Sandra W. K. De Kort

Preterm birth does not affect bone mineral density in young adults.

OBJECTIVE Previous studies showed conflicting data on the effect of prematurity on bone mineral density (BMD) in infants and children. Only a few studies investigated the long-term effects of prematurity on BMD in early adulthood. The objective of our study was to assess the long-term effects of preterm birth on BMD of the total body (BMD(TB)), lumbar spine (BMD(LS)) and bone mineral apparent density of the LS (BMAD(LS)). DESIGN Cross-sectional study. METHODS It consists of two hundred and seventy-six healthy subjects without serious postnatal complications, aged 18-24 years. The contribution of gestational age to the variance in BMD in young adulthood and the differences in BMD between 151 subjects born preterm (median gestational age 32.2 weeks (interquartile range (IQR) 30.3-34.0)) and 125 subjects born at term (median gestational age 40.0 weeks (IQR 39.0-40.0)) were investigated. BMD was determined by dual-energy X-ray absorptiometry. RESULTS There were no significant linear correlations between gestational age and BMD(TB) (r=0.063, P=0.30), BMD(LS) (r=0.062, P=0.31) and BMAD(LS) (r=0.069, P=0.26). Also after adjustment for possible confounders, gestational age was no significant contributor to the variance in BMD(TB) (P=0.27), BMD(LS) (P=0.91) and BMAD(LS) (P=0.87). No significant differences were found between preterm and term subjects with regard to BMD(TB), BMD(LS) and BMAD(LS). CONCLUSION In our cohort of 276 young adults, aged 18-24 years, gestational age was not a significant determinant in the variance of BMD. Preterm birth without serious postnatal complications is not associated with a lower BMD in young adulthood.

Serum insulin-like growth factor-binding protein-2 levels and metabolic and cardiovascular risk factors in young adults and children born small for gestational age

BACKGROUND IGF binding protein (IGFBP)-2 might protect against cardiovascular disease. Small for gestational age (SGA) birth could be associated with a higher risk for type 2 diabetes mellitus and cardiovascular disease in later life. No data are available on the relationship between serum IGFBP-2 levels and cardiovascular risk factors in young adults and children born SGA. OBJECTIVE The aim of the study was to determine circulating IGFBP-2 levels in subjects born SGA and to investigate the association with cardiovascular risk factors. METHODS IGFBP-2 levels were measured in sera from 151 young adults born SGA and 147 short SGA children. Age- and gender-adjusted sd scores (SDS) were calculated. We determined blood pressure, serum lipids, body composition by dual-energy x-ray absorptiometry, and glucose homeostasis by homeostasis model of assessment for insulin resistance or frequently sampled iv glucose tolerance test. RESULTS Serum IGFBP-2 SDS was significantly reduced in SGA young adults (with normal or short stature). Fat mass SDS was relatively high in SGA young adults and was reduced in short SGA children. Serum IGFBP-2 SDS in SGA young adults correlated positively with insulin sensitivity and negatively with fat mass SDS, insulin secretion (acute insulin response), fasting insulin, homeostasis model of assessment for insulin resistance, total cholesterol, triglycerides, and blood pressure SDS. The association between serum IGFBP-2 SDS and insulin sensitivity, blood pressure, total cholesterol, and triglyceride levels persisted after adjustment for known covariates including fat mass SDS. In short SGA children, IGFBP-2 SDS did not correlate with any of the cardiovascular risk factors. CONCLUSION In young adults who were born SGA, serum IGFBP-2 levels associate with cardiovascular risk markers.

Insulin-Like Growth Factor-Binding Protein-1: Serum Levels, Promoter Polymorphism, and Associations with Components of the Metabolic Syndrome in Short Subjects Born Small for Gestational Age

CONTEXT IGF binding protein (IGFBP)-1 is the only acute regulator of IGF-I bioavailability. Its production is suppressed by insulin, and low levels are associated with hyperinsulinemia and cardiovascular disease risk in adults. Data on IGFBP-1 levels in short, small for gestational age (SGA) subjects are scarce, and associations with IGFBP1 promoter single nucleotide polymorphisms have not been established. OBJECTIVE The aim of the study was to determine IGFBP-1 levels in short SGA subjects compared with those in controls, to assess genotype frequency of the -575 G/A single nucleotide polymorphism, and to determine its impact on IGFBP-1 levels. SUBJECTS A total of 272 short subjects born SGA and 330 subjects with normal stature (245 children, 85 young adults) participated in the study. OUTCOME MEASURES We measured fasting levels of IGFBP-1, IGF-I, insulin and lipid parameters, and body composition. RESULTS IGFBP-1 sd score (SDS) was comparable to controls in lean, short, SGA children but significantly lower in short SGA adults with normal fat mass (P < 0.001). IGFBP-1 SDS correlated significantly with insulin levels, systolic blood pressure SDS, and various lipid parameters. Baseline IGFBP-1 SDS was lowest in SGA children with -575 GG genotype and significantly higher in SGA children with one or two copies of the A allele. In response to a given insulin level, children with the AA genotype had a significantly higher IGFBP-1 SDS compared to children with the GG genotype. CONCLUSION Normal IGFBP-1 levels in lean, short, SGA children may reflect a normal metabolic state, despite reported hyperinsulinemia. IGFBP-1 is modulated by polymorphic variability and seems to be an additional player in the complex interaction between the IGF-IGFBP axis, glucose homeostasis, and lipid metabolism.

The effect of growth hormone treatment on metabolic and cardiovascular risk factors is similar in preterm and term short, small for gestational age children

Context  We previously reported that short, small for gestational age (SGA) children who were born preterm have a lower body fat percentage and a higher blood pressure, insulin secretion and disposition index than short SGA children born at term. Whether preterm birth also influences these parameters during GH treatment is unknown.

Does preterm birth influence the response to growth hormone treatment in short, small for gestational age children?

Objective  To investigate whether prematurity has an independent influence on the response to GH treatment in short, small for gestational age (SGA) children.

Type 2 diabetes gene TCF7L2 polymorphism is not associated with fetal and postnatal growth in two birth cohort studies

BackgroundAn inverse association between birth weight and the risk of developing type 2 diabetes (T2D) in adulthood has been reported. This association may be explained by common genetic variants related to insulin secretion and resistance, since insulin is the most important growth factor in fetal life. The objective of this study was to examine whether T2D gene polymorphism TCF7L2 rs7903146 is associated with growth patterns from fetal life until infancy.MethodsThis study was performed in two independent birth cohort studies, one prospective population-based (Generation R), and one of subjects born small-for-gestational-age (SGA cohort). Fetal growth was assessed by ultrasounds in second and third trimesters of pregnancy in Generation R. Growth in infancy was assessed in both cohorts at birth and at 6, 12 and 24 months postnatally. TCF7L2 genotype was determined in 3,419 subjects in Generation R and in 566 subjects in the SGA cohort.ResultsMinor allele frequency did not differ significantly (p = 0.47) between Generation R (T-allele: 28.7%) and the SGA cohort (T-allele: 29.8%). No differences at birth were found in gestational age or size (head circumference, length, weight) between the genotypes in either cohort. TCF7L2 genotype was also not associated with any pre- or postnatal growth characteristic in either Generation R or the SGA cohort.ConclusionWe found no evidence for an association between TCF7L2 genotype and fetal and early postnatal growth. Furthermore, this TCF7L2 polymorphism was not associated with an increased risk of SGA.

Plasma matrix metalloproteinase-9 levels and blood pressure in short children born small for gestational age and effects of growth hormone treatment

Context  Short small‐for‐gestational‐age (SGA) children have an increased systolic blood pressure (BP) that decreases during long‐term GH treatment. The underlying mechanism is still unknown. Matrix metalloproteinases (MMPs) are zinc‐dependent endoproteinases that are involved in the remodelling of the extracellular matrix (ECM) and are thought to play a role in atherosclerosis. High MMP‐9 levels are found in hypertensive patients and predict cardiovascular mortality.

Interactions between TCF7L2 genotype and growth hormone-induced changes in glucose homeostasis in small for gestational age children

Context  The Transcription factor 7‐like 2 (TCF7L2) rs7903146 gene polymorphism has been associated with risk of developing type 2 diabetes mellitus (DM), possibly by decreasing insulin secretion. Small for gestational age (SGA) birth has been associated with type 2 DM in later life. Growth hormone (GH) treatment reduces insulin sensitivity and increases insulin secretion. Therefore, GH‐treated SGA children are an ideal group to investigate whether the TCF7L2 rs7903146 genotype is associated with changes in glucose homeostasis.

The PPAR-γ Pro12Ala polymorphism associates with weight gain during GH-treatment in short children born small for gestational age

CONTEXT Short children born small for gestational age (SGA) have a lean phenotype with lower insulin sensitivity and higher blood pressure. GH treatment results in weight gain, and a decrease in blood pressure and insulin sensitivity. However, not all children respond in the same way. The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR-gamma) gene is inversely associated with body mass index (BMI), changes in BMI and the risk to develop type 2 diabetes mellitus. OBJECTIVE To analyze the contribution of the PPAR-gamma Pro12Ala polymorphism to GH induced changes in determinants of metabolic and cardiovascular disease in short SGA children. METHODS PPAR-gamma was genotyped in 238 Caucasian short SGA children (mean age 7.5 years). Height, weight, blood pressure, and serum lipids were measured before start and during 4 years of GH treatment. In addition, glucose homeostasis by homeostasis model assessment insulin resistance ratio (HOMA-IR) (n=148) and by frequently sampled i.v. glucose tolerance test (n=51), and body composition by dual energy X-ray absorptiometry (n=79) were measured. RESULTS At baseline, the Ala12 allele was not associated with any determinant of metabolic and cardiovascular disease. After 4 years of GH treatment, the increase in weight for height SDS and BMI SDS was significantly greater in carriers of an Ala12 allele than in noncarriers. The change in all other parameters was not associated with Pro12Ala genotype. CONCLUSION The Ala12 variant of the PPAR-gamma gene is associated with higher weight gain during GH treatment but not with changes in determinants of metabolic and cardiovascular diseases in Caucasian subjects born SGA.

Cardiovascular risk factors in parents of short children born small for gestational age

Small for gestational age (SGA) children have a higher prevalence of cardiovascular risk factors at a young age. It is not known whether this increased risk is caused by their size at birth, a familial predisposition for cardiovascular disease or smallness at birth or a combination of these factors. The cardiovascular risk profile of parents of SGA children is unknown. We compared anthropometry, blood pressure, fasting serum lipid, glucose, and insulin levels of 482 parents (mean age 41 y) and 286 short SGA children with age- and sex-matched references. We also investigated whether these parameters correlated between parents and their offspring. Mothers had higher systolic blood pressure, fathers had a higher body mass index and parents had more frequently high fasting glucose levels than age- and sex-matched references. Children had significantly higher systolic and diastolic blood pressure than sex- and height-matched references. Twenty-four percent (mothers) and 10% (fathers) were born SGA but they did not have more cardiovascular risk factors than those born appropriate for gestational age. Cardiovascular risk factors did not correlate between parents and children. In conclusion, parents of short SGA children have a modest increase in some cardiovascular risk factors but risk factors did not correlate between parents and children.