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Background: Preterm birth is associated with impaired brain functions, but it is unknown whether fetal growth restriction (GR) makes these deficits worse. Using piglets as a model for preterm infants, we hypothesized that moderate GR reduces growth rate, physical activity, and spatial memory in the first weeks after preterm birth., Methods: Preterm pigs were delivered by caesarean section and fed until 19 days (n = 830 from 55 pregnant sows) and received intensive clinical care. GR pigs were classified as animals with the lowest 5-20% percentile birth weight within each litter and were compared with litter-mate controls (21-100% percentile birth weight). Basic motor skill development, physical activity, and morbidities (e.g., necrotizing enterocolitis) were recorded within the first week. Weight of internal organs and data from a T-maze spatial memory test were noted until 19 days., Results: Moderate GR and control preterm pigs (birth weights 728 ± 140 and 1,019 ± 204 g, respectively) showed similar relative weights of internal organs (relative to body), except higher adrenal gland weights in GR pigs (+20-50%, p < 0.05). This was associated with a tendency to higher plasma cortisol (p < 0.05 on day 11). GR preterm pigs showed delayed ability to stand and walk (days 2-5, p < 0.01), but physical activity and proportion of correct choices in a T-maze test (70.3 vs. 71.6%) were similar., Conclusion: Moderate GR has limited effect on motor function and spatial memory in the early postnatal period of preterm pigs, despite some initial delays in basic motor skills. In the postnatal period, moderately growth-restricted preterm infants may adapt well with regards to organ growth and neurodevelopment., (© 2020 S. Karger AG, Basel.)

It is well established that nutrition during the first 1,000 days of life can have a long-term effect on growth, metabolic outcome, and long-term health. We review the long-term anthropometric follow-ups of children with risk of later morbidity: (a) very-low-birth-weight (VLBW) infants who have birth weights <10th percentile of weight and receive fortified breast milk, (b) infants from developing countries who are breastfed according to the present recommendations but have low birth weight and length, and (c) children from developed countries who were enrolled in randomized controlled trials (RCTs) to test if breastfeeding and low-protein formulas can prevent from rapid weight gain and childhood obesity. VLBW infants can be appropriate, small for gestational age (SGA), or intrauterine growth retarded (IUGR). SGA and IUGR (due to placenta insufficiency) infants are born with birth weights <10th percentile of weight for gestational age (GA). We provided fortified breast milk until 52 weeks of GA to 31 SGA and 127 IUGR infants and followed up growth until 24 months. IUGR infants showed lower weight gain between birth and 3 months and had lower weight between 3 and 24 months (p < 0.05; ANCOVA). No significant BMI differences between SGA and IUGR infants were observed. It seems that IUGR infants receiving fortified breast milk need special attention, because without further improvement in breast milk fortification weight gain after discharge from hospital might be too slow. In developing countries, length and weight of breastfed infants during the first 2 years are strongly influenced by the respective anthropometric parameters at birth. Studies in the Gambia and Zimbabwe indicate that only breastfed infants with birth length and weight above the respective WHO 0 z-scores continue with adequate growth and have length and weight above the WHO 0 z-scores at 18 and 24 months. Prevalence of stunting and wasting in the overall Gambia breastfed infant population rapidly increases during the first year, peaks at around 3 years, but decreases thereafter. Long-term growth trajectories indicate later start of puberty and slow pubertal growth, but adult weight and height are not reached before 20-24 years. In adulthood, prevalence of stunting and wasting is much lower than during any period of childhood. Maternal risk factors, such as childhood marriage and poor nutrition before and during pregnancy, need to come into focus to improve birth length and weight and lower high stunting rates. Term breastfed infants from overweight/obese mothers and breastfed infants with rapid weight gain during infancy have increased risk of childhood obesity. Infants who are exclusively breastfed 4-6 months or receive low protein follow-up formulas (high-quality protein) grow slower during the first 2-3 years than infants fed high-protein formulas. During follow-up examinations at 5-6 years, they have lower BMI and obesity prevalence. Body composition measurements (DEXA) at 5-8 years in children who were breastfed and received low- or high-protein formula during infancy indicate that breastfeeding and feeding low-protein formulas are associated with lower gain of fat mass. Longitudinal cohort studies show that high-protein intake during the first 2 years results in higher BMI at 9 years and during adulthood. The studies presented indicate that breastfeeding but also other pre- and postnatal nutritional, epigenetic, and environmental factors influence growth trajectories and long-term health., (© 2019 Nestlé Nutrition Institute, Switzerland/S. Karger AG, Basel.)

Objective: To investigate the placental and umbilical cord histopathology in intrauterine growth restriction (IUGR) and their relation to second-trimester maternal hematological parameters., Materials and Methods: Patients were selected for the IUGR group based on estimated fetal weight below the 10th percentile. Patients were recruited into the control group randomly. Patients were followed up with ultrasound, and blood samples were taken between the 20th and 24th gestational weeks. After delivery and formalin fixation, weight and volume of the placenta were recorded and histologic samples were processed., Results: Maternal platelet count strongly correlates with placental weight (r = 0.766). On the other hand, neonatal weight correlates with placental volume (r = 0.572) rather than with placental weight (r = 0.469). Umbilical arterial lumen cross-sectional area correlates with birth weight (r = 0.338)., Conclusions: Maternal hematological parameters do not seem to affect neonatal outcome. Our main findings are the correlation of maternal platelet count with placental weight, the correlation of placental volume with birth weight being stronger than the correlation of placental weight with birth weight, and the correlation of umbilical artery lumen cross-sectional area with neonatal weight. Mild histopathologic alterations might occur in normal pregnancies; however, sufficient fetal nutrition can be maintained. This compensatory function of the placenta seems to be insufficient when two or more pathologies are present, which is characteristic for IUGR., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Stunting of linear growth, a highly prevalent problem in children of low- and middle-income countries, is the result of the exposure of the fetus and/or young child to nutritional deficiencies and infectious diseases. Maternal undernutrition results in fetal growth restriction, and infectious diseases in pregnancy can result in preterm delivery. Both of these conditions are important contributors to stunting in early childhood, albeit their relative contribution varies by world region. After birth, growth faltering may begin at 3-5 months of life and becomes more prominent from 6 to 18 months. During this time, the young child is exposed to many infectious diseases, such as diarrhea, that have an adverse effect on growth. There is also increasing evidence that frequent ingestion of microorganisms results in damage to the small intestine. The resulting condition, referred to as environmental enteric dysfunction, even without clinical symptoms, may cause growth faltering. The complementary foods that the child receives in addition to breast milk are often inadequate in nutrients and energy, negatively affecting growth. Harmful exposure during pregnancy and the first 2 years of life, a critical period for growth and development, has led to a programmatic focus on this "1,000 days" in the life cycle. Dietary interventions, including nutrition education and for undernourished women provision of food supplements during pregnancy, result in improvements in fetal growth that position the newborn for healthier growth. Interventions in the first 2 years of life include promotion of exclusive breastfeeding for the first 6 months of life and continued breastfeeding for at least the first 2 years, nutritional counseling to assure adequate complementary feeding, and, if necessary in food insecure areas, the provision of supplemental food to be given to the child. Evidence shows that each of the interventions has a beneficial effect on the growth of the young child, yet that the effect is modest in relation to the degree of stunting observed in these underprivileged populations. Nevertheless, in recent years, reductions in the prevalence of stunting in some low-income countries show that substantial improvements are possible as a result of socioeconomic changes along with specific infection control and dietary interventions., (© 2018 Nestlé Nutrition Institute, Switzerland/S. Karger AG, Basel.)

Epidemiological and experimental studies have shown that the peri-conception period, pregnancy, and infancy are windows of particular sensibility to environmental clues which influence lifelong trajectories across health and disease. Nutrition, stress, and toxins induce epigenetic marks that control long-term gene expression patterns and can be transmitted transgenerationally. Chronic diseases of adulthood such as hypertension, diabetes, and obesity thus have early, developmental origins in the perinatal period. The early epigenome, in interaction with other actors such as the microbiome, add powerful layers of diversity to the biological predisposition generated by the genome. Such "programming" is a normal, adaptive component of development, including in normal pregnancies and births. However, perinatal disease, either maternal (such as pre-eclampsia, ges-tational diabetes, or inflammatory disease) or fetal, and neonatal diseases (such as intrauterine growth restriction and preterm birth) are major conditions of altered programming, translated into an increased risk for chronic disease in these patients when they reach adulthood. Early prevention, optimal perinatal nutrition, and specific follow-up measures are key factors in the early preservation of long-term health., (© 2018 S. Karger AG, Basel.)

Intrauterine growth restriction (IUGR) is estimated to occur in 5% of pregnancies, with placental insufficiency being the most common cause in developed countries. While it is known that white matter injury occurs in premature infants, the extent of IUGR on white matter injury is less defined in term infants. We used a novel murine model that utilizes a thromboxane A2 (TXA2) analog (U46619), a potent vasoconstrictor, to induce maternal hypertension and mimic human placental insufficiency-induced IUGR to study the white matter. We also investigated the role of hyperoxia as an additional risk factor for white matter injury, as IUGR infants are at increased risk of respiratory comorbidities leading to increased oxygen exposure. We found that TXA2 analog-induced IUGR results in white matter injury as demonstrated by altered myelin structure and changes in the oligodendroglial cell/oligodendrocyte population. In addition, our study demonstrates that hyperoxia exposure independently results in white matter perturbation. To our knowledge, this is the first study to report single and combined effects of IUGR with hyperoxia impacting the white matter and motor function. These results draw attention to the need for close monitoring of motor development in IUGR babies following hospital discharge as well as highlighting the importance of limiting, as clinically feasible, the degree of oxygen overexposure to potentially improve motor outcomes in this population of infants., (© 2018 S. Karger AG, Basel.)

Background: Intrauterine growth restriction is associated with arterial hypertension in adulthood; however, the underlying mechanism is unclear., Objectives: We hypothesized that serum insulin-like growth factor-1 (IGF-1) levels affect central aortic elastic properties and structure in small-for-gestational-age (SGA) infants., Methods: Eighteen SGA infants and 22 appropriate-for-gestational-age (AGA) infants were enrolled in this study. The serum IGF-1 level within 1 h of birth and abdominal aortic echo parameters at 1 week of age were retrospectively compared., Results: In the SGA infants, IGF-1 levels (27.6 ± 17.7 vs. 42.6 ± 15 ng/ml, p = 0.006), aortic strain (10.2 ± 3.1 vs. 12.8 ± 3.1%, p = 0.01), and aortic distensibility (0.73 ± 0.19 vs. 0.92 ± 0.34 cm2/dyn × 10-4, p = 0.05) were significantly lower compared with AGA infants. By contrast, blood pressure, aortic intima-media thickness (aIMT) in relation to body weight (383 ± 163 vs. 256 ± 43 μm/kg, p < 0.001), aortic stiffness index in relation to body weight (2.0 ± 1.7 vs. 1.1 ± 0.4, p = 0.005), and arterial pressure-strain elastic modulus (293 ± 72 vs. 242 ± 78 mm Hg, p = 0.04) were higher compared with AGA infants. In the SGA infants, IGF-1 levels were significantly correlated with aortic strain (r = 0.49, p = 0.04), aIMT in relation to body weight (r = -0.61, p = 0.007), and aortic stiffness index in relation to body weight (r = -0.63, p = 0.005)., Conclusions: Decreased serum IGF-1 levels in SGA infants may affect the vascular compliance and structure of the central aorta., (© 2016 S. Karger AG, Basel.)

Background: Diuretics are administered to neonates to control fluid balance. We studied whether clinical doses affected kidney development and function and whether extrauterine growth retardation (EUGR) could be a modulator., Methods: Wistar rats were cross-fostered in normal food or food restricted litters at postnatal day (PND) 2 and treated daily with 0.9% NaCl, 5 mg/kg furosemide or 5 mg/kg hydrochlorothiazide (HCTZ) up to PND 8. Kidneys were evaluated on proliferation, apoptosis and a set of mRNA target genes at PND 8, glomerular- and glomerular generation count at PND 35, clinical pathology parameters at 3- and 9 months, neutrophil gelatinase-associated lipocalin at PND 8, 3 and 6 months, monthly blood pressure from 3 months onward and histopathology at study end., Results: Treatment with furosemide or HCTZ did not have relevant effects on measured parameters. EUGR resulted in lower body weight from day 3 onwards (-29% at weaning; p < 0.001, -10% at necropsy; p < 0.001), less glomerular generations (4.4 ± 0.32 vs. 5.0 ± 0.423; p = 0.025, males only), decreased glomerular numbers (27,861 ± 3,468 vs. 30,527 ± 4,096; p = 0.026), higher creatinine clearance (0.84 ± 0.1 vs. 0.77 ± 0.09 ml/min/kg; p = 0.047) at 3 months and lower plasma creatinine (25.7 ± 1.8 vs. 27.5 ± 2.8 µmol/l; p = 0.043) at 9 months., Conclusion: Furosemide and HCTZ did not influence kidney development or function when administered in a clinically relevant dose to rat pups at a stage of ongoing nephrogenesis. EUGR led to impaired kidney development but did not modify furosemide or HCTZ findings., (© 2016 S. Karger AG, Basel.)

Intrauterine growth restriction (IUGR) is most commonly caused by placental insufficiency, in response to which the fetus adapts its circulation to preserve oxygen and nutrient supply to the brain ('brain-sparing'). Currently, little is known about the postnatal course and consequences of this antenatal adaptation of the cerebral circulation. The altered cerebral haemodynamics may persist after birth, which would imply a different approach with regard to cerebral monitoring and clinical management of IUGR preterm neonates than their appropriately grown peers. Few studies are available with regard to this topic, and the small body of evidence shows controversy. This review discusses the cerebral circulatory adaptations of IUGR fetuses and appraises the available literature on their postnatal cerebral circulation with potential clinical consequences., (© 2015 S. Karger AG, Basel.)

Exposure to adverse prenatal factors can result in abnormal brain development, contributing to the aetiology of several neurological disorders. Intrauterine insults could occur during neurogenesis and gliogenesis, disrupting these events. Here we investigate the effects of chronic placental insufficiency (CPI) on cell proliferation and the microenvironment in the subventricular zone (SVZ). At 30 days of gestation (DG; term ∼67 DG), CPI was induced in pregnant guinea pigs via unilateral uterine artery ligation to produce growth-restricted (GR) foetuses (n = 7); controls (n = 6) were from the unoperated horn. At 60 DG, foetal brains were stained immunohistochemically to identify proliferating cells (Ki67), immature neurons (polysialylated neuronal cell adhesion molecule), astrocytes (glial fibrillary acidic protein), microglia (ionised calcium-binding adaptor molecule-1, Iba-1) and the microvasculature (von Willebrand factor) in the SVZ. There was no overall difference (p > 0.05) in the total number of Ki67-immunoreactive (IR) cells, the percentage of SVZ occupied by blood vessels or the density of Iba-1-IR microglia in control versus GR foetuses. However, regression analysis across both groups revealed that both the number of Ki67-IR cells and the percentage of SVZ occupied by blood vessels in the ventral SVZ were negatively correlated (p < 0.05) with brain weight. Furthermore, in the SVZ (dorsal and ventral) the density of blood vessels positively correlated (p < 0.05) with the number of Ki67-IR cells. Double-labelling immunofluorescence suggested that the majority of proliferating cells were likely to be neural precursor cells. Thus, we have demonstrated an association between angiogenesis and neurogenesis in the foetal neurogenic niche and have identified a window of opportunity for the administration of trophic support to enhance a neuroregenerative response., (© 2015 S. Karger AG, Basel.)

Aims: The aim of this study was to determine if maternal nutritional status, as defined by body composition, leptin, and insulin-like growth factor (IGF)-I levels, relates to foetal growth., Methods: In this prospective study, mothers of foetuses with foetal growth restriction (FGR; cases; n = 46) and mothers of appropriate-for-gestational-age (AGA) foetuses (controls; n = 81) were consecutively recruited over a 14- month period. A maternal blood sample was obtained during the third trimester (between 32 and 34 weeks of gestation) for the assessment of IGF-I and leptin. Body composition was assessed by dual-energy X-ray absorptiometry within the first 15 days after delivery. The study used the SPSS-PC statistical package, version 19.0, and p < 0.05 was considered statistically significant., Results: Mean serum IGF-I levels were lower in the cases than in the controls (p < 0.05), whereas leptin concentrations were higher in the cases after adjusting for age, body mass index and cigarette consumption (p < 0.05). Cases had less lean and fat tissue than controls (p < 0.05) but a relatively higher fat percentage., Conclusions: The mothers of foetuses with FGR have a body composition pattern characterized by a slightly increased fraction of fat mass, lower IGF-I concentrations, and increased serum leptin levels. Optimization of maternal nutritional status should be considered, as the nutritional status may be involved in the pathogenesis of FGR., (© 2015 S. Karger AG, Basel.)

The worldwide rate of premature birth is increasing. Survival has also improved, even for very preterm infants, meaning greater numbers of preterm infants surviving into later life. This has led to greater attention being focused on long-term outcomes. Recent interest in the Developmental Origins of Health and Disease has highlighted the importance of early life growth and nutritional exposures for chronic diseases such as cardiovascular disease, osteoporosis and type 2 diabetes. There is evidence linking preterm birth and poor growth in utero with worse long-term cognitive outcome, but also evidence to link more rapid growth in certain epochs of early life with adverse metabolic outcomes. The current data suggest that a diverse range of metabolic outcomes are affected by preterm birth, and that adult survivors may be more likely to develop certain chronic diseases. There are data to show that catch-up growth during the neonatal period and in infancy may affect these later outcomes, but studies are inconsistent in their findings. In addition, it is clear that lifestyle factors during childhood and adolescence have a major impact on metabolic disease that may be greater in magnitude to the effects of early growth and nutritional exposures., (© 2015 Nestec Ltd., Vevey/S. Karger AG, Basel.)

Growth restriction among low-birthweight (LBW) infants occurs prenatally as well as postnatally. Regardless of when and how the growth restriction occurs, growth-restricted infants have the potential for catch-up growth. Catch-up growth has decidedly beneficial effects on later cognition. It also may have adverse effects on cardiovascular and metabolic health. Although the benefits for later cognition are well documented in a number of studies, growth-restricted LBW infants often do not experience catch-up growth and therefore do not enjoy its benefits. One reason is that for catch-up growth to occur, extraordinarily high protein intakes are required. Nutrient intakes have been estimated with the use of the factorial method based on the assumption that catch-up growth comprises essentially a restoration of lean body mass, with restoration of fat mass optional. The basic (no catch-up) nutritional needs of growth-restricted LBW infants are altered to a modest degree, with energy needs increased and protein needs decreased. With catch-up, however, protein needs are increased sharply. Since energy needs are only modestly increased, the protein/energy ratio of requirements is appreciably increased. The high protein needs are difficult to meet with the usual feedings for LBW infants unless special measures are taken to increase protein intakes and to increase the protein/energy ratio. Without the necessary protein intake, catch-up growth is not possible or will be delayed, which may compromise the realization of the long-term benefits on cognition., (© 2015 Nestec Ltd., Vevey/S. Karger AG, Basel.)

Background: Perinatal lung growth is highly vulnerable to inflammation and intrauterine growth restriction (IUGR), two major risk factors for chronic lung disease (CLD) in preterm neonates. However, the balance between extremely low gestational age (ELGA) and IUGR in very preterm infants as risk factors for CLD and co-morbidities remains poorly explored., Objectives: This single-center study aims to compare neonatal morbidity (including CLD) and mortality among ELGA infants with normal birth weight (ELGA-AGA), very preterm infants with IUGR <3rd percentile (VLGA-IUGR) and very preterm infants with a birth weight appropriate for gestational age (VLGA-AGA), matched with VLGA-IUGR infants., Methods: Selected characteristics of the perinatal and neonatal periods were recorded and retrospectively compared among the three groups. Infants with major congenital anomalies were excluded. The diagnosis of CLD was based on whether the infant was receiving supplemental oxygen and/or non-invasive ventilation at a postmenstrual age of 36 weeks., Results: We found that, despite a median difference of 3 weeks in gestational age at birth between VLGA-IUGR and ELGA-AGA infants, neonatal mortality was 35% higher in neonates who had experienced fetal growth restriction, and that VLGA- IUGR was five times more predictive of CLD than was ELGA-AGA. These differences persisted after adjustment for confounding factors such as antenatal steroids, gender and respiratory distress syndrome., Conclusions: This study reports that VLGA-IUGR infants are at higher risk of neonatal mortality and CLD than both ELGA-AGA and VLGA-AGA infants.

Background/aims: We studied the association of low birth weight with ultrasound-assessed nonalcoholic fatty liver disease (NAFLD) to test the hypothesis that fetal growth retardation followed by a rapid weight catch-up growth might be an additional factor responsible for liver steatosis via insulin resistance (IR) and/or intra-abdominal fat., Methods: We enrolled 23 children born small for gestational age (SGA) with a rapid catch-up growth within the first 6-12 months, and 24 appropriate for gestational age (AGA) children as controls. All children underwent anthropometric, body composition measurements and evaluation of liver function tests, lipid profile, plasma glucose and insulin levels. Abdominal ultrasonography was performed in order to asses liver steatosis and thickness of subcutaneous and visceral adipose tissue., Results: NAFLD were observed in 8 out of the 23 SGA children (34.8%). IR and visceral fat were significantly increased in children with hepatic steatosis compared to those without. IR index was significantly related to liver steatosis, independently of body mass index standard deviation score and visceral fat., Conclusions: NAFLD should be recognized as an emerging problem in SGA prepubertal children who presented a rapid weight gain in postnatal life, and IR plays the key role. An appropriate diet during pregnancy and in the first year of life might prevent metabolic syndrome and NAFLD in these subjects., (Copyright © 2013 S. Karger AG, Basel.)

Objective: To evaluate changes in central and peripheral circulation, including new and standard parameters of the fetal brain and heart in fetuses with intrauterine growth restriction (IUGR) in relation to progressive deterioration of the umbilical artery (UA)., Methods: Seventy-two IUGR fetuses were studied longitudinally. IUGR was defined as an estimated fetal weight <10th centile for gestational age. Fetuses were classified according the UA pulsatility index (PI) as: group 1, normal UA-PI (<95th centile; <1.645 z-scores), group 2, UA-PI (≥95th centile and <99th centile; ≥1.645 and <3 z-scores), group 3, UA absent end-diastolic flow, and group 4, UA reversed end-diastolic flow. Middle cerebral artery (MCA), anterior cerebral artery segments 1 (ACA1) and 2 (ACA2), aortic isthmus blood flow index (IFI), modified myocardial performance index (Mod-MPI), ductus venosus (DV), renal artery (RA), femoral artery (FA) and amniotic fluid index (AFI) were weekly evaluated until delivery., Results: A total of 263 scans were performed (median, 3 (range: 1-23) per patient). There were 6 intrauterine and 2 neonatal deaths. Although all cerebral arteries showed a reduction in the PI, ACA1 showed the earliest vasodilatation. From group 2 onwards, all cerebral vessels had a similar pattern of vasodilatation. Mod-MPI became abnormal at group 1 with no further changes. IFI and DV became constantly abnormal starting from group 2. No changes in the RA-PI or FA-PI were documented., Conclusion: The process of hemodynamic deterioration in IUGR fetuses seems to be earlier represented by the ACA1 and the Mod-MPI. Signs of further deterioration were observed in the DV, IFI and MCA. The peripheral blood in the RA and FA did not show any change. AFI showed a late deterioration process., (Copyright © 2011 S. Karger AG, Basel.)

Background: Impaired fetal growth and rapid postnatal growth are associated with programming of hypertension and metabolic syndrome in adulthood., Objectives: This study evaluated this phenomenon in a novel spontaneous intrauterine growth-restricted (IUGR) model in Yucatan miniature pigs., Methods: IUGR piglets (n = 6, 3 days old, 0.73 ± 0.11 kg) were paired with a normal weight (NW) same-sex littermate (n = 6, 1.11 ± 0.13 kg), fed milk replacer for 4 weeks followed by a standard diet ad libitum for 5 h/day. At 9 months of age, arterial blood pressure (BP) telemeters were implanted to assess BP before (0.5% NaCl) and after (4.5% NaCl) a 7-day salt-loading period. At 10 months of age, nephron numbers were determined., Results: Prior to sexual maturity, IUGR pigs showed greater (p < 0.05) relative feed intake and experienced significant catch-up growth. Adult IUGR pigs also had higher BP (diastolic BP: 93.8 ± 5.5 vs. 90.0 ± 8.7 mm Hg, p < 0.05) and 43% fewer nephrons per kidney (p < 0.05). Nephron number was positively associated with birth weight and negatively correlated with BP (p < 0.05). Acute salt loading increased BP in both groups (p < 0.05); however, the degree of salt sensitivity was similar between groups (p > 0.05)., Conclusions: In conclusion, IUGR piglets have reduced nephron endowment associated with a modest BP increase in early adulthood. This new model can be used to conduct longitudinal mechanistic studies on the early programming phenomenon., (Copyright © 2011 S. Karger AG, Basel.)

The hypothalamic-pituitary-adrenal axis is susceptible to programming during fetal development and may be linked to risk of disease later in life. In a former prospective study the cohort was divided into those born appropriate for gestational age (AGA) or small for gestational age (SGA; birth weight <10 percentile). In 52 adolescent boys (17.5 years) we assessed circulating androgen levels (T, Δ(4)-adione, DHEAS), overnight serum cortisol profiles (every 20 min), ACTH stimulation test (250 μg i.v.) and analysis of 24-hour urinary adrenal steroid excretion. Urinary excretion of adrenal androgen and cortisol metabolites were significantly lower in the SGA compared to the AGA group. Basal morning cortisol levels were lower in adolescents born SGA compared to those born AGA (365 mmol/l, interquartile range (IQR) 284-413 vs. 445 mmol/l, IQR 377-495, p = 0.04), but overnight cortisol profiles (AUC) did not differ. The ACTH test showed equally stimulated levels of cortisol for those born SGA and AGA. There was no difference in serum testosterone, dehydroepiandrosterone sulfate and Δ(4)-adione levels between the SGA and AGA subjects. This suggests impaired excretion of adrenal androgen and cortisol metabolites in young men born SGA compared to AGA. In conclusion, this study demonstrated subtle changes in adolescent adrenal function associated with birth weight., (2010 S. Karger AG, Basel.)

Maternal dietary protein restriction during pregnancy results in an increase in offspring blood pressure in the rat. The kidneys of the low protein (LP) rat have fewer nephrons, increased hemodynamic sensitivity to angiotensin II and lower glomerular filtration rate, suggesting altered activity of the renin-angiotensin system. Angiotensin II plays a role in nephrogenesis through the AT(1) and AT(2) receptor subtypes. The aim of this study was to determine expression levels of both subtypes during nephrogenesis. Pregnant Wistar rats were fed either a control 18% protein diet or a low 9% protein (LP) diet. A 35% reduction in nephron number (p < 0.05) associated with a 50% reduction in total glomerular volume (p < 0.001) was seen in LP rats. Renal AT(1) (p < 0.0001) and AT(2) (p < 0.0001) receptor protein expression were significantly lower in LP rats from E18 to day 10. AT(1) expression in LP rat kidneys tended to increase over time while AT(2) expression declined until day 10, when it began to increase again. Angiotensin II-regulated cell proliferation may be perturbed in the LP rat kidney during nephrogenesis which could contribute to the reduction in nephron number and the elevation in blood pressure observed in this model of programmed hypertension., (Copyright (c) 2010 S. Karger AG, Basel.)

Background/aims: There is limited information about adult height (AH) outcomes and the factors influencing outcomes of growth hormone (GH) therapy in short children born small for gestational age (SGA)., Methods: AH (SDS) and Δheight (SDS) from GH start to AH were analyzed in 161 SGA children who had reached AH (55 with Silver-Russell syndrome, SRS)., Results: SGA patients treated to AH were started on GH (median) 0.25 mg/kg/week at an age of 7.8 years with a height of -3.8 SDS. AH after 7.7 years was -2.2 SDS and -1.1 SDS below mid-parental height (MPH). AH (SDS) was explained by: height (SDS) at GH start (+), Δheight (SDS) 1st year on GH (+), years on GH (+), maternal height (SDS) (+), length (SDS) at birth (+), and the diagnosis of SRS (-) (explained variability 70%; error 0.6 SD). Gain in height (SDS) was explained by: Δheight (SDS) 1st year on GH (+), years on GH (+), height - MPH (SDS) at GH start (-) (explained variability 60%; error 0.7 SD)., Conclusions: Algorithms for AH outcomes provides useful information about the potential of long-term growth on GH in short children born SGA., (Copyright © 2010 S. Karger AG, Basel.)

Intrauterine growth restriction (IUGR) can lead to infants being born small for gestational age (SGA). SGA is associated with increased neonatal morbidity and mortality as well as short stature, cardiovascular disease, insulin resistance, diabetes mellitus type 2, dyslipidemia and end-stage renal disease in adulthood. In addition, SGA children have decreased levels of intelligence and cognition, although the effects are mostly subtle. The overall outcome of each child is the result of a complex interaction between intrauterine and extrauterine factors. Animal and human studies show structural alterations in the brains of individuals with IUGR/SGA. The presence of growth hormone (GH) receptors in the brain implies that the brain is also a target for GH. Exogenous GH theoretically has the ability to act on the brain. This is exemplified by the effects of GH on cognition in GH-deficient adults. In SGA children, data on the effect of exogenous GH on intelligence and cognition are scant and contradictory.

Background: Low birth weight is a risk factor for the development of a more severe course of secondary renal diseases. We tested the hypothesis that experimental mesangioproliferative glomerulonephritis (GN) shows an aggravated course in rats inflicted with experimental uteroplacental insufficiency during gestation., Methods: Intrauterine growth restriction (IUGR) was induced by ligation of both uterine arteries on day 19 in pregnant Wistar rat dams. GN was induced in male offspring at the age of 9 weeks by intravenous injection of an anti-Thy-1.1 antibody. At day 14 of GN, kidneys were taken and analyzed for glomerular morphometry, markers of inflammation, glomerulosclerosis and tubulointerstitial fibrosis., Results: Despite a similar extent of mesangiolysis, former IUGR animals presented with a higher level of glomerulosclerosis and increased deposition of glomerular collagens I and IV compared to nephritic control animals. Arterial blood pressure, renal function, and proteinuria after 14 days of GN were not influenced by former IUGR., Conclusion: Ligation of the uterine arteries in the rat leads to more pronounced sclerotic changes in the glomerulus in the offspring suffering from acute GN. This finding supports the hypothesis that former IUGR increases the susceptibility for a more severe course of secondary renal diseases., (Copyright © 2010 S. Karger AG, Basel.)

Background: The present study was aimed to obtain information on the interaction kinetics of L-tryptophan (L-Trp) with plasma albumin from normal, intrauterine growth-restricted (IUGR) and nutritionally recovered (NR) newborn infants., Methods: A case study cohort was planned in 37 newborns during the first 3 months of life. At birth two groups were formed. The first group included 20 newborns with IUGR. The control group (C) included 17 appropriate for gestational age newborns. At 30 days of age, 9 infants of the IUGR group showed a return to normal of the anthropometric parameters, these infants formed the NR group. Free, bound and total L-Trp were measured. To assess binding kinetics albumin was freed of fatty acids and tested in mole to mole samples from IUGR, NR and control babies., Results: Plasma free L-Trp was increased, K(d) (dissociation constant) elevated and B(max )(maximal binding)decreased in IUGR patients up to postnatal day 90. These changes remained even after nutritional recovery., Conclusions: Abnormal kinetics of L-Trp binding to albumin explains the increased availability of this precursor amino acid in the plasma of IUGR infants. This finding corroborates previous results in IUGR rats and newborn babies, indicating enhanced potential for brain serotonergic synthesis.

Background: Detrended fluctuation analysis (DFA) has recently been validated as an excellent method by which to analyze heart rate variability and distinguish healthy subjects from patients with various types of the cardiac nervous system dysfunction., Methods: One hundred and nineteen fetal heart rate (FHR) recordings obtained from healthy normal fetuses and 68 recordings obtained from small-for-gestational-age (SGA) fetuses were analyzed by DFA to examine gestational and pathologic changes of the scaling exponent, alpha., Results: In normal fetuses, a significant increase was observed in both the short-term (30 s) alpha(2) scaling exponents according to gestational age. The alpha(1) values of SGA fetuses were not significantly different from those of healthy normal fetuses; however, the alpha(2) values of the former group (0.955 +/- 0.152) were significantly higher than those of normal subjects (0.887 +/- 0.128; p = 0.001)., Conclusion: The alpha(2) exponent appears to be a sensitive probe for detecting subtle, and possibly important, changes that occur in fetuses with intrauterine growth restriction, and may be helpful in the early and noninvasive detection of placental insufficiency or incipient intrauterine growth restriction. The use of DFA techniques offers great promise for understanding FHR behavior., ((c) 2007 S. Karger AG, Basel.)

Background: After placental embolisation in pregnant sheep, we found elevated plasma taurine concentrations in several foetuses. These animals also had higher morbidity and mortality than foetuses with normal taurine concentrations. We therefore re-analysed our foetal growth and metabolism data with embolised animals divided into subgroups with high taurine concentrations (EH) and low taurine concentrations (EL)., Objective: To investigate the hypothesis that foetal plasma taurine concentrations may be used as a marker for foetal wellbeing., Methods: Growth, metabolic and endocrine parameters were measured in normally grown foetal sheep and in those who had EH or EL after placental embolisation., Results: EH animals were more compromised than the EL animals, as shown by reductions in foetal weight and hind limb length and a failure to increase growth rate (chest girth increment) after embolisation. EH foetuses were hypoxaemic, hypoglycaemic and had increased lactate concentrations. Kidney, liver and adrenal weights were increased and thymus weight was decreased in EH animals. Maternal amino acid concentrations were elevated in EL animals. Foetal amino acid concentrations were more reduced in EH animals than in EL animals. Maternal IGF-1 concentrations were increased in EL, but not EH animals., Conclusions: Animals with EH were less able to compensate for the effects of embolisation than animals with EL. Taurine may have been released by the tissues as a protective mechanism against hypoxia-induced inflammation, or in an attempt to maintain osmotic balance. The connection between taurine and foetal wellbeing deserves further investigation., (Copyright (c) 2007 S. Karger AG, Basel.)

Fetal growth retardation is a fetal adaptation in response to inadequate supply of oxygen and/or nutrients. Animal models of intrauterine growth retardation are an invaluable tool to question the genetic, molecular and cellular events that determine fetal growth and development. Rodent and non-litter bearing animals are mammalian system with similar embryology,anatomy and physiology to humans. Utilization of these systems has led to a greater understanding of the pathophysiology and consequences of intrauterine growth retardation. These observations are comparable to that observed in humans born small for gestational age, and are of interest because of the known association between poor fetal growth and development of adult disease. All the experimental manipulations described here have altered a number of metabolic and physiological variables, but the pattern of alterations seems to vary with the procedure and species employed. This review describes animal models for intrauterine growth retardation and assesses their potentials and limitations at aiming to improve strategies for the prevention of adult disease., (Copyright 2007 S. Karger AG, Basel.)

Fetal growth retardation appears to be associated with an increased risk of premature adrenarche, early puberty, polycystic ovary syndrome and associated fertility problems. In a rat model of intrauterine growth retardation, based on ligation of the uterine arteries, the onset of puberty was delayed in female pups, with anovulation during the first cycle. The ovaries showed a lower number of follicles. The onset of puberty was also delayed in male pups. Testosterone production was lower in these growth-retarded rats compared with controls. The relationship between birth weight and the onset of puberty and pubertal progression in different cohorts of healthy children has been examined. In girls, no differences were observed in timing and progression of puberty, including age of menarche, between groups of different birth weights. In boys, a relatively delayed onset of puberty was observed in those with low birth weight, with a normally timed progression. In children with low birth weight, particularly boys, higher dehydroepiandrosterone levels were found compared with children with a normal birth weight, indicating an overactive adrenal gland in children with low birth weight. These data indicate that impaired fetal growth may have long-lasting effects on pubertal development. The fact that results of human studies on the relationship between fetal growth and the onset of puberty are often controversial may be explained by the heterogeneity of children born small for gestational age with respect to the intrauterine insult that they experience. From rat studies, it is clear that a serious intrauterine insult associated with growth failure can lead to dysregulation of puberty and gonadal function., (Copyright 2006 S. Karger AG, Basel.)

Low birth weight due to intrauterine growth restriction is associated with various diseases in adulthood, such as hypertension, cardiovascular disease, insulin resistance and end-stage renal disease. The purpose of this review is to describe the effects of intrauterine growth restriction on the kidney. Nephrogenesis requires a fine balance of many factors that can be disturbed by intrauterine growth restriction, leading to a low nephron endowment. The compensatory hyperfiltration in the remaining nephrons results in glomerular and systemic hypertension. Hyperfiltration is attributed to several factors, including the renin-angiotensin system (RAS), insulin-like growth factor (IGF-I) and nitric oxide. Data from human and animal studies are presented, and suggest a faltering IGF-I and an inhibited RAS in intrauterine growth restriction. Hyperfiltration makes the kidney more vulnerable during additional kidney disease, and is associated with glomerular damage and kidney failure in the long run. Animal studies have provided a possible therapy with blockage of the RAS at an early stage in order to prevent the compensatory glomerular hyperfiltration, but this is far from being applicable to humans. Research is needed to further unravel the effect of intrauterine growth restriction on the kidney., (Copyright 2006 S. Karger AG, Basel.)

Premature infants of low and extremely low birth weight represent a challenge for neonatal intensive care units and paediatricians. These neonates may be at increased risk of insulin resistance and diabetes perinatally and during childhood. During the first week of postnatal life, infants born prematurely are at risk of abnormalities in glucose homeostasis. Additionally, there are major differences in their glucose/insulin homeostasis compared with infants born at term. Preterm infants are at risk of hypoglycaemia, due to decreases in deposits of glycogen and fat that occur during the third trimester, and also to transient hyperinsulinaemia. Hyperglycaemia may also be observed in preterm infants during the perinatal period. These infants are unable to suppress glucose production within a large range of glucose and insulin concentrations, insulin secretory response is inappropriate, insulin processing is immature and there is an increased ratio of the glucose transporters Glut-1/Glut-2 in fetal tissues, which limits sensitivity and hepatocyte reaction to increments in glucose/insulin concentration during hyperglycaemia. In addition, increased concentrations of tumour necrosis factor alpha present in intrauterine growth retardation (IUGR) and induce insulin resistance. It has been proposed that the reduced insulin sensitivity may result from adaptation to an adverse in utero environment during a critical period of development. We have investigated postnatal insulin resistance in 60 children born with very low birth weight and either small for gestational age or at an appropriate size for gestational age. This study showed that IUGR, rather than low birth weight itself, was associated with increased fasting insulin levels. As poor fetal growth may be associated with the development of obesity, type 2 diabetes and the metabolic syndrome in later life, it is important that we continue to increase our understanding of the effects of IUGR on postnatal growth and metabolism., (Copyright 2006 S. Karger AG, Basel.)

Scientific interest in morbidity in children born small for gestational age (SGA) has increased considerably over the last few decades. The elevated risk of cardiovascular and metabolic diseases in adulthood in individuals born SGA has been well documented, whereas data on gonadal development are limited. Prospective studies, case-control investigations and registry surveys show that impaired intrauterine growth increases the risks of congenital hypospadias, cryptorchidism and testicular cancer approximately two- to threefold. Although few studies focus on the effect of intrauterine growth on male pubertal development, testicular hormone production or sperm quality, available evidence points towards a subtle impairment of both Sertoli cell and Leydig cell function. Animal studies support the hypothesis that impaired perinatal growth restriction, depending on the timing, can affect postnatal testis size and function into adulthood. Current human data, however, are often based on highly selected hospital populations and lack precise distinctions between low birth weight, SGA, timing of growth restriction and a differentiation of catch-up growth patterns. Despite the methodological inadequacies of individual study results, the combined evidence from all data leaves little doubt that fetal growth restriction is associated with increased risk of male reproductive health problems, including hypospadias, cryptorchidism and testicular cancer., (Copyright 2006 S. Karger AG, Basel.)

There is increasing evidence for a link between prenatal growth and pubertal development. Here we highlight a selection of pubertal characteristics in children who were born small for gestational age (SGA). Boys born SGA are at risk of high levels of follicle-stimulating hormone (FSH) and low levels of inhibin B and a small testicular volume during adolescence. In girls born SGA, the age at pubertal onset and the age at menarche are advanced by about 5-10 months; prenatal growth restraint may also be associated with higher FSH levels and smaller internal genitalia in adolescence. The ovulation rate was found to be reduced in adolescent girls born SGA, and an insulin-sensitizing therapy was capable of raising this low ovulation rate. Menarche is definitely advanced in girls born SGA with precocious pubarche and in those with an early-normal onset of puberty. Current evidence suggests that insulin resistance is a key mechanism linking a post-SGA state to early menarche; hence, insulin sensitization may become a valid approach to prevent early menarche and early growth arrest in girls born SGA., (Copyright 2006 S. Karger AG, Basel.)

Growth hormone (GH) administration to ameliorate growth deficiency of short children born small for gestational age (SGA) is currently approved in the US and the EU. Even though regulatory bodies from each examined similar datasets concerning GH treatment of short SGA children, the specifics of indications for treatment and recommended regimens differed with respect to GH dosage, age at which therapy might be initiated, and the degree of short stature required. US product labeling allows more flexibility but provides less guidance for the practitioner. The EU tends to be more proscriptive, limiting use to shorter children, restricting the dosage, and providing specific guidelines in terms of monitoring during treatment., ((c) 2005 S. Karger AG, Basel.)

Vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF) cause vasodilation. We examined the vasomotor response of isolated placental vessels to VEGF and PlGF in normal (group I) and intrauterine growth retardation (IUGR)-complicated pregnancy (group II). Rings of vessels were prepared in vitro and mounted on the vessel myograph plunged in tissue bath. The magnitude of dilation to increased doses of VEGF and PlGF has been studied. VEGF is a more potent vasodilator than PlGF. Both, VEGF- and PlGF-induced vasorelaxation was diminished in the IUGR (group II) nearly by half, compared to control (group I). Relative placental nitric oxide deficiency, or decreased sensitivity to VEGF and PlGF may contribute to the development of high impedance fetoplacental circulation., (Copyright 2005 S. Karger AG, Basel.)

During the last decades, a secular trend of growth and timing of puberty occurred consisting of increased adult height and earlier onset of puberty. In The Netherlands although the most recent survey showed an increase of final height again, the timing of puberty onset appears to level off, and in boys pubertal onset was even slightly retarded. Different findings were reported from the United States, where a strong advancement of the onset of puberty was observed in both white and black girls, although the effect was more evident in black girls. Timing of puberty follows a familial pattern and therefore seems to be controlled by genetic factors, whereas environmental factors may influence and mediate the genetic regulation. Environmental factors such as nutritional status, chronic diseases, migration to a healthy environment, frequent infectious diseases, pollution and exposure to insecticides are all thought to influence the endocrine regulation status and therefore differentiation and development of endocrine organs. In this chapter, the physiologic mechanisms of puberty onset with the different regulatory aspects, as well as pathologic processes interfering with the onset of puberty will be discussed.

Objective: To investigate the efficacy and safety of intrapartum fetal pulse oximetry, as a predictor of metabolic acidosis at birth of fetuses with intrauterine growth retardation (IUGR)., Study Design: We studied 18 IUGR fetuses (group I) and a control group of 30 appropriate for gestational age (AGA) fetuses (group II) during labor. Both groups had abnormal fetal heart rate tracings and were monitored simultaneously throughout labor with cardiotocography and fetal pulse oximetry. Apgar scores, pH and base excess of fetal blood obtained from the umbilical artery after delivery were compared in both groups., Setting: The Fetal Surveillance Unit of the 2nd Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, Athens University., Results: In IUGR fetuses, when their oxygen saturation value (FSPO2) was less than 34%, cord artery pH was 7.10 +/- 0.04, base excess -13 +/- -1 mmol/l and Apgar scores < or =5 at the 5th min, and when FSPO2 was over 35%, artery pH was 7.29 +/- 0.08, base excess -8 +/- -2 mmol/l and Apgar scores > or =7 at the 5th minute. In cases of drops of FSPO2)below 30% for more than 2 min, labor was completed operatively and cord pH was 7.00 +/- 0.04, base excess -15 +/- -2 mmol/l and Apgar scores < or =5 at the 5th minute. In AGA fetuses, when FSPO2 was over 30%, artery pH was over 7.20, base excess <-11 mmol/l and Apgar scores > or =9 at the 5th minute; in contrast, when FSPO2 was <30% for 2 min, a cesarean section was performed and cord pH was < or =7.02, base excess > or =-13 mmol/l and Apgar scores < or =4 at the 5th minute., Conclusions: In IUGR fetuses, FSPO2 values less than 34% represent an acidotic status, while values of > or =35% are well tolerated. Fetal pulse oximetry proved reliable, according to umbilical cord blood measurements and Apgar scores, reducing cesarean deliveries in cases of nonreassuring cardiotocographic patterns in IUGR fetuses., (Copyright 2003 S. Karger AG, Basel)

The content and the distribution of the glycoconjugate sugar residues were investigated in the human umbilical cord from normally grown pregnancies and from pregnancies complicated by intra-uterine growth retardation with absent or reversed flow in the umbilical artery. The gestational age range was 29-41 weeks. For this purpose, a battery of eight horseradish peroxidase conjugated lectins was used (ConA, WGA, PNA, SBA, DBA, LTA, UEA I, and OOA; see text). Our data showed that in both study groups ConA, WGA and PNA (after neuraminidase digestion) and LTA, UEA I, and OOA reacted with Wharton's jelly and vessels of the umbilical cord from the first weeks of gestation considered. SBA reactivity was observed only in the amniotic epithelial cells of the jelly and in the endothelial cells of the vessels. The reactivity with the most part of the lectins decreased or was lacking in the various components of the umbilical cord between 39 and 41 weeks of gestation in the normal group and between 36 and 37 weeks of gestation in the pathological one. Moreover, the intensity of reactivity with ConA, WGA and PNA (after neuraminidase digestion) and LTA, UEA I, and OOA in the normal group and with PNA (before and after neuraminidase digestion) and LTA and OOA in the pathological one was stronger in the peripheral portion of the jelly with respect to the adventitial one. The reactivity with ConA and UEA I was stronger in the vein than in the arteries in both study groups. Some hypotheses are reported on the role played by the sugar residues in the normal and pathological umbilical cords., (Copyright 2003 S. Karger AG, Basel)

Background/aim: Neonates with intrauterine growth retardation (IUGR) experience higher morbidity and mortality rates than appropriate-for-gestational-age (AGA) neonates. The purpose of our study was to clarify whether IUGR has any influences on the progression of nephrotic syndrome in children., Methods: We performed a retrospective review of 56 children with nephrotic syndrome. IUGR was defined as a birth weight less than the tenth percentile for gestational age. Among 56 patients having nephrotic syndrome, 8 had IUGR, and 48 were AGA., Results: The 24-hour urinary protein level in children with IUGR was significantly higher than that in children who were AGA (7.61 +/- 6.75 vs. 3.92 +/- 3.70 g/day, p < 0.05). There was a statistically significant difference in the incidence of steroid resistance (62.5 vs. 10.4%, p < 0.05) and in the time to remission (median 60 vs. 13 days, p < 0.05) between the children with IUGR and those being AGA. Also, there was a significant difference in the incidences of treatment with cytotoxic agents (75 vs. 29.2%, p < 0.05) and complications such as hypertension., Conclusions: Our report indicates that IUGR predicts an unfavorable progression of nephrotic syndrome. So, it is important for nephrologists to pay attention to the clinical course of nephrotic syndrome in neonates with IUGR., (Copyright 2002 S. Karger AG, Basel)

Object: To investigate the influence of HELLP (hemolysis, elevated liver enzymes and low platelet count) pregnancies on the postpartal course and further development of the neonate., Methods: The postnatal course and further development up to 4 years of age of 43 infants after pregnancies complicated by HELLP syndrome were evaluated. 43 unexposed infants matched for gestational age and gender served as controls., Results: Small-for-gestational age (SGA) neonates exhibiting hypoglycemia and hypoproteinemia during the first 4 weeks after birth were significantly more commonly observed in the HELLP group (p < 0.5). No other differences in the postpartal course or clinical outcome were detected. At the age of 4 years the gains in weight and length were significantly increased in the HELLP group (p < 0.01)., Conclusion: The postnatal course of newborns after HELLP pregnancies is influenced by low energy stores. Fetal programming toward a more efficacious GH-IGF-1 pathway may explain the faster postnatal catch-up growth of premature SGA infants born to mothers with HELLP syndrome., (Copyright 2002 S. Karger AG, Basel)

Aims: To investigate (a) the prevalence of insulin resistance in children with intrauterine growth retardation (IUGR); (b) whether catch-up growth is associated with a higher risk of insulin resistance; (c) the insulin-like growth factor (IGF) system status., Methods: 49 children with IUGR aged 9.1 +/- 3.3 years underwent anthropometric measurements, and assessment of insulin resistance and IGF system parameters. A fasting glucose/insulin ratio (G/I) <6 was chosen as suggestive of insulin resistance., Results: 11/49 (22%) children had a G/I <6. Postnatal growth closely correlated with birth size and actual body mass index (BMI). None of the insulin resistance parameters was related to linear growth and BMI. Liver function markers were significantly related to insulin sensitivity status. The IGF system status was normal and did not correlate with insulin resistance indicators., Conclusions: (a) Children with IUGR have a high prevalence of reduced insulin sensitivity; (b) postnatal catch-up growth is related to intrauterine growth and actual nutritional status; (c) insulin sensitivity status is not related to postnatal growth but to liver function; (d) IGF system is normal and not related to the insulin resistance parameters during childhood., (Copyright 2001 S. Karger AG, Basel)

The fetal biophysical profile (BPP), a widely accepted modality of assessment of fetal well-being, significantly shortens the time required to document reassuring fetal testing and exhibits lower false-positive and false-negative rates than conventional nonstress testing. We describe a case in which a patient presenting for fetal testing due to suspected fetal growth restriction at 29 weeks of gestation with recent onset of decreased fetal movements exhibited a concerning nonreactive nonstress test. BPP assessment revealed active fetal tone, movements, breathing movements and amniotic fluid volume (BPP score 8/8). Despite the reassuring BPP, continued abnormal nonstress testing led to subsequent abdominal delivery of an acidotic infant with evidence of a massive antepartum intracranial insult consisting of frontal intraparenchymal hemorrhage and a right temporal-occipital cortical infarction. This case exhibits limitations of the BPP., (Copyright 2001 S. Karger AG, Basel)

Objective: In a group of diabetic pregnant women, the umbilical artery pulsatility index (PI) was compared with both pregnancy complications and perinatal outcomes., Method: We evaluated 67 women with pregnancies complicated by insulin-dependent diabetes mellitus (IDDM), without hypertension. For the study we took the last umbilical PI value before delivery into consideration. Doppler results were not used for patient management. Umbilical artery PI was correlated with the route of delivery and the following perinatal complications: intrauterine growth retardation; cesarean sections for acute fetal distress; respiratory distress syndrome (RDS); neonatal hyperbilirubinemia; hypocalcemia; hypoglycemia; macrosomia, and neonatal intensive care unit (NICU)., Results: Among the 67 diabetic patients enrolled in this study, 44 (66%) had umbilical PIs ranging from the 5th to the 95th percentile (PI mean +/- SD = 1.2 +/- 0.3), while 23 (34%) had PIs above the 95th percentile (PI mean +/- SD = 1.6 +/- 0.3). Among the group with pathologic umbilical PIs, analysis of the data revealed a significantly higher incidence of both cesarean sections for acute fetal distress and perinatal complications: RDS; hyperbilirubinemia; hypoglycemia, and the need for NICU, respectively., Conclusion: In 34% of the diabetic pregnant women without hypertension, we found increased vascular resistances. Among these patients the incidence of perinatal complications was higher, and both closer maternal metabolic control and stricter care of fetal conditions are needed., (Copyright 2001 S. Karger AG, Basel)

Fetal cord blood IGF-I, IGFBP-1 and IGFBP- 3 levels of appropriate-for-gestational-age (AGA) and intrauterine growth retardation (IUGR) babies are studied and followed up for 6-9 months, reevaluated for anthropometric measures and the effects of IGF-I, IGFBP-1 and IGFBP-3 on fetal growth and early catch-up growth is investigated. 23 AGA and 21 IUGR babies, totally 44 newborns, were included in the study protocol. IGF-I and IGFBP-3 levels were found to be high in AGAs with respect to IUGR babies and IGFBP-1 is found to be high in IUGR with respect to AGAs. IGF-I was significantly lower in IUGR babies without catch-up growth (group 2b) with respect to AGAs (group 1) and neonates with IUGR and catch-up growth (group 2a) and group 2a infants had higher IGF-I values than group 2b infants (p < 0.05). IGFBP-3 levels in group 1 were significantly higher than in the other two groups (p < 0.05), but not significantly different in group 2a with respect to group 2b (p > 0. 05). IGFBP-1 values showed no statistically significant difference with respect to the three different groups (p > 0.05). A good correlation was found between birth weight, postnatal weight and postnatal height and IGF-I and IGFBP-3 levels (p < 0.05) but not with IGFBP-1 levels. Aside from the height of the 3 groups of infants which were similar to each other after the follow-up period, IGF-I was significantly high in IUGR infants with catch-up growth with respect to IUGR infants without catch-up growth, indicating its importance in early catch-up growth of IUGR babies.

The aim of this study was to compare the fetal middle cerebral artery (MCA) Doppler waveforms in growth-retarded twin fetuses with (n = 11) and without (n = 24) twin-twin transfusion syndrome (TTTS). Umbilical artery (UA) and fetal MCA Doppler velocity waveforms were recorded on admission. The mean values of the UA pulsatility index (PI) of smaller twin fetuses with and without TTTS were significantly higher than those of normal singleton pregnancies. The mean values of the MCA PI of smaller twin fetuses in the TTTS group (+0.7 +/- 1 SD) were significantly higher than those of normal singleton pregnancies on admission, and these levels did not markedly change following amniocentesis. On the other hand, the values of the MCA of the growth-retarded fetuses without TTTS (-0.9 +/- 1 SD) were significantly lower than those of normal singleton pregnancies. Our findings suggest that measurement of fetal MCA PI is a useful method to assess growth-retarded fetuses in monochorionic twin pregnancies., (Copyright 1999 S. Karger AG, Basel)

Intrauterine growth retardation (IUGR) resulting in a reduced number of nephrons is one of the nonimmune mechanisms that have been recently proposed as contributing to the progression of renal diseases. The purpose of our study was to determine whether IUGR has any effect on the clinical course and prognosis of IgA glomerulonephritis (IgA GN) in children. Fifty children with biopsy-proven IgA GN, who were followed for at least 3 years, were included. Six of the 50 children (12%) had signs of IUGR at birth, defined as birth weight below the 10th percentile for gestational age. There were no significant differences in initial clinical presentation between children with IUGR and those without IUGR. However, in kidney biopsy specimens, we found a significantly higher mean percentage of sclerotic glomeruli in children with IUGR than in those without IUGR (33 vs. 13%, p < 0.015). At the end of the follow-up period, we observed a significantly higher incidence of arterial hypertension in children with IUGR than in those without IUGR (50 vs. 11 %, p < 0.05). Other differences between the two groups of children were not statistically significant. In conclusion, our study demonstrated an increased risk of the development of arterial hypertension and glomerulosclerosis in children with IgA GN who had suffered from IUGR with a birth weight below the 10th percentile for gestational age. IUGR may therefore help to identify early in the course of IgA GN those children who are at higher risk of an unfavorable course.

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.

Recent studies in Europe, North America and the developing world have shown that low birth weight or other indices of abnormal fetal growth in babies born at term are linked with a higher prevalence of raised blood pressure, non-insulin-dependent diabetes and cardiovascular disease in late adult life. These findings have led to the 'fetal origins' hypothesis which proposes that fetal adaptations to an adverse intrauterine environment programme persistent physiological and metabolic changes which predispose to these diseases. The mechanisms are unknown, but evidence from animal studies and preliminary evidence in humans suggest that impaired fetal nutrient supply permanently alters neuroendocrine development in the offspring resulting in long-term changes in the set point of adrenocortical and sympathoadrenal hormonal activity.

A rat model of perinatal malnutrition was designed to study the role of nutrition in postnatal somatic growth and insulin stores until adulthood. Maternal food restriction (50%) from day 15 of pregnancy resulted in intrauterine growth retardation (IUGR) in the offspring. The outcome of moderate or severe IUGR was investigated. Neonates with moderate IUGR normally nourished postnatally showed normal body and organ weights and normal insulin contents in adulthood. Offspring with severe IUGR normally nourished postnatally also rapidly recovered normal body and pancreatic weights, but liver and kidney weights were significantly reduced at adult age. Malnutrition until weaning in offspring with severe IUGR induced marked growth retardation (50%) in body and organ weights at weaning. Although pancreatic weight recovered at adult age, body, liver and kidney weights were irreversibly affected, despite several months of normal nutrition. Furthermore, severe IUGR at birth resulted in decreased insulin content at adult age, irrespective of postnatal nutrition. In conclusion, this animal model demonstrates that normalization of adult size can be dissociated from organ growth and also that altered insulin stores in adulthood are more dependent on the severity of IUGR at birth than on postnatal catch-up in organ growth.

During the first week of life, we examined the changes in the systemic, intestinal and cerebral circulation, and the circulatory responses to feeding in 10 small for gestational age (SGA) infants using the ultrasound Doppler technique. From day 1 to day 3, preprandial cardiac output decreased (p < 0.01), whereas mean blood pressure (p < 0.01), superior mesenteric artery mean flow velocity (Vmean; p < 0.01) and middle cerebral artery Vmean (p < 0.01) increased. On day 1, cardiac output was higher in the SGA than in those of term and preterm appropriate for gestational age infants reported from our laboratory. Preprandial superior mesenteric artery Vmean was inversely related to the degree of growth retardation (r = 0.63, p < 0.05). However, growth retardation did not influence the postprandial increase in superior mesenteric artery Vmean and end-diastolic flow velocity, or the cerebral circulation.

Insulin-like growth factor I (IGF-I) is the primary hormone influencing fetal growth in later gestation. The regulation of fetal IGF-I in utero is primarily influenced by placental glucose transfer, which regulates fetal insulin release. Furthermore, insulin has direct adipogenic effects on the fetus; fetal growth hormone (GH) may also have additional modes of action on fetal growth. Swallowed amniotic fluid contains IGF-I and may influence gastrointestinal maturation and fetal growth. Furthermore, both fetal and maternal IGF-I can influence placental metabolism. Experimentally, the maternal administration of GH and IGF-I can affect placental function and thus influence fetal growth; this may suggest therapeutic approaches to the treatment of intrauterine growth retardation (IUGR) in utero. Both experimental and clinical evidence support our hypothesis that IUGR is a multihormone relative resistance syndrome; relative resistance to insulin, IGF-I and GH can be demonstrated. Such resistance may be the basis of altered programming by which fetal growth retardation is associated with postnatal growth failure and a greater propensity to develop cardiovascular and metabolic disease in later life.