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Department of Pediatric Endocrinology and INSERM U-342, University of Paris V, Hopital Saint Vincent de Paul (R.C., J.-C.C., C.B., J.-L.C.); and Institut de Recherches en Thérapeutiques (M.L.) and the Department of Biostatistics (J.C.), Hopital Cochin, Paris; and the Department of Pediatric Endocrinology, Hopital Debrousse (P.C.), Lyon, France
Address all correspondence and requests for reprints to: Dr. Jean-Claude Carel, INSERM U-342, Hopital Saint Vincent de Paul, 82 avenue Denfert Rochereau, 75014 Paris, France. E-mail: carel{at}cochin.inserm.fr
Abstract
Short term studies have demonstrated the acceleration of growth velocity after the administration of GH in short children born with intrauterine growth retardation (IUGR). We report the final heights of 70 IUGR children whose short stature was attributed to idiopathic GH deficiency (peak plasma GH <10 ng/mL at 2 provocative tests) and treated with GH at a mean dosage of 0.4 ± 0.1 U/kg·week during an average of 4.6 ± 2.5 yr. They were compared to a control group of 40 untreated short children born with IUGR, without GH deficiency. At the time of evaluation, age, auxological data, and pubertal status were similar in the 2 groups (height, -2.9 ± 0.8 and -2.8 ± 0.7 SD score). Final heights were comparable in both groups of children (-2 ± 0.7 and -2.2 ± 1.1 SD score). A multivariate analysis identified 4 independent predictors of final height, namely target height, age and body mass index at evaluation, and GH treatment. Treatment was associated with a gain of 0.6 SD score, suggesting a final height gain of about 3.4 cm. Fifty-three of 70 treated children were reevaluated after completion of growth, and 43 of 53 had a peak plasma GH level of 10 ng/mL or more. Auxological characteristics of these 53 patients were not different from those of nonreevaluated patients. We believe that the transient character of the GH deficiency in most patients and the nonstringent initial criteria used for the diagnosis of GH deficiency render the spontaneous growth potentials identical in the 2 groups of patients. Our data, therefore, suggest that GH treatment at this dosage has a limited effect on the final height of short children born with IUGR.
INTRAUTERINE growth retardation (IUGR), defined as birth length below -2 SD for gestational age, concerns around 2.5% of newborn babies. Most children reach normal height during the first or second year of life, but 15–20% remain small at the age of 4 yr (1, 2, 3, 4). Among the children who do not catch up during childhood, 50% remain short when reaching final height. About 20% of the adult short population have had IUGR (5). A French retrospective study on 47 patients with IUGR and prepubertal short stature showed a mean (±SD) final height of 161.9 ± 8 cm for boys and 147.6 ± 7.2 cm for girls (6). GH treatment has been proposed in short children with IUGR. Short term results, using various doses of GH (from 0.4–2.1 U/kg·week) (7, 8, 9, 10, 11) have shown a dose-dependent catch-up growth during the first 3 yr of treatment. However, bone age (BA) maturation was increased during treatment, and growth velocity was markedly decreased after interruption of treatment, potentially reducing the beneficial effect of GH. No data are currently available on the final heights of these patients.
Among patients treated with GH for GH deficiency since the mid 1980s, several had IUGR. The centralized database of Association France Hypophyse allowed us to identify such patients and evaluate the end results of GH treatment using conventional doses. We report the final heights of 70 IUGR children without postnatal catch-up growth, who were treated with GH (0.4 ± 0.1 U/kg·week) because their short stature was believed to result from idiopathic GH deficiency. They were compared to a control group of 40 children with IUGR not considered GH deficient and therefore not treated with GH. In addition, we could reevaluate GH secretion after completion of growth in 53 of 70 GH-treated patients.
Subjects and Methods
Patients
Seventy IUGR children with GH deficiency (IUGR-GHD) were included after meeting the following criteria: 1) birth length -2 SD or more below the mean for gestational age (12), 2) height at the time of evaluation below -2 SD (13), and 3) diagnosis of idiopathic GH deficiency defined as peak plasma GH below 10 ng/mL after 2 conventional stimulation tests (55 patients) or integrated concentration of GH below 3 ng/mL (15 patients) (14) (see below). All children had a normal cranial magnetic resonance imaging or computed tomography scan at diagnosis. Criteria for exclusion were chromosomal abnormalities, dysmorphic syndromes, skeletal dysplasia, chronic illness, and hypothyroidism. These children had no specific syndrome, and the causes of IUGR were unknown.
Forty untreated short children with IUGR were identified by the same auxological criteria. Among them, 30 had a peak plasma GH level of 10 ng/mL or more, whereas auxological and clinical data were used to exclude GH deficiency in the other 10. These patients were followed to final height without treatment.
Fifty-three of the IUGR-GHD children had a reevaluation of GH secretion by pharmacological testing at the end of treatment, whereas the remaining 17 refused to undergo a new test.
The SD scores of birth weight (12), height, weight, and growth velocity for age and sex were calculated (13). Genetic target height (midparental height) was calculated as previously described (15), using height standards obtained during the approximate parental generation (16). Predicted height was calculated using the Bayley-Pineau method (17, 18).
Diagnosis of GH deficiency
The stimuli used for pharmacological testing of GH secretion were arginine (9%), ornithine (27%), insulin hypoglycemia (9%), arginine and insulin hypoglycemia (12%), clonidine and betaxolol (6%), glucagon and betaxolol (8%), glucagon and propranolol (9%), or others (20%) (19). Plasma GH was measured by RIA using kits obtained from CEA (Saclay, France) or BioMerieux (Marcy-l’Etoile, France), calibrated against the first International Reference Preparation (MRC 66/217). GH results are expressed in MRC 66/217 units (2 µU = 1 ng). In addition, 15 patients with peak plasma GH levels of 10 ng/mL or more were considered GH deficient on the basis of nocturnal GH secretion (neurosecretory dysfunction).
Treatment and follow-up
Sixty-seven of 70 patients received exclusively recombinant GH (6–7 times weekly), and 3 patients were treated with human extracted GH during the first 2 yr. Children started the treatment between 1980 and 1993.
Treated children were followed every 6 months or less. The following data were recorded: height, weight, pubertal stage (20, 21), and BA assessed at least each year (17). Untreated children were followed at Saint Vincent de Paul hospital.
Criteria for discontinuation of GH treatment was a growth velocity below 2 cm in the previous 6 months with a BA greater than 13 yr for girls and 14.5 yr for boys. The mean delay between end of the treatment and the last visit was 6 ± 1 months.
Final height
Final height was measured in boys at pubertal stage G5 with a BA of 15 yr or more (96.8% of final height according to Bayley-Pineau) (18). For treated boys, chronological age (CA) was 17.4 ± 1.2 yr (range, 15–19.5), and BA was 16.4 ± 0.7 yr (98.7% of final height). For untreated boys, CA and BA were more than 18 yr in all cases.
Final height was measured in girls at pubertal stage B5 and a BA of 13.5 yr or more (96.8% of final height) (18). For treated girls, CA was 15.8 ± 1.1 yr (range, 13.5–18), and BA was 14.9 ± 0.8 yr (98.9% of final height). For untreated girls, CA and BA were more than 18 yr in all cases.
Statistical analysis
Results are expressed as the mean ± SD.
Student’s t test (two-sided, 
level of 0.05) and
variance analyses followed by Newman-Keuls tests were used for
comparisons. Growth was analyzed as proposed by Cole (22). A model for
predicting the 
height SD score (difference between
final height and height at first evaluation) was constructed to compare
the growth of treated and untreated subjects. Regression analyses were
performed using data at initial evaluation (CA, BA, body mass index,
target height SD score, and GH secretion). These parameters
were first individually tested to select those associated with a
statistically significant regression coefficient. Parameters selected
at this first step were used to construct the final model. To account
for the effect of regression toward the mean (23), all regressions
included height SD score at evaluation, the time interval
(years) between evaluation and final height, and the interaction
between these two variables (22). In addition, all regressions included
the effect of treatment (1 = treated, 0 = untreated) and were
adjusted for sex, stage of puberty at evaluation, and height gain
SD score between birth and the time of evaluation.
Statistical tests were performed with the SAS statistical package
(24).
Results
Baseline characteristics of the patients (Table 1
)
At the time of evaluation, auxological data, age, and pubertal status were similar in the two groups. Both had a similarly reduced target height, indicating a genetic participation in their short stature. Birth length SD score was slightly lower in the untreated group (-3.5 ± 1.3 vs. -3 ± 0.8; P < 0.05). However, height at the age of 4 yr and that at the time of evaluation were not different. Most of the height deficit was already constituted at birth and at the age of 4 yr in both groups; the difference between height SD score at the time of evaluation and that at age 4 yr was similar (-0.5 ± 0.7 and -0.2 ± 0.7 SD score, treated and untreated groups; P = NS), suggesting that GHD had a minimal role in the short stature of patients in the treated group.
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Evolution of height during treatment (Fig. 1)
Treated patients received an average GH dose of 0.4 ± 0.1 U/kg·week (range, 0.21–0.63) over 4.6 ± 2.5 yr. The mean delay between evaluation and initiation of GH treatment was 8 ± 7 months.
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). Height gain was 0.3 ± 0.3, 0.3 ± 0.3, and 0.2 ± 0.3 SD score during the first, second, and third years of treatment, respectively. Height gain was 0.9 ± 0.8 SD score during the entire period of treatment.
Final height in treated and untreated children (Table 1 and Fig. 2)
Final height was -2.0 ± 0.7 SD score in treated
children and -2.2 ± 1.1 SD score in untreated
children. height SD score (difference between height
SD score at final height and that at first evaluation) was
slightly higher in the treated group (0.9 ± 0.8 SD
score in treated and 0.6 ± 0.9 in untreated children). In treated
children, the height gain was 1.0 ± 0.8 SD score for
patients prepubertal at the initiation of treatment (n = 60) and
0.7 ± 0.7 SD score for children who had begun puberty
before initiation of treatment (n = 10). The corresponding values
for untreated children were 0.7 ± 0.8 (n = 30) and 0.5
± 1 SD score (n = 10). The evolution of height in the
two groups of children is summarized in Fig. 2.
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height SD score was analyzed in a multiple
regression model including several adjustment variables (Table 2). Four independent variables were
identified: target height, age and body mass index at initial
evaluation, and GH treatment. The ß coefficient associated with
treatment was 0.58, suggesting that, on the average, treated subjects
had gained 0.58 SD more than untreated ones, corresponding
approximately to 3.4 cm (SD in the adult French population,
5.6 cm for girls, and 6 cm for boys (13). In addition, due to the
slightly different age of the two groups of patients at the time of
measurement of final height (see Subjects and Methods), the
actual height gain of treated subjects might have been underestimated
by approximately 1.5 cm. Several variables were not associated with
height SD score: sex, height gain between birth and
evaluation, BA, pubertal stage and growth velocity at evaluation, and
initial peak plasma GH.
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Fifty-three of the 70 treated children underwent pharmacological
GH testing after completion of GH treatment and pubertal development.
Eighty-one percent (43 of 53) had a peak plasma GH of 10 ng/mL or more.
Thirty-nine of the reevaluated patients had peak plasma GH levels below
10 ng/mL at initial evaluation; among those, 30 (77%) had peak plasma
GH levels of 10 ng/mL or more at reevaluation. We found no difference
between reevaluated vs. nonreevaluated patients, with the
exception of height SD score at 4 yr (Table 3). The characteristics of the 3 groups
of patients (nonreevaluated, reevaluated and persistently deficient,
and reevaluated and not persistently deficient) are presented in Table 3. The 10 persistently GHD patients who continuously lost height
SD score from birth to the time of evaluation were younger
(P < 0.05) and shorter (P < 0.01) at
evaluation. Their height gain after GH treatment was 1.5 ± 1
compared to 0.8 ± 0.7 SD score for the reevaluated
and not persistently deficient patients (P <
0.05).
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In this report, we have analyzed the growth data of two groups of patients with short stature born with IUGR: patients considered GH deficient and treated with recombinant GH at a mean dose of 0.42 IU/kg·week and untreated patients without GH deficiency. We observed that although peak plasma GH was clearly different between the two groups, auxological data at the time of evaluation, in particular growth velocity, were not different. A multivariate analysis identified several variables predictive of final height, among which was GH treatment. This suggests a significant effect of GH treatment on the final heights of these patients. However, the effect was modest under these GH treatment conditions.
GH treatment has been proposed in GH-sufficient IUGR patients with persisting postnatal very short stature and has been registered in France for treatment of such prepubertal children. Several studies (7, 8, 9, 10, 11), some of which included untreated control groups (9, 10), have demonstrated a short term growth benefit after 2–3 yr of treatment. In addition, with doses ranging from 0.4–2.1 U/kg·week, the effect was clearly dose dependent, with height improvement ranging up to 1.8 SD score. However, to date, final heights from these studies are not available, and our data provide timely information that can help predict their end results.
The two groups of patients compared here had clearly different peak plasma GH at initial evaluation, and we cannot ascertain that their spontaneous outcomes would have been similar. However, pharmacological GH testing has proved to be unreliable (25, 26), and low reproducibility is particularly evident when peak plasma GH is in the 5–10 ng/mL range (19). Indeed, more than 80% of our treated patients had a peak plasma GH level of 5 ng/mL or more. In addition, growth velocity, a good marker of GH deficiency, was not different in the two groups, and most of the height deficit was already constituted before the age of 4 yr, further reinforcing our impression that the lack of GH was not the cause of short stature in most of these patients. Moreover, reevaluation of GH secretion after completion of puberty, which could provide a way to retrospectively discriminate truly GH-deficient from transiently or non-GH-deficient individuals (26, 27, 28, 29), showed that a vast majority of our retested patients had normal GH secretion. All of these facts suggest that the diagnosis of GH deficiency, and therefore the decision to initiate GH treatment, was a random event in the majority of the patients.
Several studies of GH treatment in IUGR patients have used dosages of
0.4–0.7 U/kg·week (7, 8, 11, 30), and the initial responses were
close to our results. After 3 yr, height gains were 0.6–0.9
SD score, compared to 0.8 in our study. However, the mean
age at onset of treatment in these studies was lower than that in our
study (7.3–10.1 vs. 10.8 yr), and the percentage of
patients who entered puberty during treatment was lower (50–57%
vs. 81%). In our patients, after adjustment on several
variables, GH treatment was associated with a 0.6 SD score
(
3.4 cm) higher final height. Whether GH treatment at theses doses
(0.4–0.7 U/kg·week), given several years before the onset of puberty
would have yielded better results remains to be determined. In our
view, this is unlikely given the positive association between age at
evaluation and final height found in our multivariate analysis (older
patients did better). Similarly, recent reports of final heights in
small groups of short normal children treated with GH (0.4–0.7
U/kg·week) have shown a limited effect (31, 32).
Higher GH doses (1–2.1 U/kg·week) given to strictly prepubertal children produce 3-yr height gains of 1.5–2 SD score (7, 8, 9, 10, 30), roughly 1 SD score more than lower doses. Whether this catch-up growth will be translated into equivalently increased final heights remains to be evaluated. Accelerated BA maturation has been demonstrated in patients treated with GH doses of 1.2 IU/kg·week or more compared with that in untreated patients or patients treated with lower doses (7, 9), suggesting that some of the apparent benefit observed at the end of treatment could be lost when final heights are achieved (33).
Our group of untreated patients is of interest because they exhibited an average 2-yr delay in BA over CA around the age of 10 yr, as previously described in children with IUGR (8). Despite this 2-yr delay, they only gained 0.5–0.8 SD score when final height was achieved, suggesting that it does not fully translate into catch-up growth and that growth predictions should be made with great caution in short children with former IUGR.
In conclusion, we believe that the nonstringent initial criteria used for the diagnosis of GH deficiency and the transient character of GH deficiency render the spontaneous growth potentials similar in the two groups of patients we have studied. GH treatment was associated with an approximately 3.4-cm higher final height, suggesting a limited benefit on the final height of short children born with IUGR. However, long term results in patients treated with doses higher than 0.4 IU/kg·week will be necessary to reach a final conclusion. In addition, we add new evidence on a peculiar bone aging process in short children with IUGR, reinforcing the need for untreated control children in therapeutic trials aimed at this patient population.
Received July 22, 1997.
Revised January 15, 1998.
Accepted January 15, 1998.
References
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, Pubertal children 2 yr after the onset of treatment
(n = 50); 
, prepubertal children 2 yr after the onset of
treatment (n = 20). *, P < 0.05.