Sequelae of syndrome X in children born small for gestational age

OBJECTIVE: Low birth weight is associated with the presence of syndrome X in adults. We studied the components of this syndrome in prepubertal children born SGA (small for gestational age) and children born AGA (appropriate for gestational age). METHODS: Twenty-nine SGA children, age (mean +/- SD) 9.1 +/- 1.1 years and 24 AGA children, age 9.0 +/- 1.1 years were studied. Fasting serum lipid concentrations were determined. A hyperinsulinemic euglycemic clamp was performed to measure insulin sensitivity. Ambulatory monitoring was performed to obtain 24-hour recordings of blood pressure. RESULTS: Prepubertal SGA children are less insulin sensitive and have a higher nighttime systolic blood pressure (SBP) after correction for BMI than children born AGA. No differences were found in lipid concentrations between the 2 groups. CONCLUSIONS: Not all components of syndrome X can yet be found in 9-year-old children born SGA; follow-up of this cohort is required.     

Impact of birth weight and early infant weight gain on insulin resistance and associated cardiovascular risk factors in adolescence

Background

Low birth weight followed by accelerated weight gain during early childhood has been associated with adverse metabolic and cardiovascular outcomes later in life. The aim of this study was to examine the impact of early infant weight gain on glucose metabolism and cardiovascular risk factors in adolescence and to study if the effect differed between adolescents born small for gestational age (SGA) vs. appropriate for gestational age (AGA).

Methodology/Principal Findings

Data from 30 SGA and 57 AGA healthy young Danish adolescents were analysed. They had a mean age of 17.6 years and all were born at term. Data on early infant weight gain from birth to three months as well as from birth to one year were available in the majority of subjects. In adolescence, glucose metabolism was assessed by a simplified intravenous glucose tolerance test and body composition was assessed by dual-energy X-ray absorptiometry. Blood pressures as well as plasma concentrations of triglycerides and cholesterol were measured. Early infant weight gain from birth to three months was positively associated with the fasting insulin concentration, HOMA-IR, basal lipid levels and systolic blood pressure at 17 years. There was a differential effect of postnatal weight gain on HOMA-IR in AGA and SGA participants (P for interaction = 0.03). No significant associations were seen between postnatal weight gain and body composition or parameters of glucose metabolism assessed by the simplified intravenous glucose tolerance test. In subgroup analysis, all associations with early infant weight gain were absent in the AGA group, but the associations with basal insulin and HOMA-IR were still present in the SGA group.

Conclusion

This study suggests that accelerated growth during the first three months of life may confer an increased risk of later metabolic disturbances – particularly of glucose metabolism – in individuals born SGA.     

Hyperinsulinemia in pre- and post-pubertal children born small for gestational age

BACKGROUND: Reduced fetal growth is a potential risk factor for development of metabolic abnormalities in later life. The relationship between low birthweight and impaired glucose tolerance, type 2 diabetes and insulin resistance in adulthood has been well documented. PURPOSE: Assuming that fetal undernutrition is associated with insulin resistance in middle age, we elected to study whether this process may already be present in young adults and adolescents born small for gestational age (SGA). SUBJECTS AND METHODS: Children born in Vall d'Hebron Hospital Infantil, Barcelona, between 1986 and 1989 and between 1978 and 1983 with birthweights below the third centile for the local standard values, were invited to participate in the present study. Of those, 51 (22 girls and 29 boys) were pre-pubertal with 9.4 +/- 0.2 years of age and 49 (29 girls and 20 boys ) were post-pubertal, with 17.3 +/- 0.3 years of age. All patients underwent a standard, 2-hour oral glucose tolerance test. Insulin and glucose responses were compared with our previously published data in control children with normal birthweight. RESULTS: The insulin response at 30 min after glucose load was significantly higher (p < 0.001) in pre- and post-pubertal girls and boys formerly SGA than in controls. In addition, the girls also had a higher insulin response at 60 and 120 min. Mean serum insulin (MSI), the area under the insulin curve during the glucose challenge, was statistically increased in pre- and post-pubertal boys and girls born SGA when compared to controls. CONCLUSION: The presence of high insulin levels after an oral glucose challenge in children and adolescents born SGA might be considered as an early marker of subsequent insulin resistance in adulthood. Furthermore, our population offers the opportunity to study the natural course of hyperinsulinemia and its outcome. Follow-up of this cohort may be helpful in distinguishing a subset of young children and adolescents in whom therapeutic intervention could be done.     

Progression of Cardio-Metabolic Risk Factors in Subjects Born Small and Large for Gestational Age

Background

Subjects born small (SGA) and large (LGA) for gestational age have an increased risk of cardio-metabolic alterations already during prepuberty. Nevertheless, the progression of their cardio-metabolic profile from childhood to adolescence has not been fully explored. Our aim was to assess potential changes in the cardio-metabolic profile from childhood to adolescence in subjects born SGA and LGA compared to those born appropriate (AGA) for gestational age.

Methods

This longitudinal study included 35 AGA, 24 SGA and 31 LGA subjects evaluated during childhood (mean age (±SD) 8.4±1.4 yr) and then re-assessed during adolescence (mean age 13.3±1.8 yr). BMI, blood pressure, insulin resistance (fasting insulin, HOMA-IR) and lipids were assessed. A cardio-metabolic risk z-score was applied and this consisted in calculating the sum of sex-specific z-scores for BMI, blood pressure, HOMA-IR, triglycerides and triglycerides:high-density lipoprotein cholesterol ratio.

Results

Fasting insulin and HOMA-IR were higher in SGA and LGA than AGA subjects both during childhood (all P<0.01) and adolescence (all P<0.01). Similarly, the clustered cardio-metabolic risk score was higher in SGA and LGA than AGA children (both P<0.05), and these differences among groups increased during adolescence (both P<0.05). Of note, a progression of the clustered cardio-metabolic risk score was observed from childhood to adolescence within SGA and within LGA subjects (both P<0.05).

Conclusions

SGA and LGA subjects showed an adverse cardio-metabolic profile during childhood when compared to AGA peers, with a worsening of this profile during adolescence. These findings indicate an overtime progression of insulin resistance and overall estimated cardiovascular risk from childhood to adolescence in SGA and LGA populations.     

Adult height distribution in subjects born small for gestational age

The aim of the study was to investigate the post-natal growth of subjects born small for gestational age (SGA) by describing adult height distribution and by testing the effects of parental, neonatal and pregnancy-related parameters on the risk for adult short stature. The study population was made of adults selected on birth data from a maternity registry and born either small (SGA, n = 734, birth weight < 10th percentile) or appropriate for gestational age (AGA, n = 886, 25th < birth weight < 75th percentile) in whom anthropometric parameters were measured at 22 years of age. The SGA group demonstrated significantly reduced body size in comparison to the AGA group with a mean loss of 0.7 standard deviation (SD) in adult height. The frequency of adult short stature (< -2 SD) was 10.3% in the SGA group vs. 2.4% in the AGA group (p = 0.0001), adult height < -2.5 SD was observed in only 3.7% of the SGA group. Maternal (OR = 0.31 (0.16-0.62), p = 0.0001) and paternal (OR = 0.45 (0.31-0.67), p = 0.0001) heights and subjects birth length (OR = 0.78 (0.62-0.99), p = 0.04) significantly influenced the risk of adult short stature. In summary, post-natal growth defect remains moderate in the majority of subjects born SGA and < 4% only will end up with severe short stature requiring GH therapy according to most current recommendations. The role of parental height and birth length suggests that adult short stature in SGA subjects results at least in some cases from a familial and likely genetic growth disorder with antenatal onset.     

Psychosocial functioning of adolescents with idiopathic short stature or persistent short stature born small for gestational age during three years of combined growth hormone and gonadotropin-releasing hormone agonist treatment

AIM: To examine psychosocial functioning of medically referred adolescents with idiopathic short stature (ISS) or persistent short stature born small for gestational age (SGA) during 3 years of combined growth hormone (GH) and gonadotropin-releasing hormone agonist (GnRHa) treatment. METHODS: Thirty-eight adolescents participated in a controlled trial with GH/GnRHa treatment or no intervention. Each year the adolescents and their parents completed questionnaires and structured interviews. Multilevel analysis was used to analyze data. RESULTS: The adolescents of the treatment group showed a worse outcome than the adolescents of the control group on 3 of 16 variables: perceived competence of scholastic (p < 0.01) and athletic ability (p < 0.05) and trait anxiety (p < 0.05). Adolescents in both the treatment and control groups perceived improved current height (p < 0.001) and self-appraisal of physical appearance (p < 0.05). The parents did not report changes in their children during treatment. CONCLUSION: The observation of some adverse psychological consequences as experienced by the adolescents indicates that it is useful to monitor psychosocial functioning during a combined GH/GnRHa treatment in adolescents with ISS or SGA. It is uncertain whether the hypothesized positive effects of the expected gain in final height by adulthood can sufficiently counterbalance possible short-term negative effects.     

Visfatin levels in prepubertal children born small or large for gestational age

Children born small (SGA) or large (LGA) for gestational age are prone to develop insulin resistance (IR) during childhood. Visfatin, a hormone with insulin-mimetic actions, has been associated with IR. This study was designed to examine whether serum level of visfatin is correlated with metabolic indices of IR, in prepuberty in association with the intrauterine growth pattern. The following parameters were evaluated at a mean age of 6.5±1.2 years in 155 prepubertal children born appropriate for the gestational age (AGA) (n=63), or SGA (n=42), or LGA (n=50): serum levels of visfatin, adiponectin, leptin, fasting glucose (G(F)) and insulin (I(F)), the homeostasis model assessment IR index (HOMA-IR), plasma lipids, anthropometric indices at birth and the time of evaluation, and obesity indices [waist circumference (WC), body mass index (BMI) and skinfold thickness]. The mean serum level of visfatin was lower in the SGA than in the AGA and the LGA children (9±5.2 vs. 11.8±5.1 and 12.7±5.6?ng/ml, respectively, p<0.01). Girls had lower visfatin levels than boys (10.4±4.3?ng/ml vs. 12.5±6.7?ng/ml, p<0.05). Visfatin was not correlated with IR indices. In multiple regression analysis visfatin level was positively correlated with birth weight z-score (t=2.56, beta=0.24, p<0.01) and crown to heel z-score (t=2.46, beta=0.22, p=0.014), independent of age, gender, maternal weight before pregnancy, maternal weight gain during pregnancy, BMI z-score, WC z-score, serum leptin and adiponectin, and HOMA-IR. In conclusion serum visfatin level was lower in prepubertal SGA children but not correlated with IR indices. Low birth weight was an independent predictor of visfatin level.     

DNA methylation of IGF2, GNASAS,INSIGF and LEP and being born small for gestational age

Being born small for gestational age (SGA), a proxy for intrauterine growth restriction (IUGR), and prenatal famine exposure are both associated with a greater risk of metabolic disease. Both associations have been hypothesized to involve epigenetic mechanisms. We investigated whether prenatal growth restriction early in pregnancy was associated with changes in DNA methylation at loci that were previously shown to be sensitive to early gestational famine exposure. We compared 38 individuals born preterm (&lt;32 weeks) and with a birth weight too low for their gestational age (-1SDS) and a normal postnatal growth (>-1SDS at 3 months post term; “AGA”). The SGA individuals were not only lighter at birth, but also had a smaller length (P=3.3x10^-13) and head circumference at birth (P=4.1x10^-13). The DNA methylation levels of IGF2, GNASAS, INSIGF and LEP were 48.5%, 47.5%, 79.4% and 25.7% respectively. This was not significantly different between SGA and AGA individuals. Risk factors for being born SGA, including preeclampsia and maternal smoking, were also not associated with DNA methylation at these loci. Growth restriction early in development is not associated with DNA methylation at loci shown to be affected by prenatal famine exposure. Our and previous results by others indicate that prenatal growth restriction and famine exposure may be associated with different epigenetic changes or non epigenetic mechanisms that may lead to similar later health outcomes.     

Effects of growth hormone treatment on cognitive function and head circumference in children born small for gestational age

Short stature is not the only problem faced by children born small for gestational age (SGA). Being born SGA has also been associated with lowered intelligence, poor academic performance, low social competence and behavioural problems. This paper summarizes the results of a randomized, double-blind, growth hormone (GH) dose-response study (1 or 2 mg/m2/day [ approximately 0.035 or 0.07 mg/kg/day]) on growth, intelligence quotient (IQ) and psychosocial functioning in 79 children born SGA at the start, and after 2 and 8 years of GH therapy, and addresses the associations with head circumference. Mean age at start of therapy was 7.4 years; mean duration of GH treatment was 8.0 years. In 2001, 91% of children born SGA had reached a normal height (> -2.0 standard deviation score [SDS]). Block-design s-score (Performal IQ) and Total IQ score increased (p < 0.001 for both indices) from scores significantly lower than those of Dutch peers at the start of therapy (p < 0.001) to scores that were comparable to those of Dutch peers in 2001. Vocabulary s-score (Verbal IQ) was normal at the start of therapy and remained so over time. Externalizing Problem Behaviour SDS and Total Problem Behaviour SDS improved during GH therapy (p < 0.01-0.05) to scores comparable to those of Dutch peers. Internalizing Problem Behaviour SDS was comparable to that of Dutch peers at the start of therapy and remained so, whereas Self-Perception improved from the start of GH therapy until 2001 (p < 0.001), when it reached normal scores. Head circumference SDS at the start of GH therapy and head growth during GH therapy were positively related to all IQ scores (p < 0.01), whereas neither were related to height SDS at the start of, or to its improvement during, GH therapy. A significant improvement in height and head circumference in children born SGA was seen after only 3 years of GH therapy, in contrast to randomized SGA controls. In conclusion, most children born SGA showed a normalization of height during GH therapy and, in parallel to this, a significant improvement in Performal IQ and Total IQ. In addition, problem behaviour and self-perception improved significantly. Interestingly, Performal, Verbal and Total IQ scores were positively related to head circumference, both at the start of, and during, GH therapy; head circumference increased in GH-treated children born SGA, but not in untreated SGA controls. These results are encouraging but also warrant confirmational studies and further investigations into the effects of GH on the central nervous system.     

Aortic Intima-Media Thickness and Aortic Diameter in Small for Gestational Age and Growth Restricted Fetuses

ObjectiveThe objective of this study is to measure aortic intima-media thickness (aIMT) and aortic diameter (AD) in appropriate for gestational age (AGA) fetuses, small for gestational age (SGA) fetuses, and intrauterine growth restricted (IUGR) fetuses.MethodsCase-control study performed between June 2011 and June 2012. Forty-nine AGA fetuses, 40 SGA fetuses, and 35 IUGR fetuses underwent concomitant measurement of aIMT and AD at a mean gestational age of 34.4 weeks.ResultsMedian aIMT was higher in fetuses with IUGR (0.504 mm [95%CI: 0.477-0.530 mm]), than in SGA fetuses (0.466 mm [95% CI: 0.447–0.485 mm]), and AGA fetuses (0.471 mm [95% CI: 0.454-0.488 mm]) (p = 0.023). Mean AD was significantly lower in fetuses with IUGR (4.451 mm [95% CI: 4.258–4.655 mm]), than in AGA fetuses (4.74 mm [95% CI: 4.63-4.843 mm]) (p = 0.028).ConclusionsGrowth restricted fetuses have a thicker aortic wall than AGA and SGA fetuses, which possibly represents preclinical atherosclerosis and a predisposition to later cardiovascular disease.     

DNA methylation of IGF2, GNASAS,INSIGF and LEP and being born small for gestational age

Being born small for gestational age (SGA), a proxy for intrauterine growth restriction (IUGR) and prenatal famine exposure are both associated with a greater risk of metabolic disease. Both associations have been hypothesized to involve epigenetic mechanisms. We investigated whether prenatal growth restriction early in pregnancy was associated with changes in DNA methylation at loci that were previously shown to be sensitive to early gestational famine exposure. We compared 38 individuals born preterm (<32 weeks) and with a birth weight too low for their gestational age (less than −1SDS; SGA) with 75 individuals born preterm but with a birth weight appropriate for their gestational age (greater than −1SDS) and a normal postnatal growth (greater than −1SDS at three months post term; AGA). The SGA individuals were not only lighter at birth, but also had a smaller length (p = 3.3 × 10⁻¹³) and head circumference at birth (p = 4.1 × 10⁻¹³). The DNA methylation levels of IGF2, GNASAS, INSIGF and LEP were 48.5, 47.5, 79.4 and 25.7% respectively. This was not significantly different between SGA and AGA individuals. Risk factors for being born SGA, including preeclampsia and maternal smoking, were also not associated with DNA methylation at these loci. Growth restriction early in development is not associated with DNA methylation at loci shown to be affected by prenatal famine exposure. Our and previous results by others indicate that prenatal growth restriction and famine exposure may be associated with different epigenetic changes or non-epigenetic mechanisms that may lead to similar later health outcomes.Key words: SGA, DOHAD, IUGR, DNA methylation, famine, IGF2, LEP, INS, GNASAS     

Adult height in patients treated for isolated growth hormone deficiency: role of birth weight

To evaluate the effect of growth hormone (GH) administration on adult height (AH) in two groups of isolated GH-deficient (IGHD) children born either small (birth weight below -2 SD) or appropriate (birth weight above -2 SD) for gestational age (GA). Out of 35 prepubertal IGHD children, 14 small for GA (SGA, group A) and 21 appropriate for GA (AGA, group B) were examined. All patients received continuous GH treatment at a median dose of 0.028 mg/kg/day (range 0.023-0.032) in group A and 0.024 (range 0.023-0.028) in group B. GH treatment was administered for a period of 67.0 months (range 42.37-96.05) in group A and 54.31 months (range 47.14-69.31) in group B. All children were measured using a Harpenden stadiometer every 6 months until they reached AH (growth velocity <1 cm/year). The patients underwent a retesting a few months after stopping GH therapy. A significant difference was found between group A and B as expected for birth weight SD, -2.70 (range -2.87 to -2.29) and -0.73 (range -1.30 to 0.14) respectively (p < 0.000001) and interestingly also for body mass index SDS (BMI SDS) at retesting, 0.08 (range 0.30 to -1.51) and 0.61 (range 0.73 to -1.10) respectively (p < 0.04). We observed no significant differences between groups A and B in height (expressed as the SDS for chronological age, height SDS) at diagnosis (p = 0.75), height SDS at start of puberty (p = 0.51), height SDS at retesting (p = 0.50), target height SDS (TH SDS) (p = 0.47), AH SDS (p = 0.92), corrected height SDS (height SDS - TH SDS) (p = 0.60), BMI SDS at diagnosis (p = 0.25), GH dosage (p = 0.34) and therapy duration (p = 0.52). GH treatment with a standard dose in short IGHD children leads to a normalization of AH without any significant difference between SGA and AGA patients.     

Low birth weight for gestational age associates with reduced glucose concentrations at birth, infancy and childhood

BACKGROUND/AIMS: Our aim was to investigate glucose homeostasis, insulin sensitivity and insulin-like growth factor (IGF) system status in children born small for gestational age (SGA). METHODS: A case-control study was carried out at birth, infancy and childhood, comparing SGA with children appropriate for gestational age strictly matched for age, gender, pubertal status and body mass index. Ninety newborns, 52 infants, and 68 children were studied. Fasting insulin (I(F)), fasting glucose (G(F)) to I(F) ratio (G(F)/I(F)), the homeostasis model assessment of insulin sensitivity, the quantitative insulin sensitivity check index, insulinogenic index and the triglyceride/high-density lipoprotein-cholesterol ratio were measured. IGF-I, IGF-binding protein-3 and the IGF-I/IGF-binding protein-3 molar ratio were assessed. RESULTS: Glucose concentrations were lower in SGA newborns (p < 0.0001), infants (p = 0.01), and children (p = 0.001). Birth weight correlated with glucose levels at birth (r = 0.59, p < 0.0001), 12 months (r = 0.29, p = 0.04) and childhood (r = 0.44, p < 0.0001). CONCLUSION: Our results provide evidence for a developmental adaptation of glucose metabolism in SGA children leading to reduced glucose concentrations.     

Efficacy and safety of long-term continuous growth hormone treatment of children born small for gestational age

Twelve years of growth hormone (GH) therapy of short children born small for gestational age (SGA) have demonstrated that GH is an effective and well-tolerated therapy. Most children will reach a normal adult height (AH). AH of 55 SGA adolescents was comparable for those treated with a GH dose of 1 or 2 mg/m2 (approximately 0.033 or 0.066 mg/kg) per day, mean (SD) AH SDS being -1.2 (0.7) and -0.8 (0.7), respectively. GH therapy had no influence on the age at onset, the progression of puberty, duration of puberty and pubertal height gain. GH therapy induced higher fasting and glucose-stimulated insulin levels after 1 and 6 years, but 6 months after GH stop, all levels returned to normal. At baseline mean systolic blood pressure was significantly increased, but both systolic and diastolic blood pressure decreased significantly during 6 years of GH and remained so after GH stop. GH therapy demonstrated a beneficial effect on serum lipid profiles, body composition, bone mineral density and head growth. Treatment with 2 mg GH/m2 per day induced mean serum IGF-I levels of +2 SDS, whereas IGF-I levels remained within the normal range with 1 mg GH/m2 per day. In conclusion, long-term GH therapy of short SGA children with 1 mg/m2 per day appears to be effective and safe. Since the future consequences of high serum IGF-I levels during long-term GH therapy with 2 mg/m2 per day are as yet unknown, it seems safer to treat short prepubertal SGA children with a GH dose of 1 mg/m2 per day when children are to be treated continuously for many years.     

A comparison of the effectiveness, tolerability and safety of high and low carbohydrate diets in women with gestational diabetes

INTRODUCTION: Nutrition therapy is an integral part of the management of gestational diabetes mellitus (GDM). Most women with GDM are treated by nutritional management alone. The goal of our study was to compare low and high carbohydrate diets in their effectiveness, safety and tolerability in women with GDM. MATERIAL AND METHODS: The study group consisted of 30 Caucasian women newly diagnosed with GDM, with a mean age of 28.7 +/- 3.7 years and pregnancy duration of 29.2 +/- 5.4 weeks. The patients were randomised into two groups: those on a low and those on a high carbohydrate diet (45% vs. 65% respectively of energy supply coming from carbohydrates). The presence of urine ketones was controlled every day. After two weeks daily glucose profiles and compliance with the recommended diets were analysed. RESULTS: Glucose concentration before implementation of the diet regimen did not differ between groups. No changes in fasting blood glucose were noticed in the group that had followed a low carbohydrate diet, although a significant decrease in glucose concentration was observed after breakfast (102 +/- 16 vs. 94 +/- 11 mg/dl), lunch (105 +/- 12 vs. 99 +/- 9 mg/dl) and dinner (112 +/- 16 vs. 103 +/- 13 mg/dl) (p < 0.05). In the high carbohydrate diet group fasting and after-breakfast glucose concentration did not change. A significant decrease in glycaemia was noticed after lunch (106 +/- 15 vs. 96 +/- 7 mg/dl) and dinner (107 +/- 12 vs. 97 +/- 7 mg/dl) (p < 0.05). Ketonuria was not observed in either group. Obstetrical outcomes did not differ between groups. CONCLUSIONS: Both high and low carbohydrate diets are effective and safe. A diet with carbohydrate limitation should be recommended to women who experience the highest glycaemia levels after breakfast.     

Rapid recovery of fat mass in small for gestational age preterm infants after term

Background

Preterm small for gestational age (SGA) infants may be at risk for increased adiposity, especially when experiencing rapid postnatal weight gain. Data on the dynamic features of body weight and fat mass (FM) gain that occurs early in life is scarce. We investigated the postnatal weight and FM gain during the first five months after term in a cohort of preterm infants.

Methodology/Principal Findings

Changes in growth parameters and FM were prospectively monitored in 195 infants with birth weight ≤1500 g. The infants were categorized as born adequate for gestational age (AGA) without growth retardation at term (GR−), born AGA with growth retardation at term (GR+), born SGA. Weight and FM were assessed by an air displacement plethysmography system. At five months, weight z-score was comparable between the AGA (GR+) and the AGA (GR−), whereas the SGA showed a significantly lower weight.The mean weight (g) differences (95% CI) between SGA and AGA (GR−) and between SGA and AGA (GR+) infants at 5 months were −613 (−1215; −12) and −573 (−1227; −79), respectively. At term, the AGA (GR+) and the SGA groups showed a significantly lower FM than the AGA (GR−) group. In the first three months, change in FM was comparable between the AGA (GR+) and the SGA groups and significantly higher than that of the AGA (GR−) group.The mean difference (95% CI) in FM change between SGA and AGA (GR−) and between AGA (GR+) and AGA (GR−) from term to 3 months were 38.6 (12; 65); and 37.7 (10; 65). At three months, the FM was similar in all groups.

Conclusions

Our data suggests that fetal growth pattern influences the potential to rapidly correct anthropometry whereas the restoration of fat stores takes place irrespective of birth weight. The metabolic consequences of these findings need to be elucidated.     

Heart rate variability and cardiac reflexes in small for gestational age infants.

To assess the influence of intrauterine growth retardation and postnatal development on heart rate variability (HRV) and cardiac reflexes, we studied 27 healthy small for gestational age (SGA) and 23 appropriate for gestational age (AGA) infants during a nap study. Resting HRV was assessed by point dispersion of Poincaré plots for overall (SDRR) and instantaneous beat-to-beat variability (SDDeltaRR) and the ratio (SDRR/SDDeltaRR). Heart rate reflex and arousal responses to a 60 degrees head-up tilt were determined. All tests/measures were repeated twice in quiet and active sleep and in prone and supine sleep positions at 1 and 3 mo of age. SGA infants exhibited higher resting sympathetic tone [SDRR/SDDeltaRR: 1.9 (95% confidence interval: 1.7, 2.0) and 1.7 (95% confidence interval: 1.5, 1.8) in SGA and AGA, respectively; P=0.046] and a tendency for a smaller tachycardic reflex response to the tilt [Deltaheart rate: 24 beats/min (95% confidence interval: 20, 28) and 30 (95% confidence interval: 25, 34)] in SGA and AGA, respectively; P=0.06]. HRV indexes were reduced in the prone compared with supine position (P<0.0001), but reflex tilt responses were unchanged with position. SGA/AGA differences were independent of sleep position. Gestational age weight status did not influence the likelihood of arousal, but prone sleeping per se reduced the odds 2.5-fold. The findings suggest reduced autonomic activity and cardiac reflexes in SGA infants. The finding that the sympathetic component of the control of HRV was higher in SGA infants could link with findings in adulthood of an association between being born SGA and a higher risk of cardiovascular disease.     

Mitochondrial DNA depletion in small- and large-for-gestational-age newborns

Objective: To investigate whether mitochondrial DNA (mtDNA) content may be associated with clinical features, anthropometric variables, and laboratory findings in both extremes of abnormal fetal growth: small and large size for gestational age. Research Methods and Procedures: Eighty‐eight pregnant women and their infants were included in a cross‐sectional study. According to the offspring birthweight, normalized by sex and gestational age, there were 57 newborns with appropriate weight for gestational age (AGA) and 31 with abnormal weight for gestational age: 17 small for gestational age (SGA) and 14 large for gestational age (LGA). mtDNA quantification using nuclear DNA as a reference was measured by a real‐time quantitative polymerase chain reaction method. Results: The mothers’ pregestational BMI was associated with the weight of their offspring: SGA infants had lean mothers (BMI, 21.4 ± 0.7), and LGA infants had overweight mothers (BMI, 26.7 ± 1.4) in comparison with AGA infants (BMI, 23.0 ± 0.7) (p < 0.003). Newborn leptin levels were associated with birthweight after adjustment for sex and gestational age (SGA, 7.0 ± 1.1 ng/mL; AGA, 15.2 ± 1.6 ng/mL; and LGA, 25.6 ± 4.1 ng/mL) (p < 0.002). Conversely, mtDNA/nuclear DNA ratio was significantly lower in both extremes of abnormal fetal growth, SGA (18 ± 6) and LGA (9 ± 2), at birth in comparison to AGA‐weight infants (28 ± 4) (p < 0.03). Discussion: Our findings show that mtDNA content is decreased in newborns with abnormal weight in comparison with AGA infants. On the basis of a cumulative body of evidence, we speculate that mtDNA depletion is one of the putative links between abnormal fetal growth and metabolic and cardiovascular complications in later life.     

Elevated lipoprotein(a) as a predictor for coronary events in older men

Elevated circulating lipoprotein (a) [Lp(a)] is associated with an increased risk of first and recurrent cardiovascular events; however, the effect of baseline Lp(a) levels on long-term outcomes in an elderly population is not well understood. The current single-center prospective study evaluated the association of Lp(a) levels with incident acute coronary syndrome to identify populations at risk of future events. Lp(a) concentration was assessed in 755 individuals (mean age of 71.9 years) within the community and followed for up to 8 years (median time to event, 4.5 years; interquartile range, 2.5–6.5 years). Participants with clinically relevant high levels of Lp(a) (>50 mg/dl) had an increased absolute incidence rate of ASC of 2.00 (95% CI, 1.0041) over 8 years (P = 0.04). Moreover, Kaplan-Meier cumulative event analyses demonstrated the risk of ASC increased when compared with patients with low (<30 mg/dl) and elevated (30–50 mg/dl) levels of Lp(a) over 8 years (Gray’s test; P = 0.16). Within analyses adjusted for age and BMI, the hazard ratio was 2.04 (95% CI, 1.0–4.2; P = 0.05) in the high versus low Lp(a) groups. Overall, this study adds support for recent guidelines recommending a one-time measurement of Lp(a) levels in cardiovascular risk assessment to identify subpopulations at risk and underscores the potential utility of this marker even among older individuals at a time when potent Lp(a)-lowering agents are undergoing evaluation for clinical use.     

Prematurity--another example of perinatal metabolic programming?

Low birth weight is associated with both later adult diseases such as type 2 diabetes mellitus and a number of metabolic abnormalities, the foremost of which is insulin resistance. Indeed the link between an adverse perinatal environment, manifested by low birth weight, and adult life pathology may be an early, permanent reduction in insulin sensitivity. A reduction in insulin sensitivity has been demonstrated in small for gestational age (SGA), term subjects from childhood through to adulthood. Less is known about children born premature into an adverse neonatal environment. We present data demonstrating that premature infants also have metabolic abnormalities similar to those observed in term, SGA children and that these occur irrespective of whether they are SGA or appropriate for gestational age (AGA).