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 or with Silver–Russell syndrome: results from KIGS (Kabi International Growth Study), including the first report on final height

The response to growth hormone (GH) therapy was studied in children born small for gestational age (SGA; n = 593) and in those with Silver–Russell syndrome (SRS; n = 127) using data from KIGS (Kabi International Growth Study). For the SGA patients, median birth weight was -2.6 SD scores (SDS), treatment was started at a median age of 9.2 years, at a time when median height was -2.8 SDS while median target height was -1.4 SDS. For the SRS patients, median birth weight was -3.1 SDS, treatment was started at a median age of 7.0 years, at a time when median height was -3.4 SDS with a median target height of -0.1 SDS. GH treatment increased height SDS in both SGA children and patients with SRS; in 16 SGA patients treated to (near) final height with GH (median dose, 0.7 IU/kg/week), height minus target height SDS was -2.0 at the start of treatment and -1.0 at final height. In conclusion, the results obtained in KIGS indicate that GH treatment of short children born SGA is effective in increasing final height above the predicted height and in achieving the target height.     

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.     

Growth hormone treatment of short children born small-for-gestational-age: the Nordic Multicentre Trial

The aims of this study were to evaluate the efficacy and safety of different doses of growth hormone (GH) treatment in prepubertal short children born small-for-gestational-age (SGA). Forty-eight children born SGA from Sweden, Finland, Denmark and Norway were randomly allocated to three groups: a control group of 12 children received no treatment for 2 y, one group was treated with GH at 0.1 IU/kg/d (n = 16), and one group was treated with GH at 0.2 IU/kg/d (n = 20). In total 42 children completed 2 y of follow-up, and 24 children from the treated groups completed 3 y of treatment. Their mean (SD) age at the start of the study was 4.69 (1.61) y and their mean (SD) height was -3.16 (0.70) standard deviation scores (SDS). The children remained prepubertal during the course of the study. No catch-up growth was observed in the untreated group, but a clear dose-dependent growth response was found in the treated children. After the third year of treatment, the group receiving the higher dose of GH, achieved their target height. The major determinants of the growth response were the dose of GH used, the age at the start of treatment (the younger the child, the better the growth response) and the family-corrected individual height deficit (the higher the deficit, the better the growth response). Concentration of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 increased during treatment. An increase in insulin levels was found without negative effects on fasting glucose levels or glycosylated haemoglobin levels. GH treatment was well tolerated. In conclusion, short prepubertal children born SGA show a dose-dependent growth response to GH therapy, and their target height SDS can be achieved within 3 y of treatment given GH at 0.2 IU/kg/d. However, the long-term benefit of different regimens of GH treatment in children born SGA remains to be established.     

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.     

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.     

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。     

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。     

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.     

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??Objective??To find the difference in growth and development of children between full-term symmetric growth restriction??FSGR?? and full-term asymmetric growth restriction??FAGR?? through a general investigation of children born small for gestational age in Shanghai. Methods??This general investigation covered all children under 6 years old in Shanghai. Data on growth were retrospectively obtained from medical records. The P10 of birth head circumference/birthweight of the same gestational age and gender was used to distinguish FSGR and FAGR. Results??The sample contained 10 188 full-term SGA children among whom 8049 were FAGR and 2139 were FSGR. Up to 3 years old??both FSGR and FAGR failed to catch up in weight??height??head circumference and chest circumference. Growth restriction in FAGR was more serious. Significant difference could be seen in weight??t??-3.412??P??0.001?? and chest circumference??t??-2.526??P??0.012?? between FSGR and FAGR at 3 years old. Regarding growth speed??the growth rate of weight ??t??6.272??P??0.001????height ??t??9.143??P??0.001????head circumference ??t??6.063??P??0.001?? and chest circumference ??t??6.617??P??0.001?? were higher in FAGR 6 months after birth??while there was no difference after that. The BMI of FAGR was significantly lower than FSGR before 2 years old. The proportion of children in danger of being overweight was significantly higher in FSGR ??P??0.001??. Conclusion??Both FSGR and FAGR experience catch-up growth after birth??but not enough to catch up with normal children at 3 years old??especially in head circumference. In spite of severer growth restriction??the cath-up growth model of FAGR is superior to FSGR. The proportion of children in danger of being overweight is significantly higher in FSGR.     

小于胎龄儿婴儿期肺功能初步探讨

目的 比较小于胎龄儿（SGA）和适于胎龄儿（AGA）婴儿期肺功能的差异。方法 2010 年 7 月至 2013 年 7 月在深圳市儿童医院NICU住院的胎龄<36周、无明显影响肺功能疾病的SGA为SGA组;出生体重与SGA组匹配的AGA为AGA组。两组均于纠正胎龄12月龄随访时行潮气呼吸和功能残气量检测,比较两组肺功能参数的差异。多元线性回归分析SGA组影响小气道功能的因素。结果 SGA 组 20 例（男 12 例,女 8 例）,AGA 组 30 例（男 17 例,女 13 例）进入分析。两组在出生体重和身长,机械通气天数等基线数据差异无统计学意义（P>0.05）;SGA 组胎龄和用氧天数高于 AGA 组,SGA组随访时体重和身长均低于 AGA 组（P＜0.05）。①在纠正胎龄12 月龄随访时两组呼吸频率、潮气量、每公斤潮气量、分钟通气量和功能残气量的差异均无统计学意义（P>0.05）; 呼气达峰时间、呼气达峰容积、呼气达峰时间比、呼气达峰容积比,75%、50%和25%潮气量时呼气流速,SGA 组均低于 AGA 组（P＜0.05）。②两组NICU出院至肺功能检测期间下呼吸道感染≥3次的比例,SGA组为90%（18/20）,AGA组为50%（15/30）,差异有统计学意义。③多元线性回归显示,SGA组25%潮气量时呼气流速与检测肺功能随访时身长、体重呈正相关,与吸氧天数呈负相关。结论 SGA 婴儿期肺容积参数与出生体重相近的AGA相近,但气道阻力高于AGA,可能与SGA生后肺发育迟缓相关。     

Breastfeeding and catch-up growth in infants born small for gestational age

Postnatal growth was prospectively measured from birth to 1 y in 54 term infants born small for gestational age (SGA), fed either breast milk or a standard term infant formula. Breastfeeding was associated with a 0.36 and 0.64 standard deviation (SD) increase in weight at 2 weeks and 3 months of age. respectively, which persisted beyond the breastfeeding period (0.64 SD at 1 y). Breastfed infants also showed greater catch-up growth in head circumference [SD score (SDS) 0.53 higher at 3 months], and greater body length gain (SDS 0.68 higher at 6 months). This increased growth was independent of potentially confounding obstetric, social and demographic factors. Our findings suggest that breastfeeding may promote faster growth in infants compromised by poor growth in utero. SGA infants may be programmed for a number of adverse outcomes; the possibility that such events are altered by choice of postnatal diet is a key issue for future research.     

Dietary intakes in children born small for gestational age and appropriate for gestational age: A longitudinal study

Children born small for gestational age (SGA) have an increased risk of cardiovascular disease (CVD) and associated risk factors in later life; however, little is known about their dietary intakes. The objective of this study was to assess dietary intakes in SGA and appropriate for gestational age (AGA) at 3.5, 7, and 11 years. The Auckland Birthweight Collaborative Study is a longitudinal case–control study of children born at term (n = 871). Children were assessed at 3.5 (n = 550), 7 (n = 591), and 11 (n = 620) years of age. Diet was assessed using a 24‐hr record‐assisted recall. Reported dietary intakes were analyzed and compared with the Australian and New Zealand Nutrient Reference Values. Compared with AGA, median energy intakes were significantly lower in SGA at 3.5 years (4.2 MJ [IQR, 3.0 to 5.8] vs. 5.4 MJ [IQR, 3.9 to 6.5]; p < .0001) but not at 7 and 11 years. Inadequate dietary intakes of micronutrients were more prevalent among SGA at 3.5 years and 11 years of age. A large proportion of SGA and AGA children consumed more than the recommended amounts of saturated fats, sugars, and sodium. There was no association of dietary intake and socio‐demographic factors. This study reveals that dietary intake in 3.5‐year‐old children born SGA is lower in energy and a variety of micronutrients compared with dietary intake in AGA. These intakes may however be appropriate given their BMI z‐scores. High intakes of sodium, saturated fat, and sugars are a concern for all children in this cohort.     

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.

Effects of growth hormone therapy in prepubertal children with short stature secondary to intrauterine growth retardation

A total of 130 short children were included in a French multicentre study and randomized between a control group (group A) and two groups treated with daily subcutaneous injections of GH at doses of 0.7 IU/kg/week (group B) and 1.4 IU/kg/week (group C) for 2 years. Height velocity was significantly increased ( p <0.0005) in groups B and C, with a greater increase in group C than in group B ( p < 0.001). The benefit after 2 years compared with controls was 4.3 cm in group B and 5.9 cm in group C. The rate of bone maturation was not affected by GH therapy. These results led to the conclusion that 2 years of treatment with GH improves final height prognosis in children with short stature secondary to IUGR, and that this effect is dose dependent. The effect on final height has still to be demonstrated.     

Ghrelin mRNA和蛋白在小于胎龄仔鼠胃底组织中表达的变化

目的了解胃底组织Ghrelin mRNA和蛋白表达与小于胎龄(SGA)仔鼠追赶生长的关系。方法采用妊娠中后期食物摄入限制法获得SGA和适于胎龄(AGA)仔鼠,并设对照组。孕鼠分娩后收获仔鼠,分别于0、20、40日龄3个时间点每组随机抽取仔鼠10只,取其胃底组织。采用实时荧光定量PCR法测定其Ghrelin mRNA,免疫组织化学法测定Ghrelin蛋白在各组仔鼠胃底组织中的表达。结果0日龄限食组SGA仔鼠胃底组织Gherlin mRNA表达高于限食组AGA仔鼠和对照组AGA仔鼠(Pa<0.05);20日龄和40日龄的SGA未追赶生长仔鼠、SGA追赶生长仔鼠和对照组AGA仔鼠胃底组织Gherlin mRNA表达均无统计学差异(Pa>0.05)。0日龄限食组SGA仔鼠胃底组织Ghrelin免疫阳性细胞的积分光密度(A)值高于限食组AGA和对照组AGA仔鼠(Pa<0.05);20日龄SGA追赶生长仔鼠胃底组织中Ghrelin免疫阳性细胞的A值高于SGA未追赶生长仔鼠和对照组AGA仔鼠(Pa<0.05);40日龄时3者间无统计学差异(P>0.05)。结论0日龄SGA仔鼠Ghrelin mRNA在胃底组织中表达增加,提示Ghrelin可能在宫内就开始参与宫内发育迟缓胎鼠的生理调节或病理过程,或是宫内的营养状况和环境变化对胎鼠胃底细胞的生理功能产生了影响,使Ghrelin mRNA表达上调;20日龄追赶生长SGA仔鼠胃底Ghrelin表达的变化进一步提示,Ghrelin可能参与了SGA早期的追赶生长调控。     

Risk factors for small for gestational age

BACKGROUND: The purpose of the paper was to determine the risk factors for small-for-gestational-age (SGA) infants at full term, in Japan. METHODS: The study was conducted at four hospitals and clinics in the Tokyo metropolitan area. A retrospective review of 2972 mothers and their infants born from singleton pregnancies at any time during the years 2002 and 2003 was conducted. RESULTS: Of these women, 8.4% gave birth to SGA infants. The proportion of SGA infants was significantly higher among heavy smokers (>10 cigarettes/day; 13.7%, P < 0.01). The odds ratio (OR) for SGA decreased significantly in proportion to the pregnancy body mass index (OR, 0.89; 95% confidence interval [CI]: 0.84-0.94, P < 0.001). The OR of SGA for stratified maternal weight gain was 1.79 (95%CI: 1.24-2.58, P 12 kg. CONCLUSION: The present study clearly confirms the detrimental effect of a low prepregnancy body mass index, low maternal weight gain and maternal smoking during pregnancy on the incidence of SGA infants.