Birth Weight SD Score Research Articles

Association between serum adipocytokine and cholesterol levels in cord blood

Serum leptin and adiponectin levels are strongly associated with lipid metabolism in adults. These adipocytokines play a role in intrauterine and postnatal growth but the association between cord blood levels of these adipocytokines and cholesterol at birth remains unclear. The study involved 52 appropriate-for-gestational-age (AGA) infants (25 male, 27 female, 37-41 weeks of gestational age) born at Keiai Hospital without any maternal complications. Cord blood concentrations of leptin, total adiponectin, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), other neonatal characteristics, and maternal factors were assessed to investigate the association between cord blood leptin or adiponectin levels and cholesterol levels. Cord blood leptin levels were significantly higher in girls. Simple regression analysis indicated that cord blood leptin levels were significantly associated with birthweight, gestational age, birthweight SD score, body mass index (BMI), ponderal index, LDL-C, and TC; but total adiponectin levels were not significantly associated with any neonatal characteristics or maternal factors. A multiple regression analysis indicated that cord leptin levels were significantly associated with BMI (beta= 0.407, P= 0.001), LDL-C (beta=-0.345, P= 0.004), and infant's gender (beta=-0.332, P= 0.006); adiponectin levels were significantly associated with only gestational age (beta= 0.279, P= 0.047). Cord leptin level is significantly associated with cord cholesterol level at birth, anthropometry, and infant gender. The present study suggests that cord blood leptin may be a key hormone for controlling fetal lipid metabolism.

Contribution of Early Weight Gain to Childhood Overweight and Metabolic Health: A Longitudinal Study (EarlyBird 36)

Early weight gain (0-5 years) is thought to be an important contributor to childhood obesity and consequently metabolic risk. There is a scarcity of longitudinal studies in contemporary children reporting the impact of early weight gain on metabolic health. We aimed to assess the impact of early weight gain on metabolic health at 9 years of age. Two hundred thirty-three children (134 boys, 99 girls) with a gestational age of >37 weeks were assessed at birth, 5 years of age, and 9 years of age. Measures included weight SD scores at each time point and excess weight gained (Delta weight SD score) between them. The outcome measure included composite metabolic score (sum of internally derived z scores of insulin resistance, mean blood pressure, triglyceride level, and total cholesterol/high-density lipoprotein cholesterol ratio). Weight SD score increased by 0.29 SD score in girls and 0.26 SD score in boys from 0 to 5 years of age and by 0.03 SD score in girls and 0.11 SD score in boys from 5 to 9 years of age. Weight SD score correlated poorly to moderately before 5 years of age but strongly after 5 years of age. Birth weight SD score predicted (girls/boys) 2.4%/0% of the variability in composite metabolic score at 9 years of age. Adding Delta weight SD score (0-5 years old) contributed (girls/boys) 11.2%/7.0% to the score, and adding Delta weight SD score (5-9 years old) additionally contributed (girls/boys) 26.4%/16.5%. Importantly, once weight SD score at 9 years of age was known, predictive strength was changed little by adding Delta weight SD score. Most excess weight before puberty is gained before 5 years of age. Weight at 5 years of age bears little relation to birth weight but closely predicts weight at 9 years of age. Single measures of current weight are predictive of metabolic health, whereas weight gain within a specific period adds little. A single measure of weight at 5 years of age provides a pointer to future health for the individual. If metabolic status at 9 years of age means future risk, diabetes/cardiovascular prevention strategies might better focus on preschool-aged children, because the die seems to be largely cast by 5 years of age, and a healthy weight early in childhood may be maintained at least into puberty.

Muscle Function Improves during Growth Hormone Therapy in Short Children Born Small for Gestational Age: Results of a Peripheral Quantitative Computed Tomography Study on Body Composition

Short small for gestational age (SGA) children can be affected by a lack of muscle mass rather than fat mass. They also face a high risk of the metabolic syndrome developing after childhood. It is not known whether low muscle mass influences muscle function. Our aim was to investigate muscle-fat distribution and muscle function before and during GH treatment in short SGA children. A total of 34 prepubertal short SGA children (11 females, seven with Silver-Russell syndrome) were included in the study. Mean values were: age at GH start 7.3 yr; height sd score (SDS) -3.3; and birth weight SDS -2.7. Investigations over 24 months on GH treatment (57 microg/kg.d) were performed. Body composition, including fat area and muscle area (MA), was assessed through peripheral quantitative computed tomography (XCT 2000; Stratec, Inc., Pforzheim, Germany). Maximal isometric grip force was performed with a Jamar dynamometer (Preston, Jackson, MI). Comparison with height-dependent reference values (SDS(Height)) was calculated. MA SDS(Height) at GH start was -1.8 and increased to -0.8 (P < 0.001) and -0.8, and fat area SDS(Height) decreased from -0.6 to -2.0 (P < 0.001) and -1.5 after 12 and 24 months on GH. Maximal isometric grip force SDS(Height) increased from -0.9 to 0.3 (P < 0.001) and 0.5. MA at start correlated negatively with height velocity (R = -0.54; P < 0.001) and MA SDS at start and Delta-height SDS during the first year of GH treatment (R = -0.40; P < 0.001). Short stature in SGA children is associated with low muscle mass and function. Supraphysiological GH doses led to a concomitant increment in height, muscle mass, and function, whereas fat mass decreased. Furthermore, body composition at GH start gives insight into GH responsiveness and the individual risk of metabolic syndrome.

Effect of Intrauterine Growth Restriction on Kidney Function at Young Adult Age: The Nord Trøndelag Health (HUNT 2) Study

The hypothesis of intrauterine origin of adult disease is debated. We tested whether intrauterine growth restriction is associated with later kidney function. Prospective cohort study. 7,457 Norwegian adults aged 20 to 30 years participating in the population-based Nord Trøndelag Health Study (1995-1997) with data for birth weight, gestational age, and maternal and perinatal risk factors registered at the Medical Birth Registry of Norway. Birth weight expressed as an SD score (SDS) to adjust for gestational age and sex. Subjects with a birth weight SDS less than -2.0, -2.0 to -1.3, and -1.3 to 1.3 were defined as very small, small, and appropriate for gestational age, corresponding to less than the 3rd, 3rd to 10th, and 10th to 90th percentiles, respectively. Kidney function estimated using the Cockcroft-Gault and isotope dilution mass spectrometry-traceable 4-variable Modification of Diet in Renal Disease (MDRD) Study equation. Values less than the sex-specific 10th percentile were defined as low-normal kidney function. Compared with men with birth weight appropriate for gestational age (n = 2,755), odds ratios for low-normal creatinine clearance (<100 mL/min) were 1.66 (95% confidence interval [CI], 1.16 to 2.37) if small for gestational age (n = 261) and 2.40 (95% CI, 1.46 to 3.94) if very small for gestational age (n = 101). Kidney function estimated using the MDRD Study equation gave similar results. Women (n = 3,126, 283, and 112, respectively) had odds ratios of 1.65 (95% CI, 1.17 to 2.35) and 2.00 (95% CI, 1.21 to 3.29) for low-normal creatinine clearance (<80 mL/min), whereas the association was not significant using the MDRD Study equation. Using linear regression, creatinine clearance decreased by 4.0 mL/min (95% CI, 3.3 to 4.6) in men and 2.9 mL/min (95% CI, 2.2 to 3.5) in women per 1-SDS decrease. Adjusting for possible confounders did not influence results. Selection bias could be a problem because the participation rate was 49%, but there were no statistically significant differences between participants and nonparticipants regarding maternal and perinatal characteristics. Adjusting kidney function for body size can be a special problem in people with intrauterine growth restriction. Although effects were still small in young adulthood, intrauterine growth restriction was significantly associated with low-normal kidney function. The effect was weaker and less consistent in women compared with men.

Fat Mass and Apolipoprotein E Genotype Influence Serum Lipoprotein Levels in Early Adulthood, whereas Birth Size Does Not

An association between an unfavorable lipid profile and low birth weight has been reported, although this association remains controversial. We hypothesized that birth size does not have any influence on serum lipid levels but fat accumulation during childhood has. In the PROgramming factors for GRowth And Metabolism study, a cohort of 297 young adults, aged 18-24 yr, the influence of clinical parameters on total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, lipoprotein a, and apolipoprotein (apo) A-1 and apoB was analyzed with multiple regression modeling. In addition, differences in these lipid levels and ApoE genotype prevalence were analyzed in four subgroups: young adults either born small for gestational age with short stature or with catch-up growth, or born appropriate for gestational age with idiopathic short stature or with normal stature (controls). Birth length sd score (SDS) and birth weight SDS were no significant determinants of the serum lipid levels, whereas gender, ApoE genotype, adult height SDS, adult weight SDS, and fat mass were. Comparison of the subgroups showed that small for gestational age with short stature subjects had a significantly higher apoB than controls. There were no other significant differences in lipid levels or ApoE genotype prevalence among the four subgroups. ApoE genotype is an important genetic determinant of lipid levels in young adulthood. Furthermore, fat accumulation during childhood significantly determines serum lipid levels, whereas birth size has no significant contribution. For public health practice, this means that parents and their children need to be informed about the risks of fat accumulation during childhood.

Simultaneously reduced gene expression of cortisol-activating and cortisol-inactivating enzymes in placentas of small-for-gestational-age neonates

The enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) converts cortisol into cortisone. Reduced placental activity of 11beta-HSD2 in small-for-gestational-age (SGA) neonates results in fetal cortisol excess. In the present study, we examined the yet unknown gene expression of 11beta-HSD1, which primarily synthesizes cortisol in SGA placenta. In placentas taken from 24 women with normal-weight newborns and 16 women with SGA neonates, expression of 11beta-HSD1 and 11beta-HSD2 messenger ribonucleic acid (mRNA) was determined using reverse transcription-polymerase chain reaction. Placental mRNA expression of 11beta-HSD1 and 11beta-HSD2 was significantly reduced in the SGA group (P = .006 and P < .0001). Both enzymes showed a significant correlation to birthweight SD score and placental weight. Also, levels of both enzymes were significantly correlated. In placental tissue of SGA neonates 11beta-HSD2 and 11beta-HSD1 gene expression is reduced. Adapted levels of 11beta-HSD1 might result in a counterregulatory mechanism limiting transplacental passage of elevated cortisol levels.

Exogenous Corticosteroids andin UteroOxygenation Modulate Indices of Fetal Insulin Secretion

Low birth weight has long-term effects on glucose-insulin homeostasis. Factors that could mediate intra-uterine "programing" of glucose homeostasis include endogenous and exogenous glucocorticoids, adipose tissue-secreted factors such as adiponectin, and in utero hypoxia. Here, we studied 123 fetuses with gestational age (GA) between 25 and 37 wk and birth weight sd score (BW SDS) between -2.79 and 2.42. We measured proinsulin, C-peptide, insulin, and adiponectin in umbilical vein (UV) plasma and calculated the proinsulin to insulin ratio as a measure of beta-cell secretory function. These indices were related to GA, BW SDS, time since the last maternal betamethasone administration, and blood gas data. Insulin and C-peptide were correlated with BW SDS but not GA, whereas the proinsulin to insulin ratio was inversely correlated with BW SDS. The proinsulin to insulin ratio was raised (P = 0.002) in fetuses with UV PO(2) less than or equal to 21.3 mm Hg (i.e. the 50th percentile) compared with those with PO(2) more than 21.3 mm Hg, inferring that in utero hypoxia engenders beta-cell secretory dysfunction. Proinsulin, insulin, and C-peptide were markedly but transiently (<24 h) elevated after maternal betamethasone administration, returning thereafter to concentrations measured in noncorticosteroid-treated fetuses. However, there was considerable variability within the less than 24-h betamethasone group: the indices of insulin secretion were related to UV PO(2), suggesting that hypoxia attenuates the responsiveness of fetal beta-cells to corticosteroids. Adiponectin was not related to any of the insulin indices. In conclusion, we have identified two environmental signals that modulate fetal insulin output: maternal corticosteroids produce a transient surge in fetal insulin synthesis and secretion, whereas in utero hypoxia disturbs the insulin secretory process.

Association between Erythropoietin in Cord Blood of Twins and Size at Birth: Does It Relate to Gestational Factors or to Factors during Labor or Delivery?

We hypothesized that cord blood erythropoietin (EPO), a marker of fetal hypoxia, relates to gestational factors and not solely those associated with delivery. We investigated the association between birth weight SD score (SDS) and cord blood EPO in 290 twins (145 pairs), assessing the influence of gestational versus perinatal factors by comparing the association in those who were delivered by elective cesarean (CS) with that in other delivery modes. Blood EPO values were skewed, so geometric means are presented and log EPO values were used in statistical models. The birth size-EPO association was estimated in mixed-effects models that included terms that represented difference in log EPO and mean log EPO for each twin pair. Within-pair estimates of the association were unconfounded by maternal factors (because these were perfectly controlled). Geometric mean EPO was higher in boys versus girls (24.4 versus 17.0 IU/L; p = 0.0001) and increased with gestational age (p = 0.0003) but was similar after elective CS versus other delivery modes. The negative birth size-EPO association was stronger in infants who were delivered by elective CS than by other delivery modes [beta for log(2) EPO: -0.56 (95% CI, -0.77 to -0.36) versus -0.27 (-0.42 to -0.12), respectively; p = 0.02 for interaction). Because the association was seen after elective CS delivery, cord blood EPO must relate to factors during gestation, not just perinatal factors. There was no evidence of an association between birth weight SDS and pair mean log EPO, indicating that the association is entirely due to fetus-specific rather than pair-specific factors.

Associations between prenatal and infancy weight gain and BMI, fat mass, and fat distribution in young adulthood: a prospective cohort study in males and females born very preterm

Increasing evidence indicates that adult body composition is associated with prenatal and infancy weight gain, but the relative importance of different time periods has not been elucidated. The objective was to study the association between prenatal, early postnatal, and late infancy weight gain and body mass index (BMI), fat mass, and fat distribution in young adulthood. We included 403 men and women aged 19 y from a Dutch national prospective follow-up study who were born at <32 wk of gestation. BMI, waist circumference, and waist-to-hip ratio SD scores and subscapular-to-triceps ratio, percentage body fat, fat mass, and fat-free mass at age 19 y were studied in relation to birth weight SD scores, weight gain from preterm birth until 3 mo postterm (early postnatal weight gain), and weight gain from 3 mo until 1 y postterm (late infancy weight gain). Birth weight SD scores were positively associated with weight, height, BMI SD scores, and fat-free mass at age 19 y but not with fat mass, percentage body fat, or fat distribution. Early postnatal and late infancy weight gain were positively associated with adult height, weight, BMI, waist circumference SD scores, fat mass, fat-free mass, and percentage body fat but not with waist-to-hip ratio SD scores or subscapular-to-triceps ratio. In infants born very preterm, weight gain before 32 wk of gestation is positively associated with adult body size but not with body composition and fat distribution. More early postnatal and, to a lesser extent, late infancy weight gain are associated with higher BMI SD scores and percentage body fat and more abdominal fat at age 19 y.

Increased Response, But Lower Responsiveness, to Growth Hormone (GH) in Very Young Children (Aged 0–3 Years) with Idiopathic GH Deficiency: Analysis of Data from KIGS

In children, GH secretion and sensitivity to GH are influenced by developmental changes. It is not clear whether the response to GH in very young children with GH deficiency (GHD) is the same as that in older, prepubertal children. A cohort of 265 children (180 males and 85 females) with idiopathic GHD from KIGS (Pfizer International Growth Database), with treatment started at less than 3 yr of age (mean age, 1.9 yr; group I) was compared with a cohort of 509 children (331 males and 178 females; group II) with treatment started at 7-8 yr of age (mean age, 7.5 yr). The following differences (P < 0.01) were found (given in mean values) between groups I and II at the start of GH treatment: 9% vs. 5% breech delivery, 38% vs. 14% multiple pituitary hormone deficiency, 4.2 vs. 5.9 ng/ml maximum GH in response to tests, -0.1 vs. -0.8 midparental height (MPH) sd score (SDS), -3.1 vs. -2.5 height SDS, 0.83 vs. 0.66 IU/kg.wk GH dose. After the first year of GH, the results were: 13.3 vs. 8.6 cm/yr height velocity, and 1.7 vs. 0.6 maximum change in height SDS. Using the previously developed growth prediction models for prepubertal children with idiopathic GHD more than 2 yr of age, our analysis revealed differences in the indexes of responsiveness in prediction models (Studentized residuals SDS, 0.7 vs.-0.3) and strikingly higher responsiveness to treatment among the young cohort, but with large scatter. Thus, new prediction models of height velocity (centimeters per year) were derived by means of multiple regression analysis for the young cohort, either involving (model A) or excluding (model B) the GH peak in tests. Model A explained 54% of the total variability with an error sd of 2.1 cm. Height velocity correlated with (parameters in order of importance) age (-), maximum GH (-), GH dose (+), weight SDS (+), height SDS minus MPH SDS (-), and birth weight SDS (+). Model B explained 45% of the total variability with an error sd of 2.3 cm. Height velocity correlated with (parameters in order of importance) age (-), GH dose (+), birth weight SDS (+), height SDS minus MPH SDS (-), and weight SDS (+). The predictors were qualitatively the same as those in the total prepubertal model involving all children more than 2 yr of age, but their quantitative impact in terms of partial contribution and the order of their importance were different for the young cohort. In particular, the partial contribution of the GH dose was higher, suggesting a greater gain in height per GH dose unit in the very young than in the older children. However, the rank order of the GH dose in the new models was lower, which suggests a slightly low sensitivity to GH in toddlers after the phase of severe GH insensitivity during early infancy. The early detection and GH treatment of congenital GHD is advantageous as a cost-effective strategy for achieving greater improvement of absolute height and growth velocity.

Adiponectin Levels in the First Two Years of Life in a Prospective Cohort: Relations with Weight Gain, Leptin Levels and Insulin Sensitivity

Adiponectin, a novel adipocytokine with insulin sensitizing properties, is inversely related to obesity and insulin resistance in adults. We recently reported large variations in weight gain and insulin sensitivity during the first year in infants born small for gestational age (SGA) or appropriate for gestational age (AGA). We now determined whether adiponectin levels were related to postnatal growth and insulin sensitivity in a prospective cohort followed from birth to two years old (n = 85) (55 female/30 male, 65 SGA/20 AGA). Serum adiponectin levels at one year and two years were higher compared to reported levels in adults and older children, and decreased from one year (21.6 +/- 0.6 microg/ml) to two years (15.7 +/- 0.7 microg/ml) (p < 0.05). At two years adiponectin levels were lower in females (15.3 +/- 0.4 microg/ml) than males (16.4 +/- 0.6 microg/ml) (p < 0.05), but no gender difference was seen in leptin or insulin levels. No differences in adiponectin levels were seen between SGA and AGA infants at one or two years. However, in SGA infants changes in adiponectin between one to two years old were inversely related to weight gain (r = -0.310, p < 0.05). Changes in leptin levels between one to two years were positively related to weight gain in both SGA and AGA infants (r = 0.450 and r = 0.500 respectively, both p < 0.05). Adiponectin levels were unrelated to insulin levels at one or two years, nor to change in insulin levels between one to two years. In multiple regression analysis, adiponectin levels were related only to postnatal age; omitting age from the model, the determinants of higher adiponectin levels were male gender (p = 0.03), lower postnatal body weight (p < 0.001), and higher birth weight SD score (p = 0.004). In conclusion, fall in serum adiponectin levels during the first two years of life were related to increasing age and greater weight gain SGA infants, but were unrelated to insulin sensitivity.

34 Insulin-Like Growth Factor I Deficiency is Associated with Chronic Lung Disease of Prematurity.

Objective: Insulin-like growth factor I (IGF-I) is necessary for normal growth and development in infants. Recent research suggested that IGF-I deficiency is associated with the development of oxygen-induced retinopathy of prematurity (1). We hypothesized that low IGF-I levels might be a risk factor for oxygen-induced pulmonary damage in preterm infants, which leads to chronic lung disease (CLD) of prematurity.Methods: We measured growth hormone (GH) secretory patterns and levels of IGF-I and IGF binding protein 3 (IGFBP-3) in 34 preterm infants (gestational age(GA): 25–32 weeks, weights 526-1985 grams) at risk to develop chronic lung disease. Measurements were performed in clinically stable infants, requiring respiratory support. Between the 4th and 12th day of life, 6 h (with hourly intervals) and 24 h (with 6 h intervals) blood samples were taken for the determination of GH. In addition, IGF-I and IGFBP-3 levels were measured in the first blood sample. Results were adjusted for GA and birth weight SD score (BWSDS).Results: No significant differences in GH concentration were found between the different time points studied either in the 6 h or 24 h profiles; GH concentration between infants who developed CLD vs no CLD was not different (mean GH respectively 77±11 vs 79±8 mg/l, p=0.86, adjusted p= 0.56). IGF-I levels were significantly lower in CLD vs no CLD infants even adjusted for GA and BWSDS (respectively 1.3±0.1 vs 1.9±0.2 nmol/l, p=0.02, adjusted p=0.04). IGFBP-3 levels were not different between both groups (CLD 0.60±0.04 mg/l vs no CLD 0.71±0.05 mg/l, p=0.11, adjusted p=0.94).Conclusion: Our results support the hypothesis that IGF-1 deficiency may increase the risk to develop CLD. Since GH levels do not differ between infants who develop CLD and those who do not, differences in IGF-I levels may be explained by a relative GH resistance. Alternatively, levels of IGF-I may be lower due to a decreased production in preterm infants. With respect to the relationship between IGF-I and the development of serious sequelae associated with prematurity (1) our findings are comparable with observations by others). We therefore suggest that IGF-I may play an important role in the development of chronic lung disease of prematurity.

Cord plasma adiponectin: a 20-fold rise between 24 weeks gestation and term.

Adiponectin is an adipocyte-derived hormone with profound insulin-sensitizing, antiinflammatory, and antiatherogenic effects. Apart from its obvious potential as a mediator of adult metabolic syndrome, adiponectin could have a significant role in regulating fetal growth.We measured plasma adiponectin concentrations by ELISA in cord vein of 197 infants. Of them, 122 were born preterm (gestational age, 22-32 wk), and 75 at term (49 from a healthy and 26 from a diabetic pregnancy, with similar findings, and thus all data from term infants pooled).Mean adiponectin concentrations increased from less than 1 microg/ml at 24 wk gestation to approximately 20 microg/ml at term. One week increase in gestational age corresponded in preterm infants to 43% increase (95% confidence interval 34-53%; P < 0.0001) in adiponectin and term infants to 21% increase (12-31%; P < 0.0001). In preterm infants, one unit increase in birth weight sd score corresponded to 42% increase (22-66%; P = 0.0001) in adiponectin, and females had 57% higher adiponectin concentrations (0-146%; P = 0.05) than males. These differences were not seen in term infants. Adiponectin levels were lower in preterm infants with recent (<12 h) exposure to maternal betamethasone but were unrelated to mode of delivery, preeclampsia, or impaired umbilical artery flow. In conclusion, adiponectin concentrations in fetal circulation show a 20-fold rise between 24 wk gestation and term and, in preterm infants are associated with birth weight sd score, sex, and glucocorticoid exposure. Adiponectin may play an important role in regulating fetal growth and explaining its links to the metabolic syndrome and its consequences during adult life.

Determinants of insulin sensitivity and secretion in very-low-birth-weight children.

In prepubertal children, low birth weight is related to reduced insulin sensitivity, particularly if a history of rapid postnatal weight gain is present. We sought to determine whether these associations were also evident in premature, very-low-birth-weight (VLBW) children. We studied 60 VLBW prepubertal children aged 5-7 yr (mean age 5.7 +/- 0.7 yr). Birth weights ranged from 690 to 1500 g (mean 1195 +/- 31 g), with gestational ages between 25 and 34 wk (median 29 wk). A short iv glucose tolerance test was carried out to assess fasting insulin sensitivity and glucose-stimulated insulin secretion. The effects of current body mass index, birth weight (SD scores), postnatal growth rates, and indicators of postnatal morbidity were evaluated by analysis of covariance. Twenty children were born small for gestational age, and 40 were appropriate for gestational age. Ninety-eight percent of them had attained a height within target range. Children who were small for gestational age had lower insulin sensitivity than children who were appropriate for gestational age (homeostasis model assessment insulin resistance index 1.24 +/- 0.17 vs. 0.94 +/- 0.08, P < 0.05). Moreover, birth weight SD scores correlated significantly with homeostasis model assessment insulin resistance index (r = -0.326, P = 0.01). This effect persisted after adjustment for current body mass index, gestational age, and perinatal morbidity. In addition, fasting and postload insulin secretion during the short iv glucose tolerance test correlated significantly with early postnatal growth rates, independently of birth weight SD scores. Our findings in a cohort of VLBW prepubertal children indicate that growth in utero as well as postnatal growth rates are independent determinants of subsequent insulin sensitivity and secretion.

Birthweight of offspring and paternal insulin resistance and paternal diabetes in late adulthood: cross sectional survey.

It has been proposed that genetic factors involved in insulin action could explain part of the link between low birthweight and risk of cardiovascular disease and diabetes in adulthood. To confirm this we examined the association between offspring birthweight and paternal insulin resistance and diabetes in late adulthood. We did a cross-sectional survey of 4252 men who were 60 to 79 years of age and from 24 British towns. Of these, 2788 men provided details of their offsprings' birthweight and sex. Offspring birthweight was inversely associated with paternal insulin resistance defined by the homeostasis model assessment (HOMA) score and with Type 2 diabetes in late adulthood. Fathers of offspring in the highest quartile of sex-standardised birthweight SD scores had a 34% reduction in odds of having a high HOMA insulin resistance score (OR=0.66, 95% CI: 0.47 to 0.92) compared with fathers of offspring in the lowest quartile after adjustment for potential confounders. A stronger inverse association was seen between offspring birthweight and risk of paternal diabetes (adjusted OR=0.59, 95% CI: 0.39 to 0.88 top quartile vs lowest quartile). For each increase of offspring-birthweight SD score the odds of high HOMA scores decreased by 13% (OR=0.87, 95% CI: 0.78 to 0.98) and the odds for diabetes by 17% (OR=0.83, 95% CI: 0.72 to 0.95), after full adjustment. Offspring birthweight is inversely associated with paternal insulin resistance and diabetes in late adulthood, supporting the hypothesis that genetic factors related to insulin action contribute to the association between birthweight and adult cardiovascular disease and diabetes risk.

Blood pressure, serum lipids, fasting insulin, and adrenal hormones in 12-year-old children born with maternal preeclampsia.

Women with prior preeclamptic pregnancies have an increased risk for metabolic syndrome and cardiovascular diseases. Maternal preeclampsia has been associated with elevated blood pressure (BP) in offspring during childhood. The aim of our study was to determine whether elevated BP pressure and metabolic changes, such as dyslipidemia, insulin resistance, and increased adrenal hormonal activity, are found in 12-yr-old children of preeclamptic mothers. Sixty children born after preeclamptic pregnancy (PRE) and 60 matched control subjects born after normotensive pregnancy (non-PRE) were studied at the age of 12 yr. The case-control pairs were matched for sex, gestational age (+/-1 wk), and size at birth. We measured BP and concentrations of blood glucose, serum fasting insulin, total and high density lipoprotein cholesterol, triglycerides, cortisol, dehydroepiandrosterone sulfate, and plasma epinephrine (E) and norepinephrine (NE). Low density lipoprotein cholesterol was calculated according to the Friedewald-Fredrickson formula. The PRE children had significantly higher mean systolic (116.4 vs. 113.2 mm Hg; P = 0.021) and diastolic (73.9 vs. 70.3 mm Hg; P = 0.022) BP than the non-PRE children, even when adjusted by current weight and height. At 12 yr of age, systolic BP values correlated inversely with birth weight (r = -0.459; P < 0.001) and length SD scores (r = -0.429; P = 0.001) in the PRE children. The mean concentrations of serum total, low density lipoprotein, and high density lipoprotein cholesterol; triglycerides; fasting insulin; blood glucose; serum cortisol; and dehydroepiandrosterone sulfate did not differ between the PRE and non-PRE groups. However, the mean plasma E concentration was higher in the PRE than in the non-PRE children (0.32 vs. 0.28 nmol/liter; P = 0.042), whereas the mean NE concentration did not differ between these two groups. In conclusion, 12-yr-old children born with maternal preeclampsia had elevated systolic and diastolic BPs and slightly increased E levels in the circulation. It is not known whether these changes are caused by genetic factors or by preeclampsia itself.

Growth hormone (GH) replacement therapy in GH-deficient women during pregnancy.

The present recommendation is to discontinue GH replacement therapy in hypopituitary women, as they become pregnant. We report our experience of managing GH deficiency with GH replacement therapy in pregnant hypopituitary women. Eight hypopituitary women, median age 30.5 years (range 20-39 years), were followed prospectively during 12 distinct pregnancies. Six women were receiving replacement therapy for other pituitary hormone deficiencies and five pregnancies were achieved with ovulation induction therapy. GH replacement therapy was maintained at the same pregestational dose during the first trimester, with a gradual decrease of the dose during the second trimester and discontinuing the treatment at the beginning of the third trimester. Serum IGF-1 levels were measured in four selected pregnancies at three different points, one in each trimester of gestation. Seven pregnancies resulted in normal vaginal deliveries and five had programmed Caesarian sections. The median gestation age at time of delivery was 40 weeks (range 33-42 weeks). Newborns had a median birthweight SD score of -0.37 (range -1.93 to 1.21) and a median birthlength SD score of 0.07 (range -2.73 to 1.53). No congenital malformations were observed. Three women were able to breastfeed their babies. Before gestation, the median daily dose of GH was 0.5 mg (range 0.3-0.8 mg) and the median serum IGF-1 was 37.5 nmol/l (range 7.6-54.5 nmol/l). IGF-1 levels were fairly constant in the first and second trimesters of gestation, showing an increment during the last trimester, when GH treatment was discontinued. The GH replacement regimen presented for pregnant women with GH deficiency was safe. No major side-effects and no negative influences on maternal and fetal outcome were observed.

Fetal Growth and the Function of the Adrenal Cortex in Preterm Infants

Small for gestational age preterm infants have a higher risk of neonatal morbidity compared to appropriate for gestational age preterm infants. A diminished adrenal response to stress may be involved in the higher postnatal morbidity. The adrenal cortex response in relation to fetal growth was studied by ACTH stimulation tests in 43 preterm infants (born ≤32 wk). The cortisol and 17-hydroxyprogesterone (17-OHP) responses to 1 μg/kg ACTH were analyzed in relation to birth weight sd scores (BW-SDS) corrected for gestational age, gender, and parity. BW-SDS was significantly associated with the cortisol and 17-OHP response. Infants with the lowest BW-SDS had the lowest cortisol levels after stimulation. No effect of size at birth was found on the ratio between cortisol and 17-OHP. In addition, basal cortisone levels in a single blood sample were higher in infants with the lowest BW-SDS than in infants with higher BW-SDS, but the ratio between cortisol and cortisone was comparable in the two groups. We conclude that the response of cortisol and 17-OHP to ACTH stimulation in preterm infants is related to fetal growth. The lack of influence of fetal growth on the ratio between cortisol and 17-OHP after ACTH stimulation suggests that the activities of 21- and 11β-hydroxylase are not affected. The lower adrenal response to stimulation may be important in neonatal morbidity and possibly the development of disease in later life in growth-restricted preterm infants.

Fetal growth and the function of the adrenal cortex in preterm infants.

Small for gestational age preterm infants have a higher risk of neonatal morbidity compared to appropriate for gestational age preterm infants. A diminished adrenal response to stress may be involved in the higher postnatal morbidity. The adrenal cortex response in relation to fetal growth was studied by ACTH stimulation tests in 43 preterm infants (born < or = 32 wk). The cortisol and 17-hydroxyprogesterone (17-OHP) responses to 1 microg/kg ACTH were analyzed in relation to birth weight SD scores (BW-SDS) corrected for gestational age, gender, and parity. BW-SDS was significantly associated with the cortisol and 17-OHP response. Infants with the lowest BW-SDS had the lowest cortisol levels after stimulation. No effect of size at birth was found on the ratio between cortisol and 17-OHP. In addition, basal cortisone levels in a single blood sample were higher in infants with the lowest BW-SDS than in infants with higher BW-SDS, but the ratio between cortisol and cortisone was comparable in the two groups. We conclude that the response of cortisol and 17-OHP to ACTH stimulation in preterm infants is related to fetal growth. The lack of influence of fetal growth on the ratio between cortisol and 17-OHP after ACTH stimulation suggests that the activities of 21- and 11 beta-hydroxylase are not affected. The lower adrenal response to stimulation may be important in neonatal morbidity and possibly the development of disease in later life in growth-restricted preterm infants.

Plasminogen activator inhibitor-1 in girls with precocious pubarche: a premenarcheal marker for polycystic ovary syndrome?

In both obese and nonobese women, polycystic ovary syndrome (PCOS) is essentially a disorder of hyperinsulinemic insulin resistance, and it may be heralded by precocious pubarche (PP; appearance of pubic hair in girls aged <8 y). The risk of progression from PP to PCOS is related to low birth weight, but there are no early biochemical markers of this risk. As increased plasminogen activator-inhibitor type 1 (PAI-1) activity (act) is an early marker of cardiovascular risk in PCOS, we have sought abnormalities in young girls with PP. In 33 young PP girls (age range 6-11 y), PAI-1-act was increased (mean + SEM: 15.6 +/- 1.5 IU/mL) compared with age-, sex-, and pubertal stage-matched controls (n = 13, 10.7 +/- 1.9, p < 0.05). PAI-1-act levels were inversely related to birth weight SD score (r = -0.33, p < 0.05), and PAI-1-act levels were therefore higher in PP girls with low birth weights (n = 14, 19.5 +/- 2.5 IU/mL) than normal birth weights (n = 19, 12.8 +/- 1.5, p < 0.01). During longitudinal observation in 10 PP girls (mean time interval 2.7 y), PAI-1-act levels in early puberty were positively related to postmenarcheal insulin levels (mean serum insulin SDS postoral glucose, r = 0.65, p < 0.05), and showed a similar relationship to postmenarcheal testosterone levels (r = 0.61, p = 0.06). Together with low birth weight, increased plasma PAI-1-act levels in early pubertal PP girls may indicate those girls with greater risk of developing hyperinsulinemic-hyperandrogenism features of PCOS.