Intrauterine Growth Retardation Children Research Articles

060 An analysis of the effect of intrauterine growth retardation on spirometric lung function measures of 8-year-old children

ObjectiveIncreasing evidence suggests that intrauterine growth retardation (IUGR) is associated with long-term morbidities, including respiratory outcomes. The relationship between IUGR and lung function has been studied in adults, but few...

Relationship between selected hormonal and metabolic parameters at birth and blood pressure during pre-adolescence

Objective: The aim of the present study was to evaluate the relationship between selected hormonal parameters (at birth and at age 8 years) and blood pressure levels at pre-adolescence in a cohort of intrauterine growth retarded (IUGR) and normal birth weight infants (NBW). Methods: A cohort study from early pregnancy to childhood was performed. Seventy-six fetuses/children were evaluated between 1995 and 2004. Cord blood samples were taken at birth and several hormonal and metabolic parameters evaluated. Sixty-four children of the original cohort were available for blood sampling, blood pressure and anthropometric measures at a mean age of 8 years. 27 (42.2%) were IUGR and 37 (57.8%) were NBW. Multiple regression analyses were conducted with cord blood levels of hormonal and metabolic parameters at birth and at 8 years as independent variables and children’s blood pressure as dependent variable adjusted by IUGR status, gender, Body Mass Index and age of the child at the time of blood pressure evaluation. Results: The maternal age (26.6±5.8 vs 26.9±5.8 years old) and the gestational age at birth (39.1±1.4 vs 39.6±1.3 weeks) were similar between the groups. IUGR children were shorter (1.28± 0.09 m vs 1.33± 0.09 m, p=0.04). Growth hormone levels (GH) at birth were negatively associated with systolic blood pressure at 8 years of age (regression coefficients for umbilical cord blood levels: -0.9, 95% CI -2.03 to 0.04 mg/ml, p= 0.04). Conclusion: The alterations on blood pressure can begin in fetal life were levels of GH could have an important role.

The relation of arterial stiffness with intrauterine growth retardation

Much epidemiological evidence has linked low birthweight with late cardiovascular risk. Intrauterine growth retardation (IUGR) is associated with the increased risk of cardiovascular disease in adult life; it is unclear whether the relationship is present at younger ages. We evaluated whether abdominal aortic stiffness was altered in patients with IUGR (born at term with birthweight small for gestational age) in younger ages. Thirty-two (24 girls and eight boys) IUGR children aged 8.77 +/- 2.05 years were enrolled in the study. The birthweight was traced from the medical records. Their gestational ages were 38.9 +/- 0.85 weeks and birthweights 2130 +/- 198 g, respectively. Thirty-one healthy subjects who had normal gestational age and birthweight, matched for age and sex were recruited as a control group. Aortic strain, pressure strain elastic modulus (Ep), and normalized Ep and aortic distensibility were measured by a sphygmomanometer and transthoracic echocardiography in all subjects from the abdominal aorta. There was no statistically significant difference between the study and the control groups in sex, mean age, body mass index, lipid profile, leptin, insulin-like growth factor-1 or insulin-like growth factor binding protein 3. In IUGR children, aortic strain (0.201 +/- 0.027 vs 0.254 +/- 0.031, P < 0.001) and aortic distensibility (1.08 +/- 0.19 vs 1.42 +/- 0.24, P < 0.001) were significantly lower compared with the control group. However Ep (188 +/- 36.2 vs 146 +/- 27.1, P < 0.001) and normalized Ep (2.97 +/- 0.40 vs 2.1 +/- 0.39, P < 0.001) were significantly higher in IUGR patients. This study demonstrates that abdominal aortic stiffness is increased in IUGR patients. These data suggest that prenatal events could be related to cardiovascular risk in later life.

Deficits in spatial orientation of children with intrauterine growth retardation

The spatial orientation of intrauterine growth retarded (IUGR) children versus age-matched controls was examined using two spatial tests. The first test was the radial arm maze (RAM), a navigational test frequently used in animal models. The second test was a subtest from the Kaufman assessment battery for children (K-ABC). The IUGR group comprised 28 children aged 6 years. The control group comprised 29 appropriate-for-gestational age children. The performance of the IUGR children was significantly inferior to controls in both tests. In the RAM test, the ratio between the correct entrances to the total entrances was significantly lower in the IUGR group than in the control group ( P < 0.001). In the K-ABC, the IUGR group could not perform as well as control children ( P < 0.001). These results suggest that spatial orientation in IUGR children is inferior to their age-matched controls, possibly contributing to their potential learning difficulties. The present results also suggest that the RAM can be potentially used to test spatial orientation of children at-risk.

Metabolic effects of growth hormone in the child and adolescent.

During the year 2000, several original studies were published regarding the metabolic effects of growth hormone therapy in pediatric patients. Pharmacologic doses of growth hormone were rarely associated with abnormalities in glucose tolerance in children with intrauterine growth retardation and Turner syndrome; however, serum insulin levels were elevated. A report from the Pharmacia International Growth Study database suggested a possible increase in type 2 diabetes in growth hormone-treated patients, indicating the need for continued surveillance for this condition. Growth hormone therapy increased markers of bone turnover and bone mineral density in children with chronic renal failure and Prader-Willi syndrome. In Prader-Willi syndrome, 2 years of growth hormone therapy also induced a sustained decrease in body fat, improvement in strength and physical skills, and increased lean body mass. Serum leptin, a reflection of body fat, declined with growth hormone therapy in a dose-dependent manner in intrauterine growth retardation children; the magnitude of the decline correlated with linear growth response. Skin is a target organ for growth hormone in children; growth hormone increased dermal thickness and reduced skin stiffness in growth hormone-deficient children. Reassuring data were published regarding the risk of tumor recurrence and mortality in children with brain tumors treated with growth hormone. Growth hormone administered to short children prior to kidney transplantation did not have adverse effects on subsequent graft survival or number of rejection episodes.

Growth, IGF system, and cortisol in children with intrauterine growth retardation: is catch-up growth affected by reprogramming of the hypothalamic-pituitary-adrenal axis?

Intrauterine growth retardation (IUGR) is one of the major causes of short stature in childhood. Although postnatal catch-up growth occurs in the majority of IUGR children, approximately 20% of them remain permanently short. The mechanisms that allow catch-up growth or, on the contrary, prevent IUGR children from achieving a normal height are still unknown. Our aim was to investigate whether intrauterine reprogramming of hypothalamic-pituitary-adrenal axis may be involved in postnatal growth retardation of IUGR children through a modulation of the function of the IGF system. Anthropometry, IGF system assessment, cortisol measurement, and lipid profile evaluation were performed in 49 IUGR children. Children were subdivided into two groups according to their actual height corrected for midparental height: CG (catch-up growth) group, 19 children with corrected height >or=0 z-score; and NCG (noncatch-up growth) group, 30 subjects with corrected height <0 z-score. CG children showed significantly higher birth weight (p < 0.005) and body mass index (p < 0.05). No significant differences in IGF-I, IGF-II, IGF binding protein (IGFBP)-1, IGFBP-3, soluble IGF-II receptor levels (IGF2R), IGF-II/IGF2R ratio, and relative amounts of IGFBP-3 circulating forms were found between CG and NCG children. None of the IGF system-related variables correlated with anthropometric indices. NCG children showed significantly higher concentrations of cortisol (p < 0.005) and cortisol levels resulted inversely to birth weigh (r = -0.34, p < 0.05), birth length (r = -0.36, p < 0.05), and corrected height (r = -0.44, p < 0.01). Whereas total and HDL cholesterol concentrations were not significantly different in the two groups, LDL cholesterol levels were significantly higher in NCG children (p < 0.05), and five of 49 showed LDL cholesterol concentrations >3.4 mM (130 mg/dL). LDL cholesterol was inversely related to birth weight (r = -0.31, p < 0.05), corrected stature (r = -0.32, p < 0.05), and actual height (r = -0.31, p < 0.05) and directly related to the levels of IGF2R (r = 0.44, p < 0.01). Reanalysis of 15 of 30 IUGR newborns in whom we previously reported an inverse relationship between cord blood cortisol levels and first trimester length gain (r = -0.54, p < 0.005) showed that the relative amount of the IGFBP-3 18-kD fragment was related inversely to cortisol (r = -0.67, p < 0.01) and directly to early postnatal growth (r = 0.65, p < 0.05). Our results suggest that catch-up growth in IUGR children might be affected by intrauterine reprogramming of hypothalamic-pituitary-adrenal axis, which may result in a permanent modification of the neuroendocrine response to stress: children with increased cortisol secretion may be at higher risk of growth failure. During the neonatal period cortisol might act by limiting IGFBP-3 proteolysis and, therefore, reducing IGF bioavailability.

Amplitude of Pubertal Growth in Short Stature Children with Intrauterine Growth Retardation

Objective: Pubertal growth contributes to 15–18% of adult height. A blunted pubertal peak could contribute to short adult height in short children born with intrauterine growth retardation (IUGR). Design and Methods: Pubertal growth, from onset of puberty to final height, was investigated in 75 short IUGR children: 47 were treated with recombinant human growth hormone (GH) (tx) before pubertal onset (mean dose: 0.4 IU/kg/week); 28 were not treated (no-tx). They were compared with 98 normal children. Results: Puberty occurred later in IUGR children than in controls (boys 14.2 ± 1 years vs. 12.1 ± 0.8 years; girls 12 ± 1 years vs. 11.2 ± 0.8 years; p < 0.0001). In girls, total pubertal growth was similar in all three groups (tx: 19.3 ± 4.8 cm; no-tx 19.8 ± 4.9 cm; controls 20.2 ± 3.9 cm; non-significant). IUGR boys had a reduced pubertal growth (tx: 21.3 ± 6.2 cm; no-tx: 23.9 ± 6.1; controls 26.9 ± 3.9 cm; p < 0.05). The age at puberty onset was the major determinant of pubertal growth amplitude (boys: r = 0.53, p < 0.001; girls: r = 0.45, p < 0.001). IUGR children exhibited little catch-up growth during puberty. Conclusions: In the present study, we describe a delayed onset of puberty in short children born with IUGR. Moreover, prepubertal GH treatment was associated in boys with a decrease in the amplitude of the pubertal spurt, a finding that should be further evaluated in clinical trials.

IGFs and Binding Proteins in Short Children with Intrauterine Growth Retardation

The aim of this study was to examine the relationship between the IGF-IGF binding protein (IGFBP) axis and insulin secretion in short intrauterine growth retardation (IUGR) children. Fifteen IUGR and 12 normal short prepubertal subjects had a 90-min frequently sampled iv glucose tolerance test performed to measure plasma glucose, insulin, IGF-I, IGF-II, IGFBP-3, and IGFBP-1. In addition, 29 nonobese prepubertal subjects of normal height had fasting plasma IGF-I and IGFBP-3 levels measured. In comparison to short normal subjects, IUGR subjects had higher plasma values for IGF-I (42 ± 10 vs. 77 ± 31 μg/liter; P < 0.0001), IGF-II (291 ± 76 vs. 370 ± 66 μg/liter; P < 0.008), IGFBP-3 (1.66 ± 0.28 vs. 2.07 ± 0.48 mg/liter; P < 0.0005), fasting insulin (2 ± 1 vs. 4 ± 2 mU/liter; P < 0.004), and acute insulin response (AIR; 215 ± 36 vs. 504 ± 90 mU/liter; P = 0.008). Nonobese subjects of normal height had higher plasma IGF-I (117 ± 9 μg/liter; P < 0.0001) and IGFBP-3 (2.34 ± 0.12 mg/liter) values than the IUGR group (P < 0.0005). During the frequently sampled iv glucose tolerance test, the magnitude of the AIR in short normal subjects was related to the fall in IGFBP-1 levels (P = 0.03); however, no relationship was seen between AIR and fall in IGFBP-1 in IUGR subjects (P = 0.24). In conclusion, short IUGR children have higher plasma IGF-I, IGF-II, and IGFBP-3, when compared with normal children matched for height, weight, and pubertal status. We speculate that hyperinsulinism secondary to insulin resistance may have led to these changes to the IGF-IGFBP axis in the IUGR group.

IGFs and binding proteins in short children with intrauterine growth retardation.

The aim of this study was to examine the relationship between the IGF-IGF binding protein (IGFBP) axis and insulin secretion in short intrauterine growth retardation (IUGR) children. Fifteen IUGR and 12 normal short prepubertal subjects had a 90-min frequently sampled iv glucose tolerance test performed to measure plasma glucose, insulin, IGF-I, IGF-II, IGFBP-3, and IGFBP-1. In addition, 29 nonobese prepubertal subjects of normal height had fasting plasma IGF-I and IGFBP-3 levels measured. In comparison to short normal subjects, IUGR subjects had higher plasma values for IGF-I (42 +/- 10 vs. 77 +/- 31 microg/liter; P < 0.0001), IGF-II (291 +/- 76 vs. 370 +/- 66 microg/liter; P < 0.008), IGFBP-3 (1.66 +/- 0.28 vs. 2.07 +/- 0.48 mg/liter; P < 0.0005), fasting insulin (2 +/- 1 vs. 4 +/- 2 mU/liter; P < 0.004), and acute insulin response (AIR; 215 +/- 36 vs. 504 +/- 90 mU/liter; P = 0.008). Nonobese subjects of normal height had higher plasma IGF-I (117 +/- 9 microg/liter; P < 0.0001) and IGFBP-3 (2.34 +/- 0.12 mg/liter) values than the IUGR group (P < 0.0005). During the frequently sampled iv glucose tolerance test, the magnitude of the AIR in short normal subjects was related to the fall in IGFBP-1 levels (P = 0.03); however, no relationship was seen between AIR and fall in IGFBP-1 in IUGR subjects (P = 0.24). In conclusion, short IUGR children have higher plasma IGF-I, IGF-II, and IGFBP-3, when compared with normal children matched for height, weight, and pubertal status. We speculate that hyperinsulinism secondary to insulin resistance may have led to these changes to the IGF-IGFBP axis in the IUGR group.

IGF Type 1 Receptor Ligand Binding Characteristics Are Altered in a Subgroup of Children with Intrauterine Growth Retardation

The IGFs, IGF-I and IGF-II, regulate fetal growth by activating IGF type 1 receptors (IGF-IR). We aimed to quantify the binding of IGF-I to its cognate receptors in intrauterine growth-retarded children (IUGR). We measured the affinity of the erythrocyte IGF-IR and the number of IGF-IR receptors in 17 children with retarded growth (mean height,− 2.7 sd), normal levels of GH, and a history of idiopathic intrauterine growth retardation (height at birth, −10 to −2 sd; mean, −3.1 sd). These children had reduced receptor affinity (Kd = 0.47 nm; P < 0.01) and more receptors per cell [binding capacity (Bmax) = 11.7 binding sites/cell; P < 0.05)] compared with control children (Kd = 0.32 nm; Bmax = 7.8 binding sites/cell). Moreover, the distributions of Kd and Bmax suggested that there were two groups of IUGR children. Group 1 included subjects with normal receptor binding function (Kd = 0.36 nm; Bmax = 8.2 sites/cell) and normal levels of circulating IGF-I. Group 2 comprised children with low receptor affinity (Kd = 0.56 nm) and increased receptor number (Bmax = 14.7 sites/cell). This group showed significantly decreased IGF-I levels (−2.1 sd; P < 0.01). We investigated these IGF-IR binding parameters in two additional groups of growth-retarded children (Turner syndrome and patients with chronic renal failure), in whom the IGF-I axis was not believed to be the primary cause, and found that Kd and Bmax were normal or nearly normal. We also measured IGF-IR binding parameters in 4 Seckel syndrome patients with IUGR and severely retarded growth (mean height, −7.9 sd). Their receptor affinity was reduced, but not statistically different, from that in controls, and their receptor number was normal, whereas IGF-I levels were elevated. Our results suggest heterogeneous alterations in IGF-IR binding function in IUGR patients.

Impaired insulin-mediated glucose uptake in monocytes of short children with intrauterine growth retardation.

To determine whether there was an impairment in insulin-mediated glucose uptake in monocytes from short children with intrauterine growth retardation (IUGR) when compared with control subjects. Circulating monocytes were isolated by histopaque gradient separation followed by adherence. Monocytes were incubated with insulin at the following concentrations; 0, 0.1, 0.2, 0.6, 1, 2 and 6 nm. 2-deoxyglucose (2-DG) uptake was measured after incubation with [(3)H]2-DG and expressed as pmol/min/10(6) cells. Insulin-stimulated glucose uptake was determined in two ways: 6 nm insulin concentration minus baseline (6-0 nm) and the regression slope of glucose uptake over the range of log insulin concentrations (slope value). Insulin sensitivity was determined from a 90-min frequently sampled intravenous glucose tolerance test with the minimal model. Short children with IUGR (n = 16) had lower slope (4.6 +/- 1.1 vs. 9.5 +/- 2.0, p = 0.002) and 6-0 nm (8 +/- 2 vs. 15 +/- 3 pmol/min/10(6) cells, p = 0.048) glucose uptake values than normal children (n = 11). There was no difference in baseline glucose uptake between IUGR and normal children (36 +/- 5 vs. 48 +/- 7 pmol/min/10(6) cells). In the five subjects with IUGR that were evaluated, the in vivo insulin sensitivity index and glucose effectiveness were found to be positively correlated with insulin-mediated glucose uptake in monocytes (r = 0.54) and baseline glucose uptake in monocytes, respectively (r = 0.69). Short children with IUGR have impairment in insulin-mediated glucose uptake in monocytes when compared with normal children. Our hitherto limited data indicate that insulin-mediated glucose uptake in monocytes is correlated with in vivo assessment of insulin sensitivity in children with IUGR.

Six-Year Follow-Up of Children With Intrauterine Growth Retardation: Long-Term, Prospective Study

This prospective study was designed to characterize the neurodevelopmental and cognitive difficulties specific to children with intrauterine growth retardation and to detect early clinical predictors of these difficulties. Eighty-one children with intrauterine growth retardation were monitored up to 6 to 7 years of age using biometric parameters, perinatal risk questionnaires, and detailed neurodevelopmental and cognitive assessments. Forty-one children served as age-matched, appropriate for gestational age controls. A significant difference in growth parameters (P < .001), neurodevelopmental score (P < .05), and IQ (P < .05) was found between the children with intrauterine growth retardation and controls. A specific profile of difficulties in coordination, lateralization, spatial and graphomotor skills, and abundance of associated movements is typical of the children with intrauterine growth retardation and hints at possible later learning disabilities. The clinical parameters best predicting neurodevelopmental outcome were the neonatal risk score (P < .05) and the weight and height at 6 years of age (P < .05). The children with intrauterine growth retardation with neonatal complications had lower neurodevelopmental scores than the controls but no difference in IQ. Intrauterine growth retardation children diagnosed prenatally had the same neurodevelopmental and IQ scores as those diagnosed at birth, probably due to the careful perinatal and obstetric care provided. Children with intrauterine growth retardation demonstrate a specific profile of neurodevelopmental disabilities at preschool age. Early diagnosis and intervention could probably reduce these difficulties to a minimum.

Collagen cross-links and early postnatal growth in newborns with intrauterine growth retardation

This study assessed growth and skeletal metabolism in full-term newborns with intrauterine growth retardation (IUGR) and determined the value of the urinary excretion of collagen cross-links in predicting postnatal catch-up growth. We studied 38 newborns (16 females) born at term with a birth weight less than the 10th centile of the reference and a ponderal index ([PI] 100 × weight in g/length in cm3) of 2.27 ± 0.19. The sample was divided into 23 children with proportionate ([P] PI ≥ 10th centile of the reference) and 15 with nonproportionate ([NP] PI < 10th centile of the reference) IUGR. The weight, head circumference, length, and knee-heel length of the newborns at days 7, 14, 30, 60, and 90 were measured. The height of 23 of the 38 children was also assessed at 27 ± 6 months of life. Urinary collagen cross-links were analyzed by high-performance liquid chromatography at day 14 and day 60. Most of the infants (68%) underwent catch-up growth, and the growth performance at 3 months was independent of the proportions at birth. Children who did not show catch-up growth in the first trimester of life failed to normalize in height in the following 2 years. The urinary excretion of pyridinoline (Pyd) was not related to the anthropometric measurements. In P children, urinary excretion of deoxypiridinoline (Dpd) at day 14 significantly correlated with the gain in length during the first 3 months, accounting for 25% of the variance. In NP children, these correlations between urinary Dpd and the gain in length were not significant. The evaluation of urinary Dpd excretion at 2 weeks of age might help to determine the therapeutic regimen in IUGR children. Copyright © 2000 by W.B. Saunders Company

Growth velocity, final height and bone mineral metabolism of short children treated long term with growth hormone.

Since human recombinant growth hormone (GH) became available a large number of short GH deficient and GH-sufficient children have been treated with growth hormone. Growth hormone deficient patients have been followed to final height and several studies have shown that even when treated with GH from very early on in life they tend to end up shorter than their target height. There is, however, a clear increase in their growth velocities particularly during the first 4-5 years of GH therapy so that patients end up with a height-SD score of aproximately -0.8. Recent studies have demonstrated decreased bone mineral densities (BMD) in children with growth hormone deficiency, both by areal and volumetric analysis. Therapy with growth hormone clearly increases their BMD with an increase in bone formation markers, as will be reviewed in detail. Growth hormone therapy of non-growth hormone deficient short children has increased their growth velocity short term, particularly in girls with Turner's syndrome and in children with chronic renal insuficiency. Recent final height data by Rosenfeld et al. and by Swedish and Dutch groups have demonstrated a gain of 8-12 cm in girls with Turner's syndrome treated with GH or with a combination of GH and oxandrolone. Neely et al. and we have demonstrated that growth hormone treated prepubertal age girls and adolescents with Turner's syndrome have normal BMD and Shaw et al. has suggested that they have normal BMD despite GH or estrogen therapy. However, we found the BMD of a group of previously GH treated young women with Turner's syndrome on estrogen replacement to be decreased compared to both age and gender matched controls and to controls of the same weight and pubertal status. Growth hormone therapy increases the growth velocity and the final height of children with chronic renal insuficiency, particularly in prepubertal children treated with GH before dialysis. We have demonstrated how the BMD of these patients, which at baseline is low when compared to healthy age matched controls, but normal when compared to height and bone age matched controls, increases with growth hormone treatment significantly, moreso than in untreated uremic controls or in untreated healthy controls paired for height and bone age. Short, slowly growing, non growth hormone deficient patients (idiopathic short stature) have been treated for prolonged periods of time with GH. We and others have demonstrated a clear increase in their growth velocity short term, but improvement of their final height remains unclear and controversial. After 4-8 years of GH treatment, Hintz et al. have found a 5-6 cm increase in final height compared to the predicted adult height before beginning therapy, but most patients did not reach their target heights. Other studies, however, have found no improvement in final height and Kawai et al. even suggests that GH therapy diminishes the final height of treated children due to an earlier puberty and a shorter pubertal growth spurt. We, have found decreased BMD in children with idiopathic short stature when compared to controls of their same height and bone age with a significant increase in BMD following 12 months of GH and with an increase in bone turnover as measured by bone formation and resorption markers. Recent short term studies in patients with hypophosphatemic rickets and osteogenesis imperfecta treated with rhGH have also yielded similar results which will be specified in the review. Some 10-20% of children born with intrauterine growth retardation (IUGR) end up short and we had already demonstrated 20 years ago how 2 years of GH therapy were capable of increasing their growth velocities significantly with an improvement of their height-SD scores. Recent studies mainly from Europe have corroborated this data long term, so that IUGR children have been shown by de Zegher et al. to increase their growth velocities and their height for age after 6 years of treatment, entering into the low normal centiles of their growth curves for age. Long term studies of these children to final height will be necessary to determine the usefulness and safety of this form of therapy.

The cortisol-cortisone shuttle in children born with intrauterine growth retardation.

We evaluated the involvement of a possible dysfunction of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) in the fetal growth retardation and poor growth rates of children born with intrauterine growth retardation (IUGR). Children with IUGR have a nephron deficit and are also at risk of developing cardiovascular diseases, high blood pressure, glucose intolerance, and dyslipidemia later in life. The major site of 11beta-HSD2 production is the kidney and its deficit causes hypertension. We investigated plasma concentrations of cortisol (F) and cortisone (E) and the F/E ratio in 26 control children and in 40 IUGR children without catch-up growth. We also determined cholesterol, HbA1C, insulin, and glucose levels in plasma. Mean F values were 106 +/- 54.2 ng/mL in control children and 114.6 +/- 53.2 ng/mL in IUGR children. Mean E values were 19.5 +/- 7.1 ng/mL in control children and 17.9 +/- 6.85 ng/mL in IUGR children. The mean F/E ratio for control children was 5.5 +/- 1.7. Eight (20%) of the IUGR children (IUGR children of group 1) had high F/E ratios more than 2 SD above the normal mean: 13.15 +/- 4.26, (p < 0.0001) as compared to control children, whereas the other 32 children (IUGR children of group 2) had normal F/E ratios: 5.40 +/- 1.43 (p = 0.68). Childhood height was significantly lower for group 1 than group 2 children (-3.63 SD and -2.92 SD, respectively: p < 0.01) and was negatively correlated with the F/E ratio (p < 0.01). Systolic blood pressure was higher for group 1 (p = 0.005) and for group 2 (p = 0.015) than for control children. The diastolic pressure in IUGR children of group 1 was higher than that in control children (p = 0.013) and slightly higher than that in group 2 (p = 0.1, ns). Cholesterol concentrations were higher in group 1 than in group 2 (p = 0.029), and controls (p = 0.017) and correlated positively with F/E (0.02 < p < 0.05). Fasting insulin concentrations were higher in group 1 than in group 2 (ns) and controls (ns). There was no difference in mean fasting glucose concentrations, or HbA1C between the three groups. Twenty percent of our children with IUGR and poor growth rates had high F/E ratios, suggesting a possible partial 11beta-HSD2 deficit. Whether these children are at high risk of developing cardiovascular diseases as adults remains to be further evaluated.

Intrauterine growth retardation: evidence for the activation of the insulin-like growth factor (IGF)-related growth-promoting machinery and the presence of a cation-independent IGF binding protein-3 proteolytic activity by two months of life.

Thirty-seven children with intrauterine growth retardation (IUGR) were enrolled in a 3-mo longitudinal study. Weight, length, and knee-heel length (by knemometry) were measured at birth and at 7, 14, 30, 60, and 90 d. GH, IGF-I, IGF binding protein (BP)-3, IGFBP-1, and C-peptide were measured at birth and at 2 mo. IGFBP-3 Western immunoblotting and proteolytic activity assay were also performed. Twenty-five newborns with birth weight appropriate for gestational age were chosen as controls. At birth IUGR newborns showed levels of GH and IGFBP-1 significantly higher, and IGF-I, IGFBP-3, and C-peptide significantly lower than control subjects. At 2 mo GH and IGFBP-1 levels decreased, whereas IGF-I, IGFBP-3, and C-peptide rose, attaining the concentrations found in control subjects at birth. Baseline peptide levels as well as their 2-mo variations did not correlate with the gain in weight, supine length, and knee-heel length recorded at 3 mo. Fourteen of nineteen IUGR cord blood samples showed the presence of the intact approximately 42-39-kD IGFBP-3 doublet and the major approximately 29-kD fragment. At 2 mo the IGFBP-3 band pattern was characterized by the predominance of a approximately 18-kD fragment in 6 of 19 tested IUGR infants. The incubation of 2-mo IUGR samples with normal adult serum induced the appearance of the approximately 18-kD band, which was not modified by the addition of EDTA. These results suggest that: 1) the IGF-related growth-promoting mechanism is impaired in IUGR children at birth but is fully restored at 2 mo; 2) the cord blood levels of GH, IGF-I, IGFBP-3, IGFBP-1, and C-peptide are not predictive of the weight and length gain during the first 3 mo of life; 3) IUGR children have at least two different IGFBP-3 proteases, one cation-dependent protease that is present at birth and able to yield the major approximately 29-kD IGFBP-3 fragment and a second one, with a different activation timing, which exhibits cation independence and induces the formation of a approximately 18-kD IGFBP-3 form.

Multiple Hormone Resistance in Short Children Born with Intrauterine Growth Retardation?

Intrauterine growth retardation (IUGR) is encountered in 2.5% (–2 SD) of newborns. Lack of postnatal catch-up growth is found in 8–20%. If GH secretion is increased early postnatally in IUGR, then some persistently short IUGR children may present with GH insufficiency. However, the mechanism of postnatal catch-up growth is heterogenous. The response to GH treatment with regard to plasma IGF-1, GH dose and growth velocity was analyzed in persistently short idiopathic IUGR children and compared to GH-deficient (GHD) and familial short stature (FSS) children of similar age and degree of short stature. IUGR children require both a greater basal and GH-induced plasma IGF-1 in order to achieve a growth velocity of similar magnitude to that of FSS and GHD children. These data suggest a different sensitivity to GH in IUGR compared to FSS or GHD children, sustaining the hypothesis that these idiopathic IUGR children may be partially IGF-1 resistant. The recent report of partial insulin resistance in IUGR subjects raises the possibility of an IGF-1 receptor- or post-receptor-mediated defect.

Short Stature Associated with Intrauterine Growth Retardation: Final Height of Untreated and Growth Hormone-Treated Children

Short term studies have demonstrated the acceleration of growth velocity after the administration of GH in short children born with intrauterine growth retardation (IUGR). We report the final heights of 70 IUGR children whose short stature was attributed to idiopathic GH deficiency (peak plasma GH <10 ng/mL at 2 provocative tests) and treated with GH at a mean dosage of 0.4 ± 0.1 U/kg·week during an average of 4.6 ± 2.5 yr. They were compared to a control group of 40 untreated short children born with IUGR, without GH deficiency. At the time of evaluation, age, auxological data, and pubertal status were similar in the 2 groups (height, −2.9 ± 0.8 and −2.8± 0.7 sd score). Final heights were comparable in both groups of children (−2 ± 0.7 and −2.2 ± 1.1 sd score). A multivariate analysis identified 4 independent predictors of final height, namely target height, age and body mass index at evaluation, and GH treatment. Treatment was associated with a gain of 0.6 sd score, suggesting a final height gain of about 3.4 cm. Fifty-three of 70 treated children were reevaluated after completion of growth, and 43 of 53 had a peak plasma GH level of 10 ng/mL or more. Auxological characteristics of these 53 patients were not different from those of nonreevaluated patients. We believe that the transient character of the GH deficiency in most patients and the nonstringent initial criteria used for the diagnosis of GH deficiency render the spontaneous growth potentials identical in the 2 groups of patients. Our data, therefore, suggest that GH treatment at this dosage has a limited effect on the final height of short children born with IUGR.

Insulin resistance in short children with intrauterine growth retardation.

Epidemiological studies have demonstrated an association between intrauterine growth retardation and an increased risk of adult diseases that include essential hypertension, noninsulin-dependent diabetes mellitus, and ischemic heart disease. A common feature of these diseases is insulin resistance. To investigate whether abnormal insulin sensitivity was a characteristic of subjects with intrauterine growth retardation (IUGR), we compared two groups of short prepubertal children: a group with IUGR (birth weight less than the tenth percentile; n = 15) and a normal birth weight group (n = 12). Subjects underwent a modified frequently sampled iv glucose tolerance test that permitted calculation of the acute insulin response, insulin sensitivity index, and glucose effectiveness. A marked difference in the insulin sensitivity index was noted between groups, with the IUGR group being less insulin sensitive [6.9 vs. 16.9 10(-4)min-1.(microU/mL); P = 0.0048]. The acute insulin response was also significantly different between groups, with IUGR subjects having higher insulin levels (445 vs. 174 microU/mL; P = 0.005). There was no difference in glucose effectiveness between groups. Short prepubertal IUGR children have a specific impairment in insulin sensitivity compared to their normal birth weight peers. In short IUGR children, impaired insulin sensitivity is a potential marker for the early identification and intervention in the development of late adult-onset noninsulin-dependent diabetes mellitus.

Self-Concept before and after Two Years of Growth Hormone Treatment in Intrauterine Growth-Retarded Children

Self-Concept before and after Two Years of Growth Hormone Treatment in Intrauterine Growth-Retarded Children