Growth hormone therapy in short children born small for gestational age

Being born small for gestational age (SGA) is one of the most common causes of childhood short stature, and recombinant GH therapy has been recently licensed to promote growth in short SGA children from the age of 4 years old. Studies are now reporting very encouraging effects on adult height gains, especially in those children who started GH therapy early, at least 2 years prior to the onset of puberty. Compared to the age at starting treatment, the GH dose has a less significant impact on final height, and more attention needs to be paid now to identify earlier those SGA children who fail to catch-up spontaneously. The benefits are not just in terms of height, but also in body composition and possibly blood pressure and lipid levels. However the risk of side effects and long-term complications, particularly related to the expected metabolic effects of GH in inducing insulin resistance and hyperinsulinaemia, need to be carefully monitored especially in SGA children with a family history of type 2 diabetes. Recently, GH therapy was found to amplify the adrenarche of short SGA children and to induce a pro-inflammatory shift, as judged by a rise of neutrophil count and circulating interleukin-6 (IL-6), and a fall in adiponectin levels. Further progress is anticipated to assess the addition of insulin-sensitizing therapy to attenuate the GH-induced hyperinsulinemia, in order to alter the pro-inflammatory course, to avoid excessive release of adrenal androgens, and to slow down the potential rapid tempo of pubertal progression in SGA children. In the meantime, post-SGA short stature is rapidly becoming one of the prime indications for GH therapy in childhood.     

Growth hormone treatment of short children born small for gestational age: metanalysis of four independent, randomized, controlled, multicentre studies

A minority of children born small for gestational age (SGA) fail to achieve sufficient catch-up growth during infancy and remain short throughout childhood, apparently without being growth hormone (GH) deficient. The effect of GH administration was evaluated over 2 years in short prepubertal children born SGA. The children ( n = 244), who were taking part in four independent multicentre studies, had been randomly allocated to groups receiving either no treatment or GH treatment at a daily dose of 0.1, 0.2 or 0.3 IU/kg (0.033, 0.067 or 0.1 mg/kg) s.c. At birth, their mean length SD score (SDS) was -3.6 and their mean weight SDS -2.6; at the start of the study, mean age was 5.2 years, bone age 3.8 years, height SDS -3.3, height SDS adjusted for parental height -2.4, weight SDS -4.7 and body mass index (BMI) SDS -1.4. The untreated children had a low-normal growth velocity and poor weight gain. Although bone maturation progressed more slowly than chronological age, final height prognosis tended to decrease, according to height SDS for bone age. GH treatment induced a dose-dependent effect on growth, up to a near doubling of height velocity and weight gain; BMI SDS was not altered. Bone maturation was also accelerated differentially; however, final height prognosis increased in all GH treatment groups. The more pronounced growth responses were observed in younger children with a lower height and weight SDS. In conclusion, GH administration is a promising therapy for normalizing short stature and low weight after insufficient catch-up growth in children born SGA. Long-term strategies incorporating GH therapy now remain to be established.     

Born small for gestational age: consequences for growth

A large number of studies have documented a strong correlation between size at birth and subsequent height, although the reported incidence of catch-up growth and consequently the impact on final height has varied with time and between countries. These variations may be real, but could also be related to a number of methodological problems. The aim of this study was to explore two important aspects related to postnatal growth after disturbed fetal growth: first, the definition of small for gestational age (SGA), including the selection of cut-off points in defining shortness; and, secondly, the importance of the general socio-economic status of the population with regard to the incidence of growth faltering in early life. Data were analysed from two longitudinal population-based studies, one from Sweden and one from Hong Kong. Of the Swedish cohort, 3.8% had a birth length below –2 SD scores; in the Hong Kong population the corresponding value was 11.9% (Swedish reference values were used in both studies). The following conclusions were made. Size at birth is important for postnatal growth, and the difference in length at birth of 9–10 cm between the two extreme birth length subgroups remains, on average, until maturity. This seems to be true for the two study populations with different degrees of socio-economic development. However, the rate of catch-up growth is highly dependent on the definition of SGA, on the rate of catch-up growth in early life and on the incidence of growth faltering between 6 and 18 months of age.     

Growth hormone treatment of idiopathic short stature: analysis of the database from KIGS, the Kabi Pharmacia International Growth Study

Within the Kabi Pharmacia International Growth Study (KIGS) database, there is information on 1017 (700 male/317 female) patients with idiopathic short stature (ISS). These patients were started on recombinant human growth hormone (GH) at a median age of 10.8 years, a bone age of -1.8 SDS, a height of -2.6 SDS and a predicted adult height (PAH) (Bailey–Pinneau method) of -2.5 SDS. The median dose of GH was 0.6 IU/kg body weight/week and the frequency of injections was six/week. According to the relationship with target height the patients were classified into'familial short stature (FSS)'(height SDS > target height SDS - 1.28) and into'non-FSS'(height SDS < target height SDS - 1.28). During the first year of GH treatment there was an overall increment in the median height velocity from 4.4 to 7.4 cm/year. Over 3 years of GH treatment, cross-sectional analysis demonstrated an overall increment in median PAH of 1.2 SDS. There was a positive correlation between gain in PAH and the GH dose (n = 202, r = 0.18, p < 0.01) during the first year. Longitudinal analysis in 84 patients showed an overall increment of PAH of 0.7 SDS over 2 years of treatment. When applying the KIGS first-year prediction model for patients with idiopathic GH deficiency on cohorts of prepubertal children with FSS and non-FSS, a lower responsiveness to GH in the non-FSS group was observed. It is concluded that higher than substitutive doses of GH are required for the long-term improvement of growth in ISS.     

Natural growth in children born small for gestational age with and without catch-up growth

This first report from a population-based postnatal growth study of 3650 healthy Swedish subjects born at full term provides new reference values for height and weight and shows that over the last 20 years there has been a small secular trend in height (0.2–0.4 SDS over the whole age range) in Sweden in both boys and girls. Within this cohort, 111 (3.1%) were of low birth weight (below –2 SDS) and 141 (3.5%) were of low birth length (below –2 SDS); 54 (1.5%) were both light and short at birth. Of the children born small for gestational age, 87% showed full catch-up growth within 2 years of life. They attained puberty at a normal or early age and reached a mean final height of –0.7 SDS. The remaining subgroup of 13% born small for gestational age remained below –2 SDS throughout childhood and reached puberty somewhat early. Their mean final height was –1.7 SDS. The current data set is too small to identify possible background factors, but it is being expanded with this objective in mind.     

Demography, auxology and response to recombinant human growth hormone treatment in girls with Turner's syndrome in the Kabi Pharmacia International Growth Study

Demographic and auxological data were analysed from 818 girls with Turner's syndrome treated with recombinant human growth hormone (GH) and entered into the Kabi Pharmacia International Growth Study. Size at birth was low and correlated with the heights of both parents. The median age at start of GH treatment was 11.4 years and the parents had a median height SDS of -2.9. Height SDS at the start of treatment correlated with parental heights. Height velocities conformed to Turner-specific standards. The weight-for-height index increased sharply above 9 years of age. The frequency of spontaneous appearance of Tanner breast stage 2 was high (34.1% of girls > 10 years of age). Bone age (Greulich and Pyle) data were described by the equation: bone age = 1.61 (chronological age) -0.04(chronological age)² - 3.61. This equation was used to correct adult height predictions. The median initial dose of GH was 0.8 IUkglweek and was maintained during the first 3 years of treatment. The median frequency of injections was six/week. Height velocity increased from 4.1 to 6.8 cm/year in the first year, and height velocity SDS for chronological age remained positive for 4 years. The height prediction corrected for bone age increased over the first 2 years only. Differences in demography and auxology were described according to karyotype and country of origin. A greater height velocity SDS was observed at higher GH doses and when oxandrolone was used concomitantly.     

不同剂量重组人生长激素治疗小于胎龄儿矮小症的疗效分析

目的 研究不同剂量重组人生长激素(rhGH)治疗小于胎龄儿(SGA)矮小症的效果和安全性。方法 收集SGA 矮小症患儿37 例,并根据使用剂量分为2 组:小剂量(每日0.1~0.15 IU/kg)rhGH 治疗组和大剂量rhGH 治疗组(每日0.16~0.2 IU/kg),比较两组患儿治疗后3、6、9、12 及24 个月时身高标准差的增长值(ΔHtSDS)、生长速率(HV)、血清胰岛素样生长因子-1(IGF-1)、胰岛素样生长因子结合蛋白-3(IGFBP-3)水平及空腹血糖等指标的变化。结果 大、小剂量rhGH 治疗后ΔHtSDS 及HV 均有提高,但大剂量组治疗后9、12 及24 个月时ΔHtSDS 及HV 均高于小剂量组(P<0.05)。大剂量和小剂量的rhGH 治疗均使血清IGF-1 和IGFBP-3 水平提高,且血清IGF-1 和IGFBP-3 水平与HtSDS 呈正相关。大小剂量组各有1 例患儿出现一过性空腹血糖轻微升高(均为6.1 mmol/L);两组甲状腺功能均无异常。结论 rhGH 治疗SGA 矮小症效果确切,不良反应少,其中大剂量较小剂量治疗更具优势。     

Effect of growth hormone treatment in children with craniopharyngioma with reference to the KIGS (Kabi International Growth Study) database

In children with craniopharyngioma, poor growth commonly precedes diagnosis, but is observed less frequently than neurological or visual symptoms. A deficiency of growth hormone (GH) is common before, and almost universal after, treatment of the tumour, and is usually treated with GH. However, a minority of these children with GH deficiency (GHD) grow well without GH replacement therapy but exhibit other metabolic effects of GHD that are correctable by GH treatment. This article provides a review of studies in 422 children with craniopharyngioma whose details have been entered into the database of KIGS, the Kabi International Growth Study. The response to GH during the first year of therapy was similar to that seen in children with idiopathic GHD (IGHD). Leg length was relatively greater than sitting height and this disproportion was maintained during treatment. Adiposity increased in some children receiving GH treatment. At the end of GH treatment in 82 patients, there was a median gain in height SD score of 1.51, with evidence of residual growth potential still remaining in the majority. Tumour recurrence occurred in 13.5% of the total group of patients with craniopharyngioma within KIGS, at a median of 3.9 years from diagnosis and 2.3 years from the start of GH therapy. Tumour recurrence was not associated with an impairment in height achieved, but there was a tendency towards greater adiposity in patients in whom recurrence occurred. Adverse events during GH treatment were more frequent in children with craniopharyngioma than in those with IGHD, and headache was commonly reported. The results of these studies suggest that GH treatment is recommended for the treatment of children with craniopharyngioma on the grounds of improved growth velocity, adult height and other GH-dependent metabolic functions, and of the good safety profile of GH in these patients.     

Longitudinal follow-up of height up to five years of age in infants born preterm small for gestational age; comparison to full-term small for gestational age infants

OBJECTIVE: This aims to conduct a comparative study of the height catch-up rate in preterm small for gestational age (SGA) infants during early childhood by gestational age and identify the factors affecting short stature in comparison to full-term SGA infants. METHODS: 449 SGA infants (214 full-term infants, 73 infants with gestation of less than 32 weeks, and 162 infants with gestation of more than 32 weeks but less than 37 weeks) from 25 institutions in Japan were assessed for catch-up (> or = -2SD) rate in growth by measuring for length/height at 1 year, 3 years and 5 years of age and the risk factors for no catch-up (< -2SD) at 5 years. RESULTS: The overall length/height catch-up rate was 68% at 1 year, 89% at 3 years and 88% at 5 years. The catch-up rate at 3 and 5 years of age in the group with gestation of less than 32 weeks had a rate of 74%, which was significantly less than the other two groups (approximately 90%). A significant factor associated with short stature at 5 years in the group with gestation of less than 32 weeks was the lower length SD score at time of birth, and for preterm infants born more than 32 weeks of gestation and full-term infants, significant factors were the lower maternal height and head circumference at birth. CONCLUSION: SGA infants born less than 32 weeks of gestation had a higher risk of no catch-up and different factors affecting catch-up compared to preterm SGA infants of gestation more than 32 weeks and full-term SGA infants.     

Characteristics of children with idiopathic short stature in the Kabi Pharmacia International Growth Study, and their response to growth hormone treatment

The auxological characteristics and the response to growth hormone (GH) treatment of children with idiopathic short stature were studied, using the database of the Kabi Pharmacia International Growth Study. Pretreatment data from a total of 271 children were analysed. The children were selected for a birth weight above -2 SDS. The correlation coefficient of birth weight SDS and birth length SDS was 0.51, compared with 0.72 for the reference population. Median length at birth was -0.6 SDS, which fell to -2.5 SDS by 3 years of age. Thereafter, there was no further loss in height SDS. The response to GH treatment was studied in 222 of these prepubertal children who were given six or seven injectiodweek over a 3-year period. During this time, the median height SDS increased from -2.5 to -1.5, with those children receiving more than 0.65 IU/kg/week having a greater gain in height SDS than those on 0.5 IU/kg/week or less. The degree of bone age delay did not appear to influence the response to GH therapy.     

无生长追赶小于胎龄儿胰岛素敏感性及垂体-甲状腺轴变化的研究

目的探讨无生长追赶小于胎龄儿(SGA)胰岛素敏感性及垂体-甲状腺轴的变化。方法选择近3年中山大学附属第一医院儿科内分泌专科门诊的青春前期生长迟缓儿童,按性别、年龄、体块指数(BMI)匹配分为两组,即无生长追赶SGA组和矮小适于胎龄儿组(AGA),各24例进行病例对照研究。两组均检测空腹血糖、血清胰岛素及血清TSH、T3、T4,并计算血糖/胰岛素比值(G/I比值)、胰岛素抵抗指数(HOMA-IR)和胰岛β细胞功能(HOMA%)。结果SGA组空腹血糖与AGA组比较无显著性差异,但空腹胰岛素、HOMA-IR、HOMA%均显著高于AGA组(8.0±6.2vs4.4±2.8mU/L,1.8±1.4vs1.0±0.7和183.0±145.9vs70.8±43.6,P均<0.05);SGA组HOMA-IR>3人数显著高于AGA组(7/24vs1/24,P<0.05);G/I比值显著低于AGA组(17.8±15.1vs33.2±28.9,P<0.05)。SGA组血清TSH显著高于AGA组(2.9±0.8vs1.9±0.9mU/L,P<0.01),而血清T3、T4两组比较差异无统计学意义。SGA血清胰岛素、HOMA-IR与出生体重SDS呈负相关(r=-0.547和-0.482,P均<0.05);SGA血清TSH与出生身长SDS呈负相关(r=-0.571,P<0.01)。结论无生长追赶SGA存在胰岛素抵抗和垂体-甲状腺轴的改变,无生长追赶SGA需要长期随访和早期干预,以预防或延缓代谢综合征发生。     

A regression method including chronological and bone age for predicting final height in Turner's syndrome, with a comparison of existing methods

A total of 235 measurement points of 57 Dutch women with Turner's syndrome (TS), including women with spontaneous menarche and oestrogen treatment, served to develop a new Turner-specific final height (FH) prediction method (PTS). Analogous to the Tanner and Whitehouse mark 2 method (TW) for normal children, smoothed regression coefficients are tabulated for PTS for height (H), chronological age (CA) and bone age (BA), both TW RUS and Greulich and Pyle (GP). Comparison between all methods on 40 measurement points of 21 Danish TS women showed small mean prediction errors (predicted minus observed FH) and corresponding standard deviation (ESD) of both PTS_RUS and PTS_GP, in particular at the "younger" ages. Comparison between existing methods on the Dutch data indicated a tendency to overpredict FH. Before the CA of 9 years the mean prediction errors of the Bayley and Pinneau and TW methods were markedly higher compared with the other methods. Overall, the simplest methods—projected height (PAH) and its modification (mPAH)—were remarkably good at most ages. Although the validity of PTS_RUS and PTS_GP remains to be tested below the age of 6 years, both gave small mean prediction errors and a high accuracy. FH prediction in TS is important in the consideration of growth-promoting therapy or in the evaluation of its effects.     

Onset of puberty and near adult height in short children born small for gestational age and treated with GH: Interim analysis of up to 10 years of treatment in Japan

The safety and effectiveness of long-term (10-yr) GH treatment in short Japanese children born small for gestational age (SGA) were evaluated based on interim data analysis from a clinical study, including the findings concerning the influence on the onset of puberty and subjects who achieved near adult height (NAH). Sixty-one subjects were analyzed at baseline in this study. Eleven subjects (6 boys and 5 girls) achieved NAH (mean 157.4 cm and 145.5 cm, respectively), and the Δ height SDS from the start of GH treatment was +1.6 in boys and +1.8 in girls. The median age (yr) at onset of puberty was 11.4 in boys and 9.9 in girls, comparable to healthy children. However, the mean height (cm) at onset of puberty (137.0 in boys; 125.5 in girls) was shorter than that of healthy children. Treatment-related adverse events were generally mild to moderate in severity; however, adenoidal hypertrophy was observed in two subjects as a serious adverse event. One subject had jaw malformation related to GH treatment at a dose of 0.067 mg/kg/d. No notable changes in HbA1c levels were observed, and the levels remained within the reference range. We have confirmed the safety and effectiveness of long-term GH treatment through this ongoing clinical study.     

Postnatal management of growth failure in children born small for gestational age

Objectives

To discuss the etiology and growth consequences of small size at birth and the indications, effects, and safety of biosynthetic growth hormone therapy in children born small for gestational age.

Auxology and response to growth hormone treatment of patients with intrauterine growth retardation or Silver-Russell syndrome: analysis of data from the Kabi Pharmacia International Growth Study

Using the database from the Kabi Pharmacia International Growth Study, 105 patients with intrauterine growth retardation (IUGR) (82 males, 23 females) and 45 with Silver-Russell syndrome (SRS) (32 males, 13 females) with persistent postnatal growth failure were studied. Patients with IUGR had a birth length and birth weight more than 2 SD below the mean for gestational age. Their height deficit at the start of GH treatment was -3.0 SDS at a median chronological age of 8.7 years and a median bone age of 7.0 years. Mean paternal and maternal heights were 166 and 153 cm, respectively. The median dose of GH was 0.5 IU/kg/week, given at a median frequency of five injections/week. The median height SDS for chronological age after 1, 2 and 3 years of GH treatment were -2.5, -2.1 and -1.9, respectively. In the 45 patients with SRS, median chronological age and median bone age at the start of treatment were 6.7 and 3.2 years, respectively, and mean paternal and maternal heights were 167.5 and 160 cm, respectively. The median dose of GH was 0.7 IU/kg/week, given at a median frequency of six injections/week. The median height SDS for chronological age at the start of treatment and after 1, 2 and 3 years were -3.5, -2.9, -2.8 and -2.2, respectively. Although the criteria used by physicians when diagnosing SRS were not controlled or verified in this study, it appears that patients with SRS can be differentiated from those with IUGR with persistent growth failure by their reduced bone age for chronological age at the start of treatment, and by the fact that patients with SRS tended to be born to parents of normal height. GH treatment in both groups induced catch-up growth, though long-term follow-up studies will be required to assess the effects of treatment on final height.     

Prediction of the growth response in children with various growth disorders treated with growth hormone: analyses of data from the Kabi Pharmacia International Growth Study

Analyses to predict the growth response to recombinant human growth hormone (GH) in prepubertal children during the first year of treatment were performed on data from 472 patients with idiopathic GH deficiency (IGHD), 202 children with Turner's syndrome, 327 children with idiopathic short stature (ISS) and 135 children with intrauterine growth retardation (IUGR). In IGHD, 56% of the variability of the response could be predicted from a model based on six variables. These variables could be ranked in order of importance as follows: target height SDS minus height SDS, chronological age, frequency of GH injections, dose of GH, weight-for-height index, and birth weight SDS. When the model for IGHD was applied to Turner's syndrome, ISS and IUGR, there was a high degree of similarity between the predicted and achieved growth response in ISS and IUGR. However, an uneven distribution within the plot of Studentized residuals in ISS and IUGR suggested heterogeneity within these populations. Prediction of growth in Turner's syndrome was greatly exaggerated by the model for IGHD, suggesting a different pathogenesis as the basis of the growth disorder. Specific prediction models were therefore developed for Turner's syndrome, ISS and IUGR. In all three disorders, the dose of GH was found to be the most important predictor, suggesting that, in contrast to IGHD, first-year growth is governed less by the difference between height and the presumed genetically determined target height. Again, in contrast to IGHD, this suggests that catch-up phenomena are not involved. As the predictability of the variation in growth response in Turner's syndrome, ISS and IUGR did not exceed 32% (for ISS), the search for new predictors should continue in these disorders.