Small for gestational age: towards 2004

Children born small for gestational age are a non-homogeneous group and etiology and diagnostic needs vary among subgroups. In view of the knowledge accumulated about immediate and future risk factors for these children it is important to study the etiology and to invest in long-term prevention programs. The aim of this report is to summarize the current knowledge on mechanisms leading to intrauterine growth retardation and to review the intervention procedures.     

Carbohydrate metabolism during long-term growth hormone treatment in children with short stature born small for gestational age

OBJECTIVE: To assess possible side-effects of long-term continuous growth hormone (GH) treatment on carbohydrate (CH) metabolism in children with short stature born small for gestational age. DESIGN: In a prospective, randomised double-blind, dose-response multicentre trial, the effect of GH treatment on CH metabolism was evaluated, comparing two GH dosages [3 vs. 6 IU/(m(2) body surface.day)]. PATIENTS: Seventy-eight children with short stature (height SD-score < - 1.88) born small for gestational age (birth length SD-score < - 1.88) being all prepubertal with a mean (SD) chronological age of 7.3 (2.2) years before start of treatment. MEASUREMENTS: Glucose and insulin concentrations during oral glucose tolerance tests (OGTTs) and glycosylated haemoglobin (HbA(1c)) were measured before and during 6 years of GH treatment. RESULTS: Before treatment, the glucose response to oral glucose after 120 min was in six of the 78 children (8%) above 7.8 mmol/l but below 11.1 mmol/l, indicating impaired glucose tolerance (IGT), whereas after 6 years of GH treatment, IGT was found in 4% of the children. None of the children developed diabetes mellitus. Mean fasting glucose levels had increased significantly by 0.5 mmol/l after 1 year of GH treatment, without a further increase thereafter. The 2-h area under the curve adjusted for fasting levels (AUCab) for glucose and the HbA(1c) levels were lower after 6 years of GH treatment compared to baseline. During GH treatment, all HbA(1c) levels were in the normal range. In contrast to the effects on glucose levels, GH treatment induced considerably higher fasting insulin levels and glucose-stimulated insulin levels. The increase in AUCab for insulin occurred particularly during the first year of treatment, whereas the fasting insulin levels showed a further increase from one to six years. As a result, the 30- and 120-min ratios of insulin to glucose were higher during GH treatment compared to the start of treatment. The children who remained prepubertal during the entire study period showed similar patterns in glucose and insulin levels compared to the children who entered puberty. None of the observed changes were different between the GH dosage groups. CONCLUSIONS: Continuous GH treatment during 6 years in children with short stature born small for gestational age has no adverse effects on glucose levels, even with dosages up to 6 IU/(m(2) d). However, as has been reported in other patient groups, GH treatment induces higher fasting insulin levels and glucose-stimulated insulin levels, indicating relative insulin resistance. Since the consequences of long-term hyperinsulinism during childhood are unknown, careful follow-up of these GH-treated children born small for gestational age is required.     

Growth hormone therapy for short children born small for gestational age

Approximately 10% of all children born small for gestational age (SGA) fail to achieve sufficient catch-up growth and remain with short stature throughout childhood and adult life. Abnormalities of the GH/IGF-1 axis are not always identified. Several studies have demonstrated that GH is an effective and well-tolerated therapy and most children will reach a normal adult height. In this review, it can be seen the encouraging results of GH treatment in growth-retarded children born SGA highlighting the benefits of early treatment.     

Improvement in adult height after growth hormone treatment in adolescents with short stature born small for gestational age: results of a randomized controlled study

The efficacy of GH for increasing adult height (AH) in short adolescents born small for gestational age (SGA) is unclear, due to the lack of long-term controlled trials. A total of 168 short children born SGA (age, 10.5 yr for girls and 12.5 yr for boys) were randomly assigned to receive either 0.067 mg/kg.d GH until attainment of AH or no treatment. In this per-protocol analysis, 91 of 102 patients in the treated group and 33 of 47 patients in the control group were followed to AH. Mean height at inclusion was -3.2 SD score (SDS). Treatment duration was 2.7 +/- 0.6 yr. AH was -2.7 +/- 0.9 and -2.1 +/- 1.0 SDS in the control and treated groups, respectively (P < 0.005). The groups differed by 0.6 SDS units (95% confidence interval, 0.2-0.9). Height gain was 0.5 +/- 0.8 and 1.1 +/- 0.9 SDS in the control and treated groups, respectively (P = 0.002). Multivariate analyses confirmed the independent effects of treatment (0.6 SDS) and treatment duration (0.4 SDS/yr). All potential biases would tend to decrease the estimate of the treatment effect. Treatment tolerance was excellent. We concluded that the potential for spontaneous catch-up in short adolescents born SGA is limited. GH treatment increases AH by at least 0.6 SDS in this population.     

Growth hormone treatment in children with short stature born small for gestational age: 5-year results of a randomized, double-blind, dose-response trial.

The growth-promoting effect of continuous GH treatment was evaluated over 5 yr in 79 children with short stature (height SD score, less than -1.88) born small for gestational age (SGA; birth length SD score, less than -1.88). Patients were randomly and blindly assigned to 1 of 2 GH dosage groups (3 vs. 6 IU/m2 body surface-day). GH deficiency was not an exclusion criterium. After 5 yr of GH treatment almost every child had reached a height well within the normal range for healthy Dutch children and in the range of their target height SD score. Only in children who remained prepubertal during the study period was the 5-yr increase in height SD score (HSDS) for chronological age significantly higher in the study group receiving 6 compared to 3 IU GH/m2 x day. Remarkably, the 5-yr increment in HSDS for chronological age was not related to spontaneous GH secretion, maximum GH levels after provocation, or baseline insulin-like growth factor I levels. GH treatment was associated with an acceleration of bone maturation regardless of the GH dose given. The HSDS for bone age and predicted adult height increased significantly. GH treatment was well tolerated. In conclusion, our 5-yr data show that long term continuous GH treatment at a dose of 3 or 6 IU/m2 x day in short children born SGA results in a normalization of height during childhood followed by growth along the target height percentile.     

Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA)

OBJECTIVE: Few data are available on the pubertal development of children born small for gestational age (SGA) who fail to show catch-up growth. DESIGN: A longitudinal analysis compared the pubertal course of persistently short children born SGA compared to children with idiopathic short stature who were appropriate for gestational age (AGA). One hundred and twenty-eight short children (height SDS<-1.7), including 76 (31 boys) born SGA and 52 (22 boys) born AGA, were regularly followed from early childhood to completion of puberty. RESULTS: Puberty was attained at normal age (10.5-14 Years in boys, 9.5-13 Years in girls) for most children in both the SGA and AGA groups (boys, 80% and 77%; girls, 76% and 78% respectively). The duration of puberty was similar in the SGA and AGA groups. Menarche occurred at normal age range but was significantly earlier in the SGA girls (P<0.01 by ANOVA). Despite the similar total pubertal growth, the patterns of growth differed significantly: SGA group - accelerated growth and bone maturation rates from onset of puberty with peak height velocity at Tanner stages 2-3, followed by a decelerated growth rate and earlier fusion of the epiphyses; AGA group - steady progression of bone elongation and maturation throughout puberty (pubertal growth, P<0.05 in both sexes; bone maturation, P<0.001 in both sexes). Final height in the SGA group was compromised compared with their target height (P<0.001). CONCLUSION: Children born SGA have a normal pubertal course with a distinct pubertal growth pattern. This pattern may represent an altered regulation of their growth modalities.     

Growth hormone treatment of short children born small for gestational age.

Short children born small-for-gestational-age (SGA) appear to be at an increased risk of having a poly-endocrinopathy, including a degree of growth hormone (GH) deficiency and/or insulin-like growth factor 1 (IGF-1) resistance. Among GH-deficient children, those born SGA present a lower growth response to GH therapy than those not born SGA. The growth response of short SGA children to GH treatment does not appear to depend significantly on the secretory status of GH (as judged by provocative testing), indicating that the SGA condition (IGF-1 resistance) predominates over the availability of endogenous GH in determining the short stature of the majority of these children. When a higher than replacement dose of GH is administered, the growth response of short SGA children matches that of GH-deficient non-SGA children, indicating that the IGF-1 resistance towards growth can be overcome, and that a normal stature can be obtained, at least throughout childhood. It is anticipated that, increasingly, the indications and the doses for GH therapy in children will become interlinked with the emerging principles of endocrine programming in early life.     

Idiopathic short stature.

The diagnostic term, idiopathic short stature, has emerged over the past 30 years and refers to children with short stature of unknown etiology. Controversy exists regarding the scope of the diagnosis and options for its treatment. This article reviews origins of the diagnosis idiopathic short stature and current diagnostic criteria, scientific advances in delineating etiologies of idiopathic short stature, management options, and implications of management decisions for child health.     

Short stature and gestational diabetes in Brazil

Aims/hypothesis. To examine the association between maternal stature and gestational diabetes mellitus.¶Methods. We studied a sample of 5564 consecutive Brazilian women 20 or more years old, who were pregnant for approximately 21–28 weeks, had no history of diabetes outside pregnancy and were attending general prenatal care units in six state capitals in Brazil from 1991 to 1995. We did a 2-h, 75-g oral glucose tolerance test, defining gestational diabetes by World Health Organisation criteria.¶Results. Those in the shortest quartile of height ( ≤ 151 cm) had a 60 % increase in the odds of having gestational diabetes, independently of prenatal clinic, age, global obesity, family history of diabetes, skin colour, referral pattern, waist circumference, parity, previous gestational diabetes, education, ambient temperature and gestational age compared with the tallest quartile [odds ratio (OR) = 1.60, p = 0.005]. This association was observed for those with above median values of skinfold thickness (OR = 1.74, p = 0.006) but not for those with below median values (OR = 1.22, p = 0.51). Associations of short stature with high 2-h glycaemia ( ≥ 7.8 mmol/l) (OR = 1.61, p = 0.005) were essentially the same as those for gestational diabetes. There was, however, no association between short stature and gestational hyperglycaemia when the latter was defined exclusively by fasting values (OR = 0.97, p = 0.90).¶Conclusion/interpretation. In Brazil short stature associates with gestational diabetes, principally in women with greater fat mass. This difference in glycaemic levels is present postprandially but not in the fasting state. [Diabetologia (2000) 43: 848–851]     

Serum levels of adiponectin and IGFBP-1 in short children born small for gestational age

OBJECTIVE: The aim of this study was to quantify serum adiponectin concentrations in short children born small for gestational age (SGA) compared with those in children born appropriate for gestational age (AGA), and to assess the relationship between the serum levels of adiponectin and insulin-like growth factor binding protein-1 (IGFBP-1) known as a predictor of the development of type 2 diabetes mellitus and cardiovascular disease. SUBJECTS AND METHODS: Sixteen prepubertal short children born SGA and 20 short children born AGA, matched for age, body mass index, height, pubertal status, gestational age, bone age and midparental height, were included in the study. The serum levels of adiponectin, IGFBP-1, insulin and insulin-like growth factor-I (IGF-I) were measured in the fasting state. RESULTS: The levels of serum adiponectin were significantly lower in the SGA than in AGA children (10.5 +/- 4.2 vs. 13.9 +/- 5.1 micro g/ml, P < 0.05). The levels of serum IGFBP-1, insulin and IGF-I were all similar in both groups. Overall, there was a significant positive correlation between adiponectin and IGFBP-1 (r = 0.40, P < 0.05). CONCLUSIONS: Our results suggest that hypoadiponectinaemia in short SGA children without catch-up growth may reflect insulin resistance and imply a higher risk of developing type 2 diabetes mellitus. Additionally, adiponectin may be a more sensitive indicator for latent insulin resistance than IGFBP-1 in short SGA children.     

Growth hormone and idiopathic short stature

Idiopathic short stature is defined by height below 3rd percentile, in a child with normal birth height and weight, lack of dysmorphy, endocrine deficiency or systemic disease. Food and Drugs administration approved GH treatment in this indication in the United States, because it induces height gain, and sometimes may increase quality of life. There is no consensus in terms of duration, monitoring parameters, benefits and risks of long term GH treatment in these patients. Cost effectiveness of such a treatment is under debate, and ethical considerations also have to be taken into account. Recombinant IGF1 should not be proposed in this indication at the moment, due to the lack of sufficient data on potential GH insensitivity in a subgroup of these patients.     

Decreased stature in gestational diabetes mellitus

Summary Short stature has been associated with various degrees of abnormal glucose tolerance in middle-aged people, where the effects of age and metabolic control would be difficult to exclude. We chose to examine body stature in women with gestational diabetes mellitus (GDM), a prediabetic state affecting a young group of people. A sample of 2772 Greek pregnant women, referred for GDM screening was examined. After a 100-g oral glucose tolerance test, 1787 women were classified as normal (N), 300 women were found with one abnormal glucose value (OAV) and 685 women with GDM. Basal insulin resistance was calculated in 640 women by homeostasis model assessment. In addition, 51 pregnant women with pre-existing Type II (non-insulin-dependent) diabetes mellitus and 109 with pre-existing Type I (insulin-dependent) diabetes mellitus were included in the study. There was a gradual decrease in mean height (cm) as glucose intolerance became more severe: N: 161.0 ± 6.2, OAV:160.2 ± 6.1, GDM:158.7 ± 6.3, Type II diabetes 158.2 ± 7.0 (p < 0.001, analysis of variance]. Height in Type I diabetes (160.1 ± 5.9) did not differ from the normal group. The difference in height between the normal and GDM groups remained (p < 0.001) when body weight, age, birth before or after 1960 and educational status were also taken into account. An independent correlation was also found between height and insulin resistance (n = 640) adjusted for the above mentioned variables. In conclusion, short stature appears to be associated with glucose intolerance as an independent variable, even when this intolerance is both mild and temporary. The previously unrecognised independent association of stature with basal insulin resistance merits further investigation. [Diabetologia (1998) 41: 997–1001] Received: 2 February 1998 and in final revised form: 28 April 1998     

Body proportions during 6 years of GH treatment in children with short stature born small for gestational age participating in a randomised, double-blind, dose-response trial

The aim of this study was to assess body proportions in children with short stature born small for gestational age (SGA) before and during 6 years of growth hormone (GH) treatment. A prospective randomised double-blind dose-response study comparing the effects of 3 vs. 6 IU GH/m2/day. Seventy-nine children with short stature (height SD-score < -1.88) born small for gestational age (birth length SD-score < -1.88). Before and during GH treatment, height, sitting height (SH), hand (Hand) and foot length (Foot), biacromial (Biac) and biiliacal diameter (Biil) were measured. All results were adjusted for age and sex, and expressed as SD-scores (SDS) using reference values for healthy Dutch children. To describe the size of SH, Hand, Foot, Biac, and Biil in relation to height, these values were adjusted for the SDS of height. At baseline, these short children had small hands and feet and narrow shoulders and pelvis compared to healthy peers. Height and SH, were, however, even more affected. Consequently, on average, these children had relatively large hands and feet, and relatively broad shoulders and pelvis compared to their height, but a normal sitting height in proportion to height. In most of the individuals, the values for body proportions were, however, within the normal range. During 6 years of GH treatment the SD-scores of all measurements increased significantly towards values more close to zero. The mean size of Hand, Foot, and Biil decreased in proportion to height. The mean SH increased relatively more than height, however, to values well within the normal range. The mean Biac in relation to height had not changed after 6 years of GH treatment. No differences in the 6-year changes in body proportions were found between the two GH dosage groups. Untreated short children born small for gestational age have, on average, relatively large hands and feet, and broad shoulders and pelvis, but a normal sitting height compared to height. The increase in height during 6 years of GH treatment is accompanied by an improvement of the proportions of the size of hands, feet, and biiliacal diameter, in relation to height. The increase in height appeared to be the result of the increase in sitting height as well as leg length, but the sitting height SD-score increased slightly more than that of leg length. The changes in body proportion during GH treatment were dose-independent. Thus, 6-year continuous GH treatment with either 3 or 6 IU/m2/day in children with short stature born small for gestational age does not negatively influence body proportions.