockholm, Sweden; Karolinska Institute (B.J.), 17176 Stockholm, Sweden; and 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. E-mail: francis.dezegher{at}uz.kuleuven.ac.be

	Abstract

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We report an epi-analysis of 6-yr growth responses obtained with GH treatment in short children born small for gestational age (SGA). Four randomized, multicenter studies explored the effects of continuous and discontinuous regimens of GH treatment in short, non-GH-deficient SGA children. A total of 49 untreated and 139 treated children were followed over 2 and 6 yr, respectively. At the start of the study, the age of these 188 children averaged 5.2 yr (range, 2–8 yr), height was -3.4 SD score, and height adjusted for parental height was -2.4 SD score. Onset of puberty was observed in 46% of the GH-treated cohort, on the average, at 10.7 yr in girls and 11.7 yr in boys.

Two studies essentially investigated the effects of continuous GH treatment at a dose of 33 or 67 µg/kg·day, and two studies focused on the growth characteristics during an initial GH treatment for 2–3 yr (dose range, 33–100 µg/kg·day), followed by a withdrawal phase of 1–2 yr, and then by either no or 1 or more episodes of further GH treatment (33 or 67 µg/kg·day).

Continuous GH treatment for 6 yr resulted in height increments of 2.0 ± 0.2 SD (33 µg/kg·day; n = 35) and 2.7 ± 0.2 SD (67 µg/kg·day; n = 27). Discontinuous GH treatment was given to 77 children, most of them experiencing only 1 (n = 47) or 2 (n = 26) treatment phases with an average duration of 2.0 yr. All these children received GH during the first 2 yr; the dose was only 32 µg/kg·day when averaged over 6 yr. Some individualization of treatment schedules was allowed, and the majority of investigators seemed to aim for a low normal height level, adjusted for parental height. After 2 yr, the mean adjusted height SD score had increased to -0.4 ± 0.1 and stabilized thereafter.

Bone maturation progressed similarly in all treatment subgroups, and after 6 yr of study, bone age remained slightly delayed compared to chronological age. Multivariate analysis identified the average GH dose over 6 yr, parental-adjusted height SD score, and age at start as prime predictors of the growth response. GH treatment was well tolerated.

In conclusion, this epi-analysis of growth responses over 6 yr confirms the administration of GH as an effective approach to normalize the stature of short, non-GH-deficient SGA children, at least during childhood and early puberty. In addition, it is now increasingly apparent that a relatively broad spectrum of GH regimens is effective, and this experience should facilitate the design of more individualized treatment schedules in the future, in particular for young children.

	Introduction

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BY DEFINITION, nearly 3% of human infants are born small for gestational age (SGA; SD score below -2 for weight and/or length at preterm or term birth). Most SGA infants present sufficient postnatal catch-up growth to normalize their stature by 2 yr of age, independently of whether they were born prematurely or at term (1). Some 10% of SGA children remain short, i.e. have a height below -2 SD score, throughout childhood (2).

GH is currently administered in childhood to treat short stature related to GH deficiency, Turner syndrome, or renal failure. Most children with one of these conditions are of normal size in early life, present gradual growth failure resulting in short stature by late childhood, and, if left untreated, reach an adult height below both target and normal range. Accordingly, GH therapy is now mostly initiated in late childhood, the prime objective being to optimize the late stage of growth, thus safely normalizing final height (3).

Here, we report an epi-analysis of 6-yr growth responses obtained with GH treatment in short SGA children (an epi-analysis is a meta-analysis of individual, not group, results from studies with a common core). In this indication, GH treatment initially focuses on the early (rather than late) childhood stage of growth. Indeed, the small body size of SGA children is present in the newborn, is more or less attenuated by spontaneous catch-up growth in infancy, and then remains stable throughout childhood and adolescence. In short children born SGA, height at the age of 2–5 yr permits an estimation of the long-term height loss, whereas predictions of final height based on estimations of bone age are notoriously unreliable (4, 5, 6, 7, 8, 9).

Four studies recently explored the effects of continuous and/or discontinuous regimens of GH treatment in non-GH-deficient SGA children who had failed to normalize their stature through spontaneous catch-up growth during infancy. This epi-analysis of 6-yr results compares with previous analyses of 2- to 4-yr data, that identified the prime factor determining the growth response of short SGA children, namely the average GH dose given over the studied timespan: the higher the GH dose, the higher the growth response (10, 11, 12, 13).

	Subjects and Methods

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The present analysis reports on a study population consisting of 49 untreated control children and 139 children treated with GH, followed over, respectively, 2 and 6 yr. Each of these 188 children was included in 1 of 4 studies conducted separately between 1990 and 1999 in a total of 68 centers in Belgium, France, Germany, or the Nordic countries (Denmark, Finland, Norway, and Sweden).

The common inclusion and exclusion criteria for this epi-analysis were the same as for the 2-yr analysis previously reported, including country-specific references (10). Briefly, the inclusion criteria were 1) birth weight or length below -2 SD score for gestational age, 2) height for chronological age below -2 SD, 3) chronological age between 2–8 yr and prepubertal condition at start of study, 4) serum GH concentration above 10 µg/L either in a random sample or after a GH stimulation test, and 5) written informed consent. The exclusion criteria were endocrine or chronic disease; previous or ongoing chemotherapy, irradiation, or GH or anabolic steroid treatment; and chromosomal anomaly, skeletal dysplasia, severe mental retardation, or malformation syndrome, except for Silver-Russell, fetal alcohol, and Dubowitz syndromes (exceptions not applicable to France and the Nordic countries). Only longitudinal data from control and treated children followed over, respectively, 2 and 6 yr were taken into account. Table 1 explains why results from some control and treated children in the studies were not included in the epi-analysis. Table 2 summarizes each trial’s quantitative contribution to the population of this epi-analysis.

After the initial 2 yr, the Nordic and German studies essentially investigated the effects of continued GH treatment at a daily dose of 33 or 67 µg/kg, whereas the Belgian and French studies mainly explored the growth characteristics after withdrawal of the initial GH treatment and, subsequently, the effects of one or more further episodes of GH treatment, if any. In Belgium, all children were first maintained off treatment for 2 yr; thereafter, continuous GH treatment could be resumed at a daily dose of 67 µg/kg, provided height was below -2 SD and/or puberty had started (17). In France, the principal guidelines were that treatment at a daily dose of 33 or 67 µg/kg could be continued until height was above -1 SD, that any off-treatment phase should have a duration of at least 1 yr (except for 4 children who received, according to protocol, an alternating on-off GH treatment in phases of 3 months), and that GH treatment could only be resumed (at the original dose) if height was below -2 SD. These guidelines allowed for individualized treatment schedules and resulted in a variety of continuous or discontinuous GH regimens.

Study visits, including auxological evaluation and dose adjustment, were scheduled at least every 6 months; biochemical and bone age examinations were performed at least annually during the first years. This report focuses on auxological changes and bone age progression over 6 yr. The effects of GH administration on growth were assessed by determining changes in height SD score with and without adjustment for midparental height SD score, changes in weight SD score, and changes in body mass index (BMI) SD score, as previously described (10). Bone age was determined centrally and independently for each trial, according to the Tanner-Whitehouse II (20-bone) method for Belgium, Germany, and the Nordic countries, and according to the method of Greulich and Pyle for France. The onset of puberty was defined for girls as breast stage 2 or more, and for boys as a testicular volume of 4 mL or more (Prader orchidometer).

Results are expressed as the mean ± SEM. Comparisons between study groups were analyzed using Student’s t test. Multivariate analysis of pooled data was performed through stepwise forward regression. P < 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Table 3 summarizes the characteristics of the study cohort (n = 188); there were no significant differences between the randomized treatment subgroups either at birth or at the start of the study. Figure 1 displays the changes in height SD score and weight SD score of untreated controls and of all children who received any of the GH regimens; GH treatment was well tolerated (Table 1). After 2 yr, the height, weight, and BMI increments in the control group were no more than 0.1 ± 0.1, 0.3 ± 0.1, and 0.2 ± 0.1 SD, respectively. After 6 yr, GH-treated children increased their baseline height by 1.9 ± 0.1 SD, their baseline weight by 1.7 ± 0.1 SD, and their baseline BMI by 0.8 ± 0.1 SD toward the norm. Puberty started in 46% of the GH-treated children within the 6 yr of study. Onset of puberty was observed in 36 of 64 girls (56%) at 10.7 ± 0.2 yr and in 28 of 75 boys (37%) at 11.7 ± 0.2 yr.

View larger version (16K): [in this window] [in a new window]   Figure 1. Increments in height SD score (left) and weight SD score (right) in short SGA children, who were randomized either to remain untreated (for 2 yr) or to receive continuous or discontinuous GH treatment. The average daily GH dose was 41 µg/kg over 6 yr. Pubertal development started in 46% of the treated children during the 6 yr of study.

View larger version (14K): [in this window] [in a new window]   Figure 2. Height SD score increments over 6 yr in randomized cohorts of short SGA children receiving continuous GH treatment at a dose of either 33 or 67 µg/kg·day (top) and in short SGA children receiving an initial GH treatment over at least 2 yr and thereafter either no further GH (n = 47) or another episode(s) of GH treatment (n = 30; bottom).

View larger version (44K): [in this window] [in a new window]   Figure 3. The top of the figure depicts height SD scores, adjusted for midparental height SD score, for untreated controls and for 77 short SGA children who received an initial GH treatment over at least 2 yr and thereafter either no further GH (n = 47) or another episode(s) of GH treatment (n = 30). The bottom of the figure displays the distribution of daily GH doses and the average () GH dose given per study year to the 77 treated children. In the majority of short SGA children, discontinuous GH treatment was capable of normalizing childhood stature (adjusted height above -1 SD).

View larger version (13K): [in this window] [in a new window]   Figure 4. Height SD scores after 6 yr were similar with an early, high dose GH course for 2 yr and with continuous low dose GH treatment for 6 yr. However, the latter regimen required 3-fold more injections and nearly 50% more GH.

Multivariate analysis identified the average GH dose over 6 yr (ß = 0.344; P < 0.0001), the parental adjusted height SD score at study start (ß = -0.493; P < 0.0001), and the chronological age at study start (ß = -0.130; P = 0.05) as the prime variables related to the growth response over 6 yr; among the variables that were rejected as possible predictors were: height velocity, height SD score, weight and BMI at baseline, birth weight and length SD score, bone age, and gender. More pronounced growth responses were thus observed when higher GH doses were given to younger children with a shorter stature adjusted for the midparental height. However, the three predictors explained together no more than 45% of the variation in the growth responses over 6 yr, suggesting that major determinants remain to be identified.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Although small body size of prenatal origin was among the first conditions treated with GH (18, 19), it was paradoxically one of the last forms of short stature to be explored with GH in a randomized, controlled fashion with (20) or without (reviewed in Ref. 12) placebo treatment.

The data from the randomly assigned, untreated control group confirm previous observations that SGA children who are still short after infancy fail to present significant catch-up growth during the childhood years (2, 4, 5, 6, 7, 8, 9). In view of the pronounced growth responses observed in the GH treatment groups, as in previous trials, the control group was abandoned after 2 yr.

The present results of GH treatment in SGA children are unprecedented because of the young age at the start of treatment, the duration of the study, the relatively large size of the cohort, and the unique spectrum of explored regimens. Overall, exogenous GH was strikingly growth promoting in these non-GH-deficient children. Clinically, no safety concerns were identified during the observation episode, even after prolonged high dose treatment. We emphasize that there was no shift toward a precocious onset of puberty, particularly if one takes into account that only 46% of the cohort started puberty and that the fraction of children with early onset of puberty is recognized before that of children with late onset, as in any longitudinal study.

Two studies essentially evaluated the effects of two doses of continuous GH treatment over 6 yr. Both regimens proved to be effective growth-promoting strategies; the observed height increments averaged 2.0–2.7 SD score with daily GH doses of, respectively, 33 and 67 µg/kg·day. The lower dose is thus relatively more effective than the higher dose when judged in terms of height gain per amount of exogenous GH. Moreover, there is evidence indicating that the GH dose (within the studied range) has more impact on short-term than on long-term growth of short SGA children (10, 21).

In the two remaining studies, the swift GH-induced height increment was considered to allow for discontinuation of GH treatment and for an ensuing recovery phase with decelerated growth until a predefined level of short stature had been reached again; in the latter case, another course of GH was possible, thus leading to an intermittent treatment, mostly using high GH doses (17). These studies thus primarily aimed at normalizing childhood stature, using few injections in an individualized fashion. This flexible strategy proved successful, as most children receiving one of these regimens managed to grow within 1 SD of the midparental height level during childhood and early puberty.

As both continuous and discontinuous GH regimens were found to be effective growth-promoting treatments over 6 yr, there will be a choice of treatment modalities in the future. Continuous treatment with relatively low daily doses has the advantage of being a well established treatment and may therefore be expected to become a first choice regimen, particularly if the primary objective is final height and if neither long-term compliance nor a relatively high cumulative dose poses any problem. Discontinuous high dose treatment is likely to become also a first choice regimen if the primary objective is rapid normalization of height and weight in early childhood, with few injections and a smaller absolute amount of GH. This regimen has the additional advantage of not requiring sustained compliance over many years, but also has the theoretical disadvantage of not resembling a physiological replacement therapy. Finally, it is anticipated that continuous high dose treatment will be rather rarely applied, for example in case of severe growth failure and/or poor growth responsiveness, which are indications for additional diagnostic explorations.

The studies yielding the reviewed results were launched a decade ago, based on knowledge then considered crucial. For example, classic proof of GH sufficiency was one of the inclusion criteria. Today, growth responses are known to be comparable in short SGA children with and without conventional GH deficiency (13, 22). Nevertheless, we would still recommend excluding GH deficiency, as a continuous low dose regimen is a conceivably more appropriate choice for GH-deficient SGA children than a discontinuous high dose regimen.

The GH dose, the parental adjusted height SD score, and the child’s age were identified as predictors of the growth response, in accord with previous short-term findings in the same cohort (10) and with other long-term studies in SGA children (9, 21). During the coming years, major advances are expected in the delineation of the different etiologies of the sequence linking prenatal growth reduction to postnatal growth failure. It is expected that those advances will contribute to identify other predictors of the growth response to GH treatment.

In conclusion, this epi-analysis of growth responses over 6 yr confirms the administration of GH as an effective approach to normalize the stature of short, non-GH-deficient SGA children, at least during childhood and early puberty. In addition, it is now increasingly apparent that a broad spectrum of GH regimens is effective, and this experience should facilitate the design of more individualized treatment schedules in the future, in particular for young children.

	Acknowledgments

 
We thank all contributing investigators from the 68 centers in Belgium, France, Germany, Sweden, Finland, Denmark, and Norway as well as the Clinical Research Staff of Pharmacia, Inc., in the same countries. The editorial assistance of Karin Vanweser is gratefully acknowledged.

	Footnotes

 
¹ This work was supported by the Swedish Medical Research Council (Grant 7509 to K.A.W.).

² Clinical Research Investigator with the Fund for Scientific Research (Flanders, Belgium).

Received December 2, 1999.

Revised February 24, 2000.

Accepted May 5, 2000.

	References

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