Growth and growth hormone in children born small for gestational age

Although most children born small for gestational age catch up in growth by age 2 y, up to 14% remain more than 2 standard deviations below the mean for height. Recombinant growth hormone is approved by the US Food and Drug Administration and by the European Agency for Evaluation of Medicinal Products for the treatment of children born small for gestational age who fail to manifest catch-up growth by 2 y or 4 y, respectively.

Conclusion: We conclude from clinical studies that growth hormone therapy can induce catch-up growth in these children.     

Growth of short children born small for gestational age and their response to growth hormone therapy

Growth hormone [GH] is licensed for use in children born small for gestational age (SGA) who fail to catch-up. We retrospectively compared the response of twenty children born SGA (who satisfied the auxological criteria) to growth hormone (Group I) versus randomly selected age and sex matched controls from a group of SGA children with growth related complaints, not treated with GH (Group II). After 2 years of GH therapy the HAZ increased from ?2.8 to ?1.6 in Group I, compared 2.2 to -1.7 in group II (P-value < 0.05). The percentage of pubertal children rose from 55% to 65% in cases versus 60% to 75% in the controls (P>0.05). GH resulted in increase in growth velocity Z-score during the first year and (4.3±0.5 in Group-I versus — 0.5±0.6 in Group-II, P<0.05) second year of treatment (1.7±0.4 in cases versus -0.6±0.7 in controls, P<0.05).Thus, GH improves height of short SGA children without accelerating pubertal progression.     

Efficacy and safety of growth hormone treatment in children born small for gestational age in Japan

Growth-promoting effects and safety of growth hormone (GH) treatment in prepubertal short-statured children born small for gestational age (SGA) were evaluated in a multicenter, open-label, randomized parallel-group comparison study. Patients were randomized to two dose groups; 34 and 33 patients received GH at 0.033 and 0.067 mg/kg/day for one year, respectively. The increase of the mean height velocity standard deviation score (SDS) was significantly (p <0.0001) higher in the 0.067-mg group (from -1.4 to 4.7) than that in the 0.033-mg group (-1.9 to 2.6). A significant (p <0.0001) increase in the mean height SDS was established in the 0.067-mg group; increases of -3.1 to -2.5 vs -3.1 to -2.2 in the 0.033- and 0.067-mg groups, respectively. The trial was non-eventful. Oral glucose tolerance tests indicated a mostly normal pattern of plasma glucose before and after 12-month GH treatment. The growth-promoting effect was significantly higher with GH treatment at 0.067 mg/kg/day.     

Final height in short children born small for gestational age treated with growth hormone

The aim of this observational study was to assess the long-term growth responses to GH treatment of children born small for gestational age (SGA). GH treatment was begun before puberty and continued to final height (FH). Seventy-seven short (height SD score below -2) prepubertal children born SGA (below -2 SD for birth weight and/or birth length), with a broad range of GH secretory capacity, were treated with GH in a daily dose of 33 microg/kg (0.1 U/kg), beginning before the onset of puberty. We observed a difference between adult and pretreatment projected height of 1.3 SD (9 cm) for the entire group. Among the children treated for >2 y before puberty, this mean gain (i.e. difference) in final height was 1.7 SD, whereas the mean gain was 0.9 SD among those in whom treatment was begun <2 y before puberty. Better catch-up growth was observed in the younger (r=-0.56, p<0.0001), shorter (r=-0.49, p<0.0001), and lighter (r=-0.46, p<0.0001) subjects. We conclude that GH treatment improves the final height of short children born SGA. The height gain attained before the onset of puberty is maintained to final height. The younger, shorter, and lighter the child at the start of GH treatment, the better the response. Moreover, most of these SGA individuals treated with GH reach their target height.     

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.     

Longitudinal follow-up of growth in children born small for gestational age

Postnatal growth was followed in a population-based group of 123 small-for-gestational-age (SGA, birth weight < -2 SD) children (66 boys and 57 girls) to four years of age in order to determine the incidence and time of catch-up growth. Gestational age was determined by ultrasound in gestational weeks 16–17 in all pregnancies, thus eliminating the problem of distinguishing between SGA and preterm infants. Infants with well-defined causes for slow growth rate, i.e. those infants with chromosomal disorders, severe malformations, intrauterine viral infections or cerebral palsy, were excluded. The boys showed an extremely fast weight catch-up, 85% of them reaching weights greater than -2 SD at the age of three months and remaining above this level to the end of the study period. Such a fast catch-up growth was observed in only two-thirds of the girls, but at four years of age 85?4 of the girls were also above -2SD. Length catch-up was more gradual than weight catch-up. Of the boys, 54% had lengths below -2 SD at birth, 26% at 1 year of age, 22% at 2 years of age, 17% at 2.5 years of age and 11% (n= 8) at 4 years of age. Corresponding figures for girls were: 69% at birth, 28%) at 1 year, 15% at 2 years, 12% at 2.5 years and 5%) (n = 3) at 4 years. At 4 years of age, only six boys and three girls remained below -2 SD for both weight and height. We conclude that in Sweden the prognosis for catch-up growth for an SGA child, when children with well-defined causes of growth disturbances are excluded, is very good and it is extremely rare for the child still to have a height below -2 SD by the age of 4 years.     

Growth hormone secretion and sensitivity in children born small for gestational age

This short communication discusses aspects of growth hormone (GH) secretion and GH insensitivity in short children born short for gestational age (SGA).     

Reduced insulin sensitivity during growth hormone therapy for short children born small for gestational age

OBJECTIVES: To examine the influence of recombinant human growth hormone (rhGH) therapy on insulin sensitivity in short children born small for gestational age (SGA). STUDY DESIGN: Twelve short (height standard deviation score, -3.2 +/- 0.1) non-GH-deficient children SGA (7 boys/5 girls) were studied at 9.3 +/- 1.0 years of age. The insulin sensitivity index was measured with Bergman's minimal model before (11 children) and during (12 children) rhGH therapy (21 +/- 6 months) administered daily at 20 IU/m(2) per week. No child had a change in pubertal status during the study. In addition, 5 children who remained prepubertal had insulin sensitivity remeasured 3 months after rhGH therapy was suspended. RESULTS: With rhGH therapy, insulin sensitivity fell 44% +/- 10% (P =.018), with a compensatory rise in the acute insulin response of 123% +/- 59% (P <.009). Reassessment of insulin sensitivity in 5 children (3 boys/2 girls) 3 months after suspension of rhGH occurred at 9.9 +/- 0.7 years. Insulin sensitivity remained unchanged after rhGH therapy was stopped: 31.6 (20.5-42.3) before treatment, 11.5 (5.7-24.4) with treatment, and 10.7 (6.2-16.9) 10(-4). min(-1) microU/mL after treatment. CONCLUSIONS: Children SGA are known to have reduced insulin sensitivity. There was a further reduction in insulin sensitivity with rhGH therapy that did not recover 3 months after rhGH therapy was stopped.     

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.

生长激素治疗宫内生长迟缓生后持续矮小儿的临床研究

目的 用生长激素治疗宫内生长迟缓（IUGR）生后持续矮小和生长激素缺乏症（GHD）儿，并进行疗效评估。方法 分泌型重组人生长激素，剂量0.1U(kg.d) ,每日1次，于晚上睡觉前30min皮下注射，结果 IUGR组及GHD组经6个月治疗后身高增长率分别为1.03cm/月及1.12cm/月，两组间差异不显著，血清胰岛素样生长因子I（IGF-I）两组均有升高，GHD组升高程度大于IUGR组。结论 生长激素对策 后持续矮小及GHD儿均有良好治疗效果。     

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.     

Perinatal predictors of growth patterns to 18 months in children born small for gestational age

AIM: To determine factors before or at birth that are predictive of growth patterns to 18 months in children born small for gestational age (SGA). METHODS: Prospective cohort study of 186 SGA babies. Catch-up growth patterns were defined as early (>10th centile at 6 and 18 months), late (<10th centile at 6 months but >10th centile at 18 months), transient (>10th centile at 6 months but <10th centile at 18 months) or none (<10th centile at 6 and 18 months). RESULTS: Most children (75%) showed catch-up growth by 6 months. Of antenatal variables studied, only early gestation at diagnosis of SGA predicted late or failed catch-up. Late or failed catch-up was also associated with short gestation, small absolute and relative size at birth, increased placental weight/birthweight ratio (Pl/BW) and prolonged neonatal hospital stay. On logistic regression, both late and failed catch-up were associated with short birth length. Late catch-up growth was also associated with prolonged hospital stay and male sex. Failed catch-up was associated with increased Pl/BW. No antenatal or perinatal variables distinguished early from transient catch-up groups. CONCLUSION: SGA babies with late onset and less severe growth restriction have a good chance of catch-up growth by 6 months of age. Catch-up growth is likely to be delayed in SGA babies who are short at birth, are boys, and have prolonged hospital stays. However, poor growth over the first 6 months does not predict later growth patterns. Failure of catch-up growth in babies with increased Pl/BW may reflect an intrinsic growth defect. Transient catch-up growth may reflect environmental factors operating after birth.     

The risk of diabetes mellitus in children born small for gestational age and treated with recombinant growth hormone

Children born small for gestational age (SGA) are known to be at risk for both short stature and type 2 diabetes mellitus in later life. To evaluate the influence of recombinant growth hormone (rhGH) therapy on insulin sensitivity, 24 children born SGA were treated with GH at traditional doses, from 0.23 mg/kg/week (group A) to 0.46 mg/kg/week (group B). We evaluated glycosylated haemoglobin, basal glucose and insulin levels before and 1 and 2 years after GH therapy. The homeostasis model assessment (HOMA) index was used to evaluate insulin sensitivity. After 2 years of GH therapy, glycosylated haemoglobin and basal glucose did not change significantly. Insulin sensitivity fell, but still remained within the normal range. In conclusion, 2-year GH therapy had beneficial effects in SGA children without changes in glucose homeostasis. Moreover, the insulin sensitivity reduction did not correlate to the GH dose used.     

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。