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Short Children Born Small for Gestational Age and Treated with Growth Hormone for Three Years Have an Important Catch-Down Five Years after Discontinuation of Treatment

Pediatric Endocrinology and Diabetes Unit (A.F.-P., D.S., P.C.), Hospital Robert Debré, 75019 Paris, France

Address all correspondence and requests for reprints to: Anne Fjellestad-Paulsen, M.D., Ph.D., Pediatric Endocrinology and Diabetes Unit, Hôpital Robert Debré, 48 Bd Serurier, 75019 Paris, France. E-mail: anne.paulsen1{at}fnac.net.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
The potential benefits of GH treatment, resulting in a significant height gain in children born small for gestational age (SGA), have been well documented for the last 10–15 yr. There is, however, no consensus on how to treat patients to attain a normal adult height. We have previously reported in a controlled study that recombinant human GH (1.4 IU/kg·wk or 0.47 mg/kg·wk) given daily induces an important increase in height velocity (HV) in young SGA children with severe short stature. Consequently, a total gain of 2 SD score (SDS) in height resulted in a mean height of -1.3 ± 0.8 SDS after 3 yr of treatment. The aim of the present report was to assess the consequences of interruption of GH treatment during a 5-yr follow-up period on HV, height, bone age (BA), puberty, and glucose tolerance in SGA children. There was a dramatic decrease of HV SDS, especially evident during the early part of the observation period, with a loss of 3.9 HV SDS during the first year. After 5 yr off treatment, mean HSDS was -2.2 ± 1.2, still above the pretreatment level (P < 0.0001). Consequently, the interruption of GH administration resulted in a reduction of 1 SDS in height. However, BA did not advance more than 4 yr, and the ratio BA/chronological age at follow-up was similar to pretreatment values. Sixty percent of the children started puberty during the follow-up, and the chronological age and BA at the onset of puberty were 11.4 ± 1.0 yr and 10.9 ± 0.5 yr in girls, and 12.1 ± 1.4 yr and 11.3 ± 1.1 yr in boys, respectively. Oral glucose tolerance testing after 1 yr and up to several years after discontinuation of GH therapy showed only minor, variable, and inconclusive changes in glucose tolerance.

In conclusion, we have shown that tolerance and safety data during and after GH treatment continue to be reassuring. A reduction of HV SDS and height SDS 5 yr after interruption of GH therapy is a strong argument for a continuous GH treatment or a discontinuous treatment with short fall-off intervals at least until puberty.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
IT IS NOW well established that GH treatment of short children born small for gestational age (SGA) increases growth velocity and induces a significant height gain during treatment (1, 2, 3, 4). The main objective is to obtain a normal height during childhood as soon as possible and to maintain that to achieve a normal adult height. It has been known for 10 yr that GH treatment induces a catch-up that in most studies results in normalization of height (5, 6, 7). However, the exact strategy to attain the final goal, a normal adult height, remains to be determined. There is no universal agreement on duration of treatment, dosage, or type of treatment (continuous or discontinuous after catch-up), and there is no consensus as to the exact protocol to follow. We previously reported the results of an open, controlled, and randomized trial (4) in which young SGA children with extremely short stature were treated with daily sc injections of recombinant human GH (Saizen, Geneva, Switzerland; 1.4 IU/kg of body weight per week or 0.47 mg/kg·wk) for 3 yr. Entry criteria for the multicenter trial were described previously (4). In brief, included children were prepubertal and had a height at least 3.0 SD below the mean height for chronological age (CA) and sex according to the standards of Sempé et al. (8). At birth, all children were SGA, defined as birth weight less than the 10th percentile corrected for gestational age (9, 10). Furthermore, CA ranged between 2 and 8 yr, bone age (BA) was less than 7 yr, and height velocity (HV) was less than +0.5 SD of the mean HV for CA and sex. In addition, the included children had a normal GH peak serum concentration of more than 10 ng/ml after a pharmacological stimulation test. Glucose tolerance during an oral glucose tolerance test (OGTT) was within normal ranges. Main exclusion criteria were dysmorphism, body hemihypertrophy, severe psychomotor retardation, chromosomal anomalies, or parents or siblings with type 1 or 2 diabetes mellitus. After 3 yr of GH treatment, height SD score (HSDS) was improved (+2.0 ± 0.5), and a 3.9-yr progression of BA was observed.

It was planned that after these 3 yr of treatment, children were followed for 5 yr. In the present analysis, the objective was to evaluate the consequences of GH treatment interruption on growth velocity, height, bone maturation, and puberty in 62 children. We found that interruption of GH administration resulted in a loss of 1 SD score (SDS) of height over a period of 5 yr.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

Sixty-two SGA children were followed for 5 yr after discontinuation of GH treatment. The subjects had been chosen initially according to their auxological characteristics at birth: birth weight, 2045 ± 574 g; birth length, 42.9 ± 4.0 cm; and gestational age, 38.0 ± 2.7 wk. They were enrolled in the treatment study for 3 yr, and GH therapy was begun at a mean age of 5.1 ± 1.9 yr. Main pre- and posttreatment data confirming earlier results (4) are summarized in Table 1, and it is evident that the GH treatment induced a significant catch-up of 2 HSDS (P < 0.0001) during the 3-yr period.

Protocol and growth parameters

During the follow-up period, the children were seen at 6-month intervals at which height, weight, and pubertal status were assessed. The height determined at each visit was the mean of three successive measurements normally performed by the same physician using the same wall-mounted stadiometer. HV was calculated from heights measured at every visit. Weight for height was assessed as body mass index (BMI) [BMI = weight (kilograms) divided by height (meters²)] SD for CA (11). BA was assessed annually and centrally by one specific radiologist (Dr. M. Sempé, Lyon, France), and the assessment was performed in a blind fashion (8, 12).

The clinical onset of puberty was defined by a testicular length of at least 30 mm or a testicular volume of at least 4 ml for at least one testicle for boys, and a stable Tanner breast stage of at least B2 for girls (13, 14).

OGTTs were performed in all children after 36 months of GH treatment, at 12 months after discontinuation, and at the end of each individual posttreatment follow-up period. World Health Organization criteria were used to classify the patients as normal, glucose-intolerant, or diabetic.

Statistical analysis

Intragroup analyses were performed using paired Student’s t tests. The level of significance was set at P < 0.05. All data are reported as mean ± SD.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Growth and BA

Auxological characteristics from the 5-yr follow-up in 62 children are listed in Table 1, including some previously reported data from the treatment period (4).

During the 5-yr follow-up without GH treatment, a decrease in HV was observed that was especially evident during the early part of the observation period. There was a loss of 3.9 HV SDS during this first year without treatment (Table 1). During the subsequent 4 yr, the HV SDS increased again and was above pretreatment values the last 2 yr. After 5 yr, HV SDS was very similar to the value observed at inclusion (Table 1). Thus, HSDS decreased during an interval of 1–5 yr after treatment (Fig. 1). HSDS was -2.2 ± 1.2 and thus still above the pretreatment value after 5 yr off treatment (P < 0.0001).

View larger version (12K): [in this window] [in a new window]   FIG. 1. HSDS (CA). Mean HSDS for CA in patients (n = 62) with SGA short stature at baseline, after 3 yr of GH treatment (1.4 IU/kg·wk or 0.47/kg·wk), and annually during the 5 yr after discontinuation of GH treatment. The dotted lines represent the upper and lower limits of a 95% confidence interval for the mean of the population. The upper solid line represents the mean annual BA/CA in the same group of children during 5-yr follow-up. C.I., Confidence interval.

Mean BMI SDS increased during the 5-yr follow-up period (Table 1).

Puberty

Time of onset of puberty is presented in Table 2. One girl developed advanced puberty at the age of 8.7 yr (BA = 8.6) after 33 months of GH treatment. During the first year off treatment, one girl developed central precocious puberty at an age of 7.8 yr and a BA of 9.4 yr. Cerebral magnetic resonance imaging was normal. During the first 3 yr of follow-up, three boys developed an advanced puberty as shown in Table 2.

Subgroup of patients who retained their height gain

To identify patients able to retain their height gain during the off-treatment period, we tried to define two subgroups of children: those who lost less than 0.5 HSDS during 3-yr follow-up (group R = retained), and those who lost more than 0.5 HSDS (group NR = not retained). Twenty of 62 children retained their HSDS during the follow-up period (Fig. 2 and Table 3) with no significant catch-down in growth 3 yr after treatment. These 20 children were older and had a more advanced BA at the start of the GH treatment. A majority of these children went into puberty during the first 3 yr of follow-up (60% vs. 30%) in comparison with the catch-down group. Other parameters were similar in both subgroups: height and weight at birth, HV, and HSDS at the start of GH treatment (Table 3).

View larger version (25K): [in this window] [in a new window]   FIG. 2. HSDS over time. Mean HSDS for CA in patients with SGA short stature at the end of 3 yr of GH treatment (1.4 IU/kg·wk or 0.47 mg/kg·wk) and during a 5-yr follow-up period after discontinuation of GH treatment. White bars correspond to the children (n = 20) who retained their HSDS (group R) after 3 yr of follow-up (0.5 HSDS), and the black bars correspond to the subgroup of children (n = 42) who did not retain their HSDS (group NR). The children in group R were older and had more advanced BA at the start of the GH therapy in comparison with group NR; a majority of the children in group R went into puberty during the first 3 yr of follow-up. Tx, treatment.

OGTT

As shown in Table 4, alterations in glucose tolerance were rare and inconsistent. A slightly abnormal OGTT test at 120 min was found in three patients before GH treatment, in two after 3 yr of treatment, in an additional two after 12 months of follow-up, and in another two patients at the last visit. Among the nine patients, all but one were prepubertal, and all had BMI SDS in the low to normal range. None of the patients had a repeatedly abnormal OGTT test, and none had an increased glycosylated hemoglobin. Among the other patients, only one had an increased glycosylated hemoglobin at two occasions.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
Most children born SGA will experience catch-up growth during the early 2 yr of life, but about 10% fail to achieve sufficient growth and present with growth failure and short stature with height below -2 SDS at the age of 2 yr (15, 16). This will persist throughout childhood and adolescence, ending with an adult short stature (17, 18). The absence of catch-up in those children is still poorly understood and is usually not due to classical GH deficiency, although some anomalies in the GH/IGF-I axis have been found in SGA children (19). There is today a consensus that GH administration will significantly increase HV in short, non-GH-deficient SGA children (1, 2, 3, 4, 5, 6, 7).

In the first phase of a controlled study, we demonstrated that recombinant human GH treatment (1.4 IU/kg·wk or 0.47 mg/kg·wk) is safe and effective in a group of SGA young children with severe short stature (4). There was a total gain of 2 SDS in height with a mean height of -1.3 ± 0.8 SDS in 46 children after 3 yr of treatment.

In the present report, covering the second phase of the study, we assessed the posttreatment growth in a 5-yr follow-up of HV and BA in 62 of the previously treated children. After discontinuation of GH treatment, there was a distinct reduction of mean HV, approaching pretreatment values. A distinct catch-down was observed after discontinuation of treatment. However, HSDS was still higher than pretreatment values because a 1.1 SDS gain over pretreatment height was observed 5 yr after termination of GH treatment.

In SGA children, a catch-down in growth after discontinuation of GH treatment has been reported in several studies. In SGA children treated with GH 1.2 IU/kg·wk for 3 yr, Job et al. (2) reported a loss of 0.3 SD after 1 yr of follow-up without treatment. Treatment had started at the age of 8 yr, and at the end of the 4-yr study, puberty had started in 67% of the patients. Similar results were shown by Rosilio et al. (20) when slightly older SGA children were treated for 2 yr with 1.4 IU/kg·wk, and also in more recent studies (6) using high-dose discontinuous GH therapy for up to 6 yr. Our study is, to our knowledge, the only one with follow-up of 5 yr. The data from the present study indicate that continuous treatment until puberty is necessary to maintain the height gain obtained during the treatment.

While searching for a group of patients who might benefit from a GH treatment, we were able to identify two subgroups able to retain (group R) or not retain (group NR) their HV after 3 yr off treatment. The children in subgroup R were taller than the NR subgroup and were in a puberty stage of at least P3, with BA nearing maturity in several children by the end of the 5-yr observation period. We therefore believe that the prognosis for adult height in this group of patients is poorer than that for children in the NR group. Because adult height prognosis based on BA is rather inaccurate in SGA children, follow-up until final height is required to answer this question. Our conclusion is that stopping GH treatment will jeopardize the final goal, which is normalization of final height. A few studies have reported on the final heights in the normal range in SGA patients continuously treated with GH (21, 22). Despite moderately low doses of GH (0.7 IU/kg·wk) and late onset of treatment, a small group of patients (n = 16) with SGA almost achieved the target height after 4.3 yr of treatment (21).

In previous studies performed by ourselves (4) and others, BA was found to accelerate during GH treatment, in contrast with untreated short SGA children or healthy children (2, 3, 23). However, after 5 yr of untreated follow-up, BA was still below CA, and no further acceleration of bone maturation was observed. Thus, final height is still expected to improve. A few earlier studies have reported (17, 24, 25) a spontaneous acceleration of bone maturation before the age of 10 yr in untreated short SGA children. Consequently, the accelerated bone maturation seen in our studies and other studies might be due to the combined effect of GH treatment and spontaneous acceleration of BA.

Earlier onset of puberty in untreated short SGA children with Silver-Russell syndrome has been shown in previous reports (24, 25). However, no precocious onset of puberty has been reported in the numerous studies on the growth-promoting effects of GH in short SGA children. In our study, 60% of the children started puberty during the untreated follow-up period, and the mean CA and BA at onset of puberty were 11.4 ± 1.0 yr and 10.9 ± 0.5 yr in girls, and 12.1 ± 1.4 yr and 11.3 ± 1.1 yr in boys, respectively. The mean age at entering puberty is within the normal range or slightly advanced in boys and is similar to the one reported by Job et al. (2) and Rosilio et al. (20) (i.e. girls entering puberty at a mean CA and BA of 11.0 and 11.7 yr and boys at 12.6 and 12.9 yr, respectively), slightly later than in other studies (5, 7), but earlier than in a more recent study (26).

During the follow-up period of 5 yr, there was a slight increase in BMI SDS values after a significant increase during the previous GH treatment period, presumably due to the pubertal status in many of the patients.

Children born SGA are known to have a specific impairment in insulin sensitivity (27, 28). This is magnified during GH treatment and is apparently non-dose-dependent (1, 5). Thus, there is a potential risk of glucose intolerance in these children. An increased incidence of non-insulin-dependent diabetes mellitus with impaired insulin sensitivity has been demonstrated in epidemiological studies on adults born SGA (29). Insulin resistance and normal glucose tolerance have been reported in children (30) and in young adults born SGA (31). Therefore, these patients have been previously considered to be at risk of glucose intolerance. However, all studies have reported normal glucose tolerance but relative insulin resistance during GH treatment in SGA short children (32). There has been little information as to the posttreatment period, and dynamic testing has rarely been conducted. de Zegher (33) reported reassuring data 3 months after discontinuation of GH in nine patients, and in a recent study, 47 adolescents born SGA had normal insulin sensitivity 6 months after discontinuation of long-term GH treatment (34). In the present study, OGTT testing after 12 months, and up to 5 yr after discontinuation of GH therapy, shows only minor, variable, and inconclusive changes. Future studies will further evaluate long-term risks of GH administration on carbohydrate metabolism.

In summary, short- and medium-term GH treatment has been documented as safe and effective in numerous studies, including large numbers of short children born SGA. In the present report, we have shown a dramatic decrease of HV more than 5 yr after the discontinuation of GH previously given for 3 yr. However, the net gain of 1 SDS in height and the lack of further acceleration of bone maturation during 5 yr of follow-up indicate improved adult final height prognosis over the two phases of the study. Although in 30% of the children HV after GH withdrawal fell by only 0.5 SDS, continuous GH treatment at least up to puberty is certainly preferable, even in this group. Tolerance and safety data during and after GH treatment continue to be reassuring, but additional studies with careful monitoring of long-term safety and data on final height are necessary.

	Acknowledgments

 
The authors are grateful to Mr. S. Fear for statistical analysis, to Mrs. A. Phelip-Van Buuren for data collection, and to Serono for continuous support of the study. This study was conducted on behalf of the SGA Study Group: M. Bost, R. Brauner, M. Colle, Y. Lebouc, M. Lecornu, B. Leheup, J. M. Limal, M. C. Raux, R. Rappaport, and J. E. Toublanc.

	Footnotes

 
Abbreviations: BA, Bone age; BMI, body mass index; HSDS, height SDS; HV, height velocity; OGTT, oral glucose tolerance test; SDS, SD score; SGA, small for gestational age.

Received June 4, 2003.

Accepted November 14, 2003.

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