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.     

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。     

Differences in insulin resistance markers between children born small for gestational age or born preterm appropriate for gestational age

Aim: To evaluate the impact of prenatal or postnatal compromised environment on glucose homoeostasis in children born preterm and appropriate for gestational age or small for gestational age (SGA) at term. Method: Seventy-seven children (median 9.9 years, range 8.5–10) born at Karolinska Hospital were allocated to three groups: 21 subjects born before 30 weeks of gestational age (preterm), 26 SGA at term and 30 at term with appropriate birth weight (control). Anthropometric measurements were taken, and fasting blood samples for haemoglobin A1c, glucose, insulin, IGFBP-1, IGF-1 and lipid profile were taken. Glucose, insulin and IGFBP-1 samples were taken at 0, 30 and 120 min during an oral glucose tolerance test (OGTT). Results: Subjects born preterm or SGA were shorter and thinner compared with Controls. After adjustment for body mass index (BMI), the SGA group had higher basal insulin levels (p = 0.029), higher homoeostasis model assessment—insulin resistance (p = 0.012) and lower whole-body insulin sensitivity index (p = 0.007) than Controls. IGFBP-1 decrease during OGTT was attenuated in the Preterm group compared with the Control (p = 0.045) and SGA groups (p = 0.007). Conclusion: The higher fasting insulin level in the SGA children, adjusted for BMI, could indicate peripheral insulin resistance. Preterm born children had reduced suppression of IGFBP-1 during OGTT, suggesting hepatic insulin resistance.     

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.     

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.     

Longitudinal study of the pubertal growth spurt in children born small for gestational age without postnatal catch-up growth

Most children born small for gestational age (SGA) experience extensive catch-up growth during the first months of life (87%) and by the age of 2 years only 13% are below -2 SDS for height. The long-term outcome, including pubertal growth spurt, of the subset of children born SGA without postnatal catch-up (SGAWPC) has been evaluated in very few surveys, and in none of them was the landmarks of puberty well described. Thus, a longitudinal study was conducted in these children throughout puberty since this is the only reliable way to accurately evaluate the pubertal growth spurt. In an observational, retrospective and multicenter collaborative study, from an initial group of 553 SGA children, a subset of 15 boys (BW = 2,070 +/- 379.6 g) and 16 girls (BW = 2,244 +/- 331.1 g) SGAWPC whose data were recorded regularly during puberty were selected. Growth standards for growth and maturity during puberty were Tanner and Whitehouse and Spanish Hernandez and Sobradillo charts. In pubertal growth spurt, 'take-off' occurred later than in the reference populations with a height SDS deficiency of -2.3 and -2.2 for boys and -2.0 and -1.9 for girls, compared with Spanish and Tanner references, respectively. Peak height velocity was normal in chronology and intensity, but the total pubertal gain was smaller. However, considering their growth from the same chronological age at which the reference populations took off until adulthood, the total gain was not significantly different in the three cohorts (32.5 +/- 5.4 cm vs 30.9 +/- 4.4 in boys, and 23.3 +/- 4.1 vs 25.7 +/- 5.4 cm in girls - Spanish reference - and 27.2 +/- 6.3 vs 27.6 +/- 3.5 cm in boys - Tanner charts), except in the case of girls (21.1 +/- 3.9 vs 25.3 +/- 4.1 cm, p <0.005 - Tanner charts). Adult height was significantly reduced (161.9 +/- 3.9 cm in males and 147.0 +/- 2.6 cm in females). Therefore, although the pubertal growth was smaller in these children, puberty probably did not modify their short final height.     

Association of serum lipid concentrations, insulin resistance index and catch-up growth with serum cortisol/cortisone ratio by liquid chromatography tandem mass spectrometry in children born small for gestational age

Intrauterine growth restriction (IUGR) may influence adrenocortical function, lipid metabolism and glucose tolerance in later life. Both cortisol (F) synthesis and metabolism contribute to serum F concentrations. 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) enzyme converts F to biologically inactive cortisone (E). Decreased 11beta-HSD2 activity has been suggested for a reason to IUGR and to its metabolic consequences. Our aim was to develop a specific liquid chromatography - tandem mass spectrometry (LC-MS/MS) method for analysing serum F and E concentrations, to determine the F/E ratios, and to correlate them with serum lipid concentrations, insulin resistance index (HOMA-IR), and catch-up growth in children born small for gestational age (SGA). The mean serum F and E concentrations, and F/E ratios did not differ between the SGA and their control children at 12 y age. The SGA children in the highest F/E ratio quartile had poorer gain in height between 0-12 y, and higher serum total and LDL cholesterol levels than those with lower F/E ratios. In logistic regression analysis, high LDL cholesterol, high HOMA-IR, and early pubertal stage associated with high F/E ratio in the SGA children. In conclusion, our LC-MS/MS method enables a reliable measurement of both F and E concentrations from a single serum sample. High serum F/E ratio may be associated with IUGR, its metabolic consequences, and poor catch-up growth in a subset of SGA children.     

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.     

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.     

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.     

The somatotropic axis in short children born small for gestational age: relation to insulin resistance.

To determine whether hyperinsulinemia and reduced insulin sensitivity in individuals born small for gestational age (SGA) could be related to persisting abnormalities of the GH/IGF-I axis, we assessed overnight GH secretory profiles and measured fasting glucose, insulin, intact and 32,33 split proinsulin, and IGF-I levels in 16 short SGA children (age range 2.3-8.0 y) and in controls. Insulin sensitivity was calculated using the homeostasis model. Compared with short normal-birthweight controls (n = 7, age range 2.3-5.0 y), short SGA children had higher fasting insulin levels (means: 26.8 vs 20.6 pmol/L, p = 0.02), lower insulin sensitivity [means: 204 vs 284 %homeostasis model assessment (HOMA), p = 0.01], and higher beta cell function (112 vs 89 %HOMA, p = 0.04). SGA children also had lower levels of IGFBP-1 (87.0 vs 133.8, p = 0.04), but similar IGF-I levels (IGF-I SDS: -1.1 vs -1.7, p = 0.4). Compared with normal-height controls (n = 15, age range 5.6-12.1 y), SGA children had higher overnight GH secretion (GH maximum: 55.9 vs 39.6 mU/L, p = 0.01; mean: 13.1 vs 8.9, p = 0.004; minimum: 1.2 vs 0.6, p = 0.02). Interestingly, among SGA children, fasting insulin levels and insulin sensitivity were significantly related to overnight GH secretion (insulin sensitivity vs maximum GH: r = -0.68, p = 0.01; vs GH pulse amplitude r = -0.71, p = 0.007). The only hormone level significantly related to current height velocity was C-peptide (r = 0.75, p = 0.008). In conclusion, elevated fasting insulin levels and reduced insulin sensitivity in short SGA children was related to elevated levels of overnight GH secretion. We hypothesize that resistance to the somatotropic actions of GH and IGF-I in short SGA children may contribute directly to reduced insulin sensitivity.     

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.

Prediction of height achievement at five years of age in children born very preterm or with very low birth weight: continuation of catch-up growth after two years of age

To predict height at five years in a cohort of 565 very preterm and/or very low-birth-weight children, hypothesized growth determinants were subjected to discriminant analysis. Many neonatal parameters were not significantly associated with short stature at five years of age. A correct classification of stature (smaller/larger than the 10th percentile at five years of age) could be obtained in 85% of children, using the following variables: height at two years of age; total (or mid) parental height; parental level of education; length at one year of age; hypertension during pregnancy; sex; weight at two years of age; length percentile at one year of age. However, when compared to actual longitudinal data, the false-positive rate was 37%. The survey also demonstrated the continuing catch-up growth in very preterm and very low-birth-weight infants after two years of age.     

Pubertal development in children born small for gestational age

Reduced fetal growth appears to be associated with precocious adrenarche, early puberty and polycystic ovary syndrome with subsequent fertility problems. We investigated pubertal development and DHEAS levels in children born small for gestational age (SGA) and children born appropriate for gestational age (AGA). Physical examination was carried out twice. Mean age (+/-SD) at the first visit: SGA group, 9.1+/-1.1 yr; AGA group, 9.0+/-1.1 yr. AT FOLLOW-UP: SGA group, 11.6+/-1.0 yr; AGA group, 11.6 +/-1.1 yr. Pubertal stages of the children were assessed. Pubic hair was recorded as a measure of androgenization. Chronological age (CA) was expressed as a percentage of the age corresponding to the pubertal stage (CA/pubertal age [PA] x 100%). Estradiol, testosterone and dehydroepiandrosterone sulfate (DHEAS) were measured in all children. FIRST VISIT: All children were prepubertal without signs of pubarche. DHEAS concentrations were higher in SGA children than in AGA children (p = 0.004). FOLLOW UP: Twenty SGA children and 15 AGA children were pubertal. CA/PA x 100% was lower in SGA girls than in AGA girls (p = 0.004). Since 2.5 years earlier all girls had been prepubertal, this means a more rapid progression in the SGA girls. CA/PA x 100% was similar in SGA and AGA boys (p = 0.1). DHEAS levels tended to be higher in SGA children than in AGA children (p = 0.06). These data support that a low birth weight may have long-lasting effects on pubertal development, as observed in a more rapid progression in SGA girls. In prepubertal SGA children, an exaggerated adrenarche is observed compared to AGA children, which tended to persist through puberty.     

Serum lipid concentrations and growth characteristics in 12-year-old children born small for gestational age

According to Barker's hypothesis, children born small for gestational age (SGA) are at increased risk for cardiovascular diseases in adulthood. The aim of our study was to determine whether retarded fetal growth is associated with dyslipidemia in childhood and, if so, to find predictive factors in the growth characteristics of SGA children. We studied the serum lipid concentrations of 55 SGA children and their 55 appropriate for gestational age control subjects at the age of 12 y. Growth variables were recorded at birth, 5 y, and 12 y of age. The study group consisted of all full-term SGA children born at our university hospital during a 22-mo period in 1984-1986. Nearly half of the SGA children (47.3%) were in the highest quartile for serum total cholesterol of the appropriate for gestational age children (p = 0.038). In multiple logistic regression analysis, poor catch-up growth in height (odds ratio, 13. 8; 95% confidence interval, 2.0-97.5), female sex (odds ratio, 8.1; 95% confidence interval, 1.3-48.9), and early stage of puberty (odds ratio, 7.5; 95% confidence interval, 1.2-46.5) predicted high cholesterol level in the SGA children. By the age of 5 y, 20 (36.4%) SGA children showed catch-up growth of > or =2 SD scores in height, and 21 (38.2%) SGA children showed catch-up growth of > or =2 SD scores in weight from birth. At the age of 12 y, the SGA children were still significantly shorter (p<0.001) and lighter (p< 0.05) than the appropriate for gestational age children, even though their pubertal development was similarly advanced. In conclusion, to be born SGA has long-term consequences for later growth and may already influence the level of serum total cholesterol before the teens. SGA children with poor catch-up growth in height may be at the highest risk for hypercholesterolemia.     

小于胎龄儿青春前期女孩硫化脱氢表雄酮和胰岛素水平的研究

目的探讨小于胎龄儿(SGA)青春前期女孩肾上腺机能初现及是否具有肾上腺机能早现、高肾上腺雄激素血症、高胰岛素血症和胰岛素抵抗现象。方法以符合纳入标准的SGA 39例为研究对象,年龄(7.4±1.7)岁,42例适于胎龄儿(AGA)为对照组,年龄(7.4±1.7)岁。在隔夜空腹12 h后,行身体检查,并抽血检测空腹血糖、胰岛素、硫化脱氢表雄酮(DHEAS)、皮质醇和雌二醇。胰岛素敏感性用空腹血糖与胰岛素乘积的倒数再取自然对数来评价。结果两组中未发现肾上腺机能早现的临床表现,两组间孕母孕龄、年龄、体重指数、空腹血糖、皮质醇、雌二醇和胰岛素敏感性指数差异无统计学意义。SGA组出生体重、研究时的身高和体重均低于AGA组,SGA血清胰岛素和DHEAS水平均高于AGA组(对数转换值:1.076±0.041vs.1.050±0.051,P<0.05;2.637±0.271vs.2.514±0.250,P<0.05)。AGA组DHEAS值在7岁以后出现明显增加,SGA组DHEAS值出现增加的趋势与AGA组比较有所提前。结论AGA女孩肾上腺机能初现的年龄约为7岁,而SGA女孩肾上腺机能初现有始动提前的趋势,青春前期SGA女孩有高肾上腺雄激素血症和胰岛素水平升高的现象,但以胰岛素敏感性指数来评价,尚未发现胰岛素抵抗现象。