Intrauterine Growth Retardation Neonates Research Articles

Interventions required and outcome in pregnancy induced hypertension patients in Intensive Care Unit: An observational study

Hypertensive disorders of pregnancy, particularly preeclampsia, eclampsia remain one of the leading causes of maternal morbidity and mortality worldwide. We studied the association between the risk factors, interventions required, diagnosis and outcome in these patients admitted to the Intensive Care Unit (ICU).: We conducted a prospective, observational study after the Institutional Scientific and Ethics committee approval. The Institutional record was taken to identify 70 women with Pregnancy Induced Hypertension (PIH) admitted to ICU after meeting the inclusion and exclusion criteria. Socio-demographic details, indication and timing of ICU admission were noted. On ICU admission; baseline vitals, detailed history, duration of complications, therapeutic interventions, laboratory parameters and imaging were compiled. Maternal outcome was assessed in terms of interventions needed, complications encountered and mortality or discharge and follow up was done up to 6 weeks postpartum. Fetal outcome was assessed in terms of live births or Intrauterine fetal death (IUFD), Apgar score, term/preterm and followed up to 7 postnatal days.: It was observed that out of 70 women enrolled in our study, 48 women were diagnosed with preeclampsia, 54 belonged to the age group of 21-30 years, 61 were unregistered for antenatal checkup, 46 had term gestation, 52 were nulliparous and 64 underwent Lower segment caesarean section (LSCS). 60 of them had postpartum ICU admission, all of them had significant rise in blood pressure. Most common interventions were transfusion of blood products (n=30) and mechanical ventilation (n=6). HELLP syndrome was the most common complication (n=7). Maternal mortality was seen in 6 women. 35 neonates had low birth weight, 6 had intra uterine growth retardation (IUGR), 19 were preterm and Apgar score was significant at 5 minutes.: From our observations, it can be concluded that majority of the women were diagnosed with preeclampsia, were relatively of younger age group, nulliparous with no antenatal checkup, underwent LSCS and were admitted postpartum to ICU. Transfusion of blood products was the most common intervention & HELLP syndrome was most common complication. Maternal mortality was higher in women with preeclampsia although overall mortality was low. The incidence of low birth weight, IUGR and preterm neonates was more in eclamptic women. Neonatal mortality was more in preeclamptic women.

Detection of urinary cystatin-c in IUGR neonates by immunoblot SDS-PAGE.

it is known that intrauterine growth retardation (IUGR) represents a risk factor for the deterioration of renal function as it can adversely impact on the number of nephrons developed in the kidney during nephrogenesis. An interesting molecule is the Cystatin-C (cyst-C): it is considered to have the potency to detect both glomerular and proximal renal injury. Recently, using a quantitative EIA cyst-C detection kit, we found increased levels of cyst-C in the urine of neonates with IUGR. Since cyst-C molecules can be present in both monomer and/or polymer forms, the purpose of this study is to investigate in which forms this molecule is present in the urine of IUGR neonates by Immunoblot SDS-PAGE in order to verify if the presence or absence of a particular type of cyst-C conformation can give more information about the renal functioning. urine samples were collected from 64 neonates with IUGR, and 86 healthy controls defined as appropriate for gestational age (AGA). Urinary cyst-C was investigated by the Immunoblot SDS-PAGE. in all urine samples, SDS-PAGE analysis showed a reactivity of the IgG anti cyst-C with a complex of about 70kDa. The monomer form at 13KDa appeared in 78% of IUGR neonates and in 12% of AGA neonates. this study revealed the presence of monomer cyst-C in the urine of IUGR neonates, and suggests an insufficient and/or non-compensatory reabsorption by tubular cells. Monomeric cyst-C can be considered an early biochemical marker to identify and to select IUGR neonates who need to be monitored for risk of renal injury.

P-gp expression inhibition mediates placental glucocorticoid barrier opening and fetal weight loss

BackgroundPrenatal adverse environments can cause fetal intrauterine growth retardation (IUGR) and higher susceptibility to multiple diseases after birth, related to multi-organ development programming changes mediated by intrauterine overexposure to maternal glucocorticoids. As a glucocorticoid barrier, P-glycoprotein (P-gp) is highly expressed in placental syncytiotrophoblasts; however, the effect of P-gp on the occurrence of IUGR remains unclear.MethodsHuman placenta and fetal cord blood samples of IUGR fetuses were collected, and the related indexes were detected. Pregnant Wistar rats were administered with 30 mg/kg·d (low dose) and 120 mg/kg·d (high dose) caffeine from gestational day (GD) 9 to 20 to construct the rat IUGR model. Pregnant mice were administered with caffeine (120 mg/kg·d) separately or combined with sodium ferulate (50 mg/kg·d) from gestational day GD 9 to 18 to confirm the intervention target on fetal weight loss caused by prenatal caffeine exposure (PCE). The fetal serum/placental corticosterone level, placental P-gp expression, and related indicator changes were analyzed. In vitro, primary human trophoblasts and BeWo cells were used to confirm the effect of caffeine on P-gp and its mechanism.ResultsThe placental P-gp expression was significantly reduced, but the umbilical cord blood cortisol level was increased in clinical samples of the IUGR neonates, which were positively and negatively correlated with the neonatal birth weight, respectively. Meanwhile, in the PCE-induced IUGR rat model, the placental P-gp expression of IUGR rats was decreased while the corticosterone levels of the placentas/fetal blood were increased, which were positively and negatively correlated with the decreased placental/fetal weights, respectively. Combined with the PCE-induced IUGR rat model, in vitro caffeine-treated placental trophoblasts, we confirmed that caffeine decreased the histone acetylation and expression of P-gp via RYR/JNK/YB-1/P300 pathway, which inhibited placental and fetal development. We further demonstrated that P-gp inducer sodium ferulate could reverse the inhibitory effect of caffeine on the fetal body/placental weight. Finally, clinical specimens and other animal models of IUGR also confirmed that the JNK/YB-1 pathway is a co-regulatory mechanism of P-gp expression inhibition, among which the expression of YB-1 is the most stable. Therefore, we proposed that YB-1 could be used as the potential early warning target for the opening of the placental glucocorticoid barrier, the occurrence of IUGR, and the susceptibility of a variety of diseases.ConclusionsThis study, for the first time, clarified the critical role and epigenetic regulation mechanism of P-gp in mediating the opening mechanism of the placental glucocorticoid barrier, providing a novel idea for exploring the early warning, prevention, and treatment strategies of IUGR.

Pterostilbene attenuates liver injury and oxidative stress in intrauterine growth-retarded weanling piglets.

The aim of the present study was to investigate the potential of pterostilbene, a beneficial component primarily found in blueberries, to alleviate the intrauterine growth retardation (IUGR)-induced early liver injury and oxidative stress in a porcine model. Thirty-six IUGR piglets and an equal number of normal birth weight (NBW) counterparts received a diet with or without pterostilbene (250 mg/kg diet) during the first week post-weaning. Parameters related to the hepatic injury, oxidative stress, and antioxidant defense mechanisms were analyzed. Relative to NBW, IUGR induced liver injury, which corresponded to increments in circulating alanine transaminase activity and hepatic apoptotic cell rate, superoxide radical generation, and the accumulation of oxidative damage products (P < 0.05). Administering pterostilbene reduced plasma transaminase activities, decreased hepatocyte apoptosis rate, and prevented the augmented levels of hepatic superoxide anion, 8-hydroxy-2 deoxyguanosine, and 4-hydroxynonenal-modified protein (P < 0.05). In terms of the hepatic antioxidant function, pterostilbene was efficient in improving the superoxide dismutase activity and the metabolic cycle between reduced glutathione and its oxidized form (P < 0.05). The pterostilbene-supplemented diet facilitated the nuclear translocation of nuclear factor erythroid-2-related factor 2 (NRF2) and promoted the expression levels of superoxide dismutase 2 in the liver of IUGR piglets (P < 0.05). This study indicates that pterostilbene treatment has an auxiliary therapeutic potential to ameliorate early liver injury in IUGR neonates, presumably by stimulating the NRF2 signals and the associated antioxidant function.

Hypophosphatemia in Refeeding Syndrome in Intrauterine Growth Restricted IUGR Neonates Who are Receiving Nutrition: A Prospective Observational Study

Objective: Electrolyte dysregulations particularly hypophosphatemia and hypokalemia following feeds in a starved person is known as refeeding syndrome, which may lead to life-threatening conditions like arrhythmias, heart failure, respiratory and neuromuscular compromise. To evaluate electrolyte dyscrasias following enteral or parenteral feeding, among intrauterine growth retardation (IUGR) neonates ie those who were starved in-utero, compared to non-IUGR neonates this study was planned.&#x0D; Methodology: From March to August 2015, 60 IUGR and non-IUGR neonates who were admitted at birth before starting of nutrition, either by breast milk or electrolyte-free intravenous fluid. An infant was classified as IUGR when his birth weight was &lt;10th percentile according to Fenton or Lubchenco growth charts. Venous blood was collected from intramural babies at zero hours of life or just before starting feeds to determine the basal level of serum electrolytes – phosphorus, magnesium and potassium, and was repeated in the following 48 and 72 hours.&#x0D; Results: There was no significant difference between the two groups based on sex, history of maternal pre-eclampsia and oligohydramnios. At 72 hours after the start of feeding, Hypophosphatemia was significantly more prevalent, in 33.33% of IUGR vs. 2% of the non-IUGR group, [RR-5, p = 0.010]. Hypokalemia 20% IUGR; 1% non-IUGR group, [RR-6, p = 0.103]. Hypomagnesemia 3% IUGR; 2% non-IUGR group, [RR-1.5, p = 0.640]. Combined electrolyte– hypophosphatemia with hypokalemia (6.6%) and hypophosphatemia with Hypomagnesemia (13.3%), were present only in the IUGR group. Hyperglycemia was not present in any neonate. &#x0D; Conclusions: IUGR neonates are more likely to develop Refeeding syndrome when compared to non-IUGR babies, manifesting as decreased phosphorus, potassium and magnesium levels. Phosphorous should be a part of feeding nutrition in IUGR babies.

Alterations in the liver of intrauterine growth retarded piglets may predispose to development of insulin resistance and obesity in later life.

Intrauterine growth retardation (IUGR) leads to increased predisposition to metabolic syndrome in adult life but the mechanisms remain obscure. Considering a significant number of functional similarities, IUGR piglets appear to be a good model to study the development of this syndrome in humans. The aim of the present study was to investigate the ultrastructure and proteomic profile of the liver in IUGR pig neonates to discover early markers of predisposition to obesity and insulin resistance. In our study intestine and liver tissue samples were investigated in 7 day old IUGR and normal body weight (NBW) littermate piglets using histometry, mass spectrometry, in-tissue cytometry analysis and confocal microscopy. Compared to NBW, the liver in IUGR neonates was characterized by a significantly enhanced ratio of Kupffer cells to hepatocytes and insulin receptor abundance as well as higher percentages of cells expressing receptors for adipokines (resistin and adiponectin), increased expression of TNF-α (as marker of inflammation), and increased expression of insulin receptor and uncoupling protein 3 (UCP3). Moreover, NBW and IUGR differed in proteomic profile, including protein metabolism (proteasomes, cathepsin D, phermitin, phosphoglucomutase), carbohydrate metabolism (hexokinase 1, phosphoglucokinase, galactokinase, aldolase B, glucose-6-phosphate isomerase), oxidative stress and chromatin organization and DNA uptake (histones, lamin a/c). Reduction of hepatocyte numbers concomitant with significant modifications of expression of key hormones and enzymes for protein and carbohydrate metabolism in IUGR neonates may predispose to insulin resistance and obesity in adult life.

Structure and Function of Enterocyte in Intrauterine Growth Retarded Pig Neonates.

The intestine of intrauterine growth retarded (IUGR) neonates showed different morphology compared to neonates born with normal body weight (NBW). The aim of the present study was to investigate the ultrastructure and proteomic profile of the gut epithelium in IUGR pig neonates with special attention to the digestive and absorptive function. Intestine tissue samples were investigated in 7-day-old IUGR and NBW littermate piglets using histometry, immunofluorescence, scanning electron microscopy (SEM), and mass spectrometry analysis. IUGR piglets have shown reduced mucosa and muscularis thickness and an enhanced number of foetal type enterocytes (FTE). SEM studies have shown the lack of the characteristic large-size vacuole in IUGR's enterocytes. Delayed removal of FTE in IUGR neonates was probably due to the inhibited apoptosis in the apical part of villi and increased apoptosis and reduced mitosis in the crypt region. In the expression of proteins in the intestinal mucosa such as hexokinase I, histones, and prelamin A/C, carbamoyl phosphate was reduced in IUGR neonates. Finally, IUGR intestines showed higher expression of HSPA9 and HSPA5 as apoptosis markers. The data indicate modifications of gut mucosa in IUGRs that may result in slower gut mucosa maturation and reduced utilisation of nutrient as compared to NBW pig neonates.

Maternal protein restriction that does not have an influence on the birthweight of the offspring induces morphological changes in kidneys reminiscent of phenotypes exhibited by intrauterine growth retardation rats.

Severe restriction of maternal protein intake to 6-8% protein diet results in intrauterine growth retardation (IUGR), low birthweight and high risk of metabolic syndrome in the adult life of the offspring. However, little information is available on the effects of maternal protein restriction on offspring under the conditions that does not have an influence on their birthweight of the offspring,. In the present study, pregnant rats were kept on a diet consisting of either 9% (low-protein, Lp rats) or 18% (normal-protein, Np rats) protein by weight/volume/etc. After birth, both Lp and Np rats were kept on a diet containing 18% protein. Neonatal body weight was significantly lower in Lp rats compared to Np rats from 4 days to 5 weeks after birth. While glomerular number per unit volume (1 mm(3) ) of the kidney (Nv) was comparable between Lp and Np rats 4 weeks after birth, the Nv was significantly decreased in Lp rats at 20 weeks after birth. Four and 20 weeks after birth, glomerular sclerosis index, interstitial fibrosis score, and ratio of ED1-positive cell ratio were all significantly higher in Lp compared to Np rats. Transforming growth factor-β1-positive cells were observed in the distal tubules in the kidney of 4- and 20-week-old Lp rats kidneys, but not in those of age-matched Np rats. Altogether, these findings revealed that maternal protein restriction that does not have an influence on the birthweight of the offspring, induces similar changes as those seen in the kidneys of IUGR neonates.

Increased Urinary Cystatin-C Levels Correlate with Reduced Renal Volumes in Neonates with Intrauterine Growth Restriction

Background: Exposure to intrauterine growth retardation (IUGR) can have a negative impact on nephrogenesis resulting in limited fetal kidney development and supporting the hypothesis that IUGR represents a risk for renal function and long-term renal disease. Cystatin-C (Cys-C), a strong inhibitor of cysteine proteinases, is freely filtered by the kidney glomerulus and is reabsorbed by the tubules, where it is almost totally catabolized; what remains is subsequently eliminated in urine. In tubular diseases and in hyperfiltration conditions, it seems reasonable to postulate that Cys-C degradation would decrease, and consequently an increase in its urinary elimination would be observed. Objectives: The aim of this study was to investigate the urinary excretion of Cys-C simultaneously with the assessment of renal volumes in adequate for gestational age (AGA) and IUGR neonates in order to identify its clinical value in IUGR. Methods: Urinary Cys-C levels were measured using the enzyme immunoassay DetectX® Human Cystatin C kit in IUGR and AGA neonates. Whole renal and renal cortex volumes were assessed with ultrasounds (Vocal II; Software, GE). Results: Urinary Cys-C levels in IUGR were significantly higher than those found in AGA and were negatively correlated to reduced whole renal and renal cortex volumes. Conclusions: The increased levels of Cys-C in the urine of neonates with IUGR were significantly associated with reduced renal/renal cortex volumes, suggesting that Cys-C could be taken as a surrogate of nephron mass. It also could be used as an early biochemical marker to identify IUGR neonates at high risk of developing long-term renal disease and to select patients for monitoring during childhood.

Effects of high nutrient intake on the growth performance, intestinal morphology and immune function of neonatal intra-uterine growth-retarded pigs

Intra-uterine growth-retarded (IUGR) neonates have shown an impairment of postnatal intestinal development and function. We hypothesised that the immune function of IUGR neonates might be affected by increased nutrient intake (NI) during the suckling period. Therefore, we investigated the effects of high NI (HNI) on the growth performance, intestinal morphology and immunological response of IUGR and normal-birth weight (NBW) piglets. A total of twelve pairs of IUGR and NBW piglets (7 d old) were randomly assigned to two different nutrient-level formula milk groups. After 21 d of rearing, growth performance, the composition of peripheral leucocytes, serum cytokines and intestinal innate immune-related genes involved in the Toll-like receptor (TLR)-4–myeloid differentiation factor 88–NF-κB pathway were determined. The results indicated that IUGR decreased the average daily DM intake (ADMI) and the average daily growth (ADG). However, the ADMI and ADG were increased by HNI, irrespective of body weight. Likewise, serum cytokines (TNF-α and IL-1β) and ileal gene expressions (TLR-4, TLR-9, TRAF-6 and IL-1β) were lower in IUGR piglets, whereas HNI significantly increased blood lymphocyte percentage and serum IL-10 concentrations, but decreased neutrophil percentage, serum IL-1β concentrations and ileal gene expressions (NF-kB and IL-1β). Furthermore, IUGR piglets with HNI exhibited lower serum concentrations of TNF-α and IL-1β than NBW piglets, and these alterations in the immune traits of IUGR piglets receiving HNI were accompanied by decreasing ileal gene expressions of TLR-4, TLR-9, NF-κB and IL-1β that are related to innate immunity. In conclusion, the present findings suggest that increased NI during the suckling period impaired the immune function of neonatal piglets with IUGR.

The Pregnant Spontaneously Hypertensive Rat as a Model of Asymmetric Intrauterine Growth Retardation and Neurodevelopmental Delay

Introduction. Hypertension in pregnancy and vascular placental insufficiency are considered common pathogenic factors in human intrauterine growth retardation (IUGR). IUGR neonates experience higher mortality, and the surviving infants have a higher incidence of neurological and intellectual impairment. Methods. To mimic this condition, we used pregnant spontaneously hypertensive rats (SHR) and performed biometric measurements on Embryonic Day 20, postnatal developmental reflexes, and locomotor activity evaluations. Results. SHR fetuses had significant decreased body weight compared to the Wistar-Kyoto control fetuses (1.51 ± 0.02 g vs. 2.05 ± 0.01 g, respectively; p < 0.0001), and were relatively microcephalic (2.86 ± 0.04 cm vs. 3.3 ± 0.03 cm, respectively; p < 0.0001). Their cephalization index (head circumference/body weight) was increased (1.88 ± 0.03 vs. 1.62 ± 0.02, respectively; p < 0.0001), indicating a “brain-sparing” process. The disproportional ratio indicated that the IUGR type in this model is asymmetric. The SHR pups exhibited a significant (p < 0.04) neurodevelopmental delay in the acquisition of neonatal reflexes (righting, negative geotaxis, placing), but they spontaneously caught up with the control pups after approximately 10 days. On Day 30, the SHR pups exhibited significantly increased walking speed and distance and spent less time in quadrant than the controls (p < 0.002). Conclusion. We speculate that the model of pregnant SHR closely simulate human IUGR caused by hypertension in pregnancy and should enable investigation of mechanisms of hypertension-mediated placenta-vascular injury as well as provide a system for preclinical evaluations of future preventive neuroprotective treatments.

78 Neutrophil Apoptosis in Neonates with Intrauterine Growth Retardation Born to Normotensive Mothers

Background: Neutropenia is a common manifestation in neonates with intrauterine growth retardation (IUGR) related to preeclampsia and has been associated with decreased neutrophil production. In addition, the increased serum levels of soluble Fas Ligand (sFasL) found in neonates born to mothers with preeclampsia have been associated with increased apoptosis. Neutropenia is uncommon in neonates with isolated IUGR. AIM. To assess neutrophil apoptosis in neonates with IUGR born to normotensive mothers. Material and methods: Neutrophil apoptosis was studied in 19 neonates with IUGR born to mothers without hypertension and 19 gestational age matched, appropriate for gestational age (AGA) neonates during the first 12 hours after birth. Neutrophil apoptosis was evaluated by flow cytometric assessment of neutrophils stained with fluorescein isothiocynate (FICT)-annexin-V, propidium iodide (PI) or expressing the Fas molecule. Results: No significant difference in the percentage of neutrophills stained with FICT-annexin-V (mean7,1%, SD 3,9% vs mean 7,8% SD 2,5%, respectively) or with PI (mean 7,6%, SD 4,3% and mean 7,8%, SD 3,4%, respectively) was found between the IUGR and the AGA neonates. Also the percentage of neutrophills expressing the Fas did not differ significantly between the IUGR (mean 30,2%, SD 11,3%) and AGA neonates (mean 24,8%, SD 9,3%). Conclusion: Neutrophil apoptosis in IUGR neonates of normotensive mothers is not increased compared to AGA neonates. We speculate that neutropenia in IUGR is rather attributed to preeclampsia than intrauterine starvation.

Identification of Macrosomic, Normal and Intrauterine Growth Retarded Neonates Using the Modified Neonatal Growth Assessment Score

Objective: Separation of Macrosomic, normal and intrauterine growth retarded (IUGR) neonates using the modified Neonatal Growth Assessment Score (NGAS). Methods: A sample of 23 neonates with evidence of growth acceleration and 74 neonates classified as normal or IUGR in a previous study was used in this investigation. The prenatal growth of all neonates had been studied longitudinally with ultrasound. From the data collected, Rossavik models describing the growth trajectories of head circumference (HC), abdominal circumference (AC), thigh circumference (ThC), femur diaphysis length, head cube (A) and abdominal cube (B) were specified. These models were used to predict birth weight (WT), crown-heel length (CHL), HC, AC and ThC at birth. Actual birth measurements of WT, CHL, HC, AC and ThC were evaluated using age-specific normal size curves and compared to predicted measurements by means of the growth potential realization index (GPRI). GPRI values were evaluated by comparison to previously established normal ranges and used to calculate Neonatal Growth Assessment Scores (NGAS₅). NGAS₅ values, together with assessments of anatomical measurements and GPRI values, were used to establish macrosomic, normal and IUGR groups. Principal components analysis was applied to the sets of GPRI values available for each neonate to provide a principal component score for separating macrosomic and normal neonates (m₂NGAS₅₁) or one to separate macrosomic, normal and IUGR neonates (m₃NGAS₅₁) using linear discriminant analysis. The groups identified by these multivariate methods were compared to the original classification and their characteristics evaluated. Results: The m₂NGAS₅₁ and a boundary value of 207.5% separated macrosomic and normal neonates with an accuracy of 97.3%. The m₃NGAS₅₁ and boundary values of 210.0 and 182.5% separated macrosomic, normal and IUGR neonates with an accuracy of 96.9%. No single GPRI value or anatomical measurement could achieve these levels of accuracy. All normal infants were AGA but only 45.5% of the IUGR group were SGA and only 60.9% of the macrosomic group were LGA. Thirteen different types of IUGR and eleven different types of macrosomia were identified based on GPRI values. Conclusion: The modified NGAS accurately separates macrosomic, normal and IUGR neonates although growth abnormalities are expressed in different ways in different individuals.

Experimental intrauterine growth retardation alters renal development.

Vascular placental insufficiency is considered a common pathogenic factor in human intrauterine growth retardation (IUGR), resulting in small-for-gestational-age, asymmetric newborns. IUGR neonates experience higher morbidity and mortality rates, as well as a possible contribution towards late sequelae, such as hypertension, and cardiovascular disease in adulthood. To simulate vascular placental insufficiency, an experimental rabbit IUGR model was used. Intrauterine growth retardation was achieved by ligation of 25-30% uteroplacental vessels of half of the fetuses during the last third of gestation. Ischemic fetuses were significantly small, asymmetric, and had a disproportionately small body with a relatively large head. The kidneys from all groups were analyzed for relative estimated glomeruli number (REGN) using an unbiased blind design. The glomeruli number was significantly reduced in the asymmetric IUGR rabbit fetuses, probably due to decreased renal vascular supply. Our results support the concept that the reduced number of glomeruli may contribute to impaired renal function, thus predisposing to neonatal renal dysfunction and late sequelae, such as adult hypertension. This study emphasizes the clinical importance of early IUGR diagnosis and prevention.

Exogenous insulin-like growth factor-I increases weight gain in intrauterine growth-retarded neonatal pigs.

Many cases of intrauterine growth retardation (IUGR) are the result of placental insufficiency, suggesting that potential therapies should focus on the neonate rather than the pregnant female. We wished to determine whether IGF-I could be used therapeutically to stimulate normal rates of growth in these neonates. Eight sows received 2.3 kg/d of either a control (13% protein) or protein-restricted (0.5% protein) diet from d 63 of pregnancy to parturition. Litters were reduced to 6 pigs at 3 d of age, and IUGR neonates were fostered onto a control sow. Three pigs/ litter received an osmotic minipump containing either saline or recombinant human IGF-I, delivered at 4 microg/h from d 3 to d 10 of age. Tissue protein synthesis was measured in all pigs using a flooding dose of [3H]phenylalanine. At birth, both body weight (10%) and circulating IGF-I concentration (30%) were significantly lower in IUGR than in control newborns. The infusion of IGF-I to IUGR neonates significantly increased the circulating concentration of IGF-I, growth rate, and protein and fat accretion to control levels. The infusion of IGF-I did not alter concentrations of insulin, glucose, IGF-II, or the thyroid hormones. Our results suggest that IGF-I may be a potential therapy to restore normal growth in IUGR infants.

Altered hepatic gene expression of enzymes involved in energy metabolism in the growth-retarded fetal rat.

Intrauterine growth retardation (IUGR) resulting from placental insufficiency is a common complication of pregnancy. Bilateral uterine artery ligation of the pregnant rat is a model which mimics intrauterine growth retardation in the human. IUGR rat fetuses have altered hepatic energy and redox states, with reduced fetal hepatic ATP/ADP ratio, increased cytosolic NAD+/NADH ratio, and decreased mitochondrial NAD+/NADH ratio. These critical changes in energy metabolism contribute to IUGR. The effects of these changes at the molecular level are largely unknown. To address these effects we compared hepatic mRNA populations of IUGR and normal fetuses and neonates using mRNA differential display, a polymerase chain reaction-based method for assaying transcriptional differences under various conditions. We isolated and sequenced 18 cDNA products whose mRNA levels were elevated in IUGR compared with normal fetal and neonatal liver. These analyses demonstrated that NADH-ubiquinone oxireductase subunit 4L mRNA (ND-4L) was significantly increased in liver of IUGR fetuses and neonates. This suggested that IUGR may be associated with altered expression of genes involved in the generation of ATP and NADH. Therefore, we measured mRNA levels of adenine-nucleotide translocator-2 (ANT-2), glucose-6-phosphate dehydrogenase (G6PD), mitochondrial malate dehydrogenase (MMD), ornithine transcarbamylase (OTC), and phosphofructokinase-2 (PFK-2) using a semiquantitative reverse transcriptase-polymerase chain reaction-based technique. In the IUGR fetus, ND-4L, ANT-2, G6PD, and MMD mRNA levels were significantly elevated; PFK-2 mRNA levels were unchanged, and OTC levels were decreased. In the IUGR newborn rat, mRNA levels of all 6 enzymes were increased suggesting that the metabolic state of the growth retarded newborn remains abnormal after birth. Uteroplacental insufficiency affects the immediate and long-term metabolic milieu of the growth retarded animal, and forces specific adjustments, including the expression of mRNA encoding enzymes involved with hepatic energy production.

Modified neonatal growth assessment score: a multivariate approach to the detection of intrauterine growth retardation in the neonate.

The objective of this investigation was the development of a modified Neonatal Growth Assessment Score (mNGAS) for use in the evaluation of neonatal growth status. The growth of 74 fetuses at risk for intrauterine growth retardation (IUGR) was followed longitudinally, beginning in the first or early second trimester. Rossavik growth models derived from data obtained in the second trimester were used to predict the weight (WT), crown-heel length (CHL) and head (HC), abdominal (AC) and thigh circumferences (ThC) at birth, which were then actually measured within 24 h after delivery. These measurements were compared to age-specific size curves and used to calculate sets of five growth potential index (GPRIi) values, which in turn were used to calculate five-variable Neonatal Growth Assessment Scores (NGAS5). Neonates were initially classified as normal or IUGR on the basis of NGAS5, GPRIi, and anatomic measurements. A final classification based on principal component analysis and linear discriminant analysis was carried out. The score obtained using the first principal component function was defined to be mNGAS51. The effectiveness of mNGASij values, determined from 1-4 GPRIi values, in separating normal and IUGR neonates was also evaluated. Neonates initially considered to be normal had very few abnormal GPRI values or anatomic measurements, whereas the frequency of these abnormalities in IUGR neonates was significantly increased. However, no single anatomic variable was 100% normal in the normal neonates and 100% abnormal in IUGR neonates. Only 40% of IUGR neonates were small for gestational age. Classification of these neonates using principal component analysis and linear discriminant analysis was essentially the same (98.6%) as that made initially after reclassification of two IUGR neonates as normal. The characteristics of the initial and final normal and IUGR groups were very similar and the mNGAS51 was strongly correlated with the NGAS5 in the IUGR group. The effectiveness of mNGASij in separating normal and IUGR neonates increased with the number of GPRIi values included and the types used. GPRIThC and GPRIWT were the most important, followed by GPRIAC. GPRICHL and GPRIHC were much less important and in some cases detrimental. These findings support the concepts of a decrease in soft tissue mass as the initial step in the development of IUGR and the protection of head growth (brain-sparing). The characteristics of mNGAS51, particularly its comprehensiveness, its independence of differences in growth potential, its weighting of GPRIi values according to their importance in the detection of IUGR and its ability to detect different manifestations of IUGR in different individuals, indicate that this should be a most effective parameter for separating normal and IUGR neonates.

Umbilical Cord Osteocalcin in Normal Pregnancies and Pregnancies Complicated by Fetal Growth Retardation or Diabetes mellitus

A homologous radioimmunoassay for human osteocalcin was used to measure cord serum osteocalcin concentrations in normal pregnancies and in pregnancies complicated by intrauterine growth retardation (IUGR) and diabetes. The mean osteocalcin concentrations in term newborns (100-110 micrograms/l) were comparable with levels that we previously measured in pubertal children. There was a small increase in mean osteocalcin concentrations during the third trimester of fetal life, with the maximum at 35 weeks; between weeks 36 and 41, the osteocalcin levels dropped by 13%. Osteocalcin was 20% lower in IUGR neonates than in age- or weight-matched newborns. The newborns of diabetic mothers had markedly lower osteocalcin concentrations than the weight-matched neonates, and 16 of the 19 samples were more than 1 SD below the mean of the gestational-age osteocalcin regression curve. Cord serum osteocalcin appears to be a useful parameter in studying normal and abnormal fetal mineralization.

Brain growth in sick newborn infants: a clinical and real-time ultrasound analysis

This study concerns 152 neonates admitted between June 1981 and December 1983 in a neonatal intensive care unit. It aims to evaluate brain growth and to analyse the influence of intrauterine growth retardation (IUGR), intracranial haemorrhage (ICH) and ventricular dilatation (VD) in pre-term infants. The babies were first analysed at birth. The sample comprised 127 normal infants and 25 IUGR neonates. An ultrasonic index of cerebral growth was devised: the height of the frontal lobes (HFL), measured in a standardised coronal slice of the brain. According to gestational age (GA), HFL and head circumference (HC) gave a similar assessment of brain growth. A regression line of normal intrauterine values of HFL has been produced according to GA and might be added to the other ways of following the intrauterine growth of the brain after 26 weeks. Brain growth was slower in IUGR, when assessed both by HFL and HC. The infants were also assessed during the postnatal period for a mean period of 27.6 days (S.E.M.: 3.5). They were divided into 5 groups: 45 preterm infants without IUGR, ICH or VD; 45 preterm neonates with ICH alone; 12 preterm babies with ICH and VD alone, 10 preterm infants with isolated FGR, and 8 preterm neonates with IUGR and ICH. A calculation of the global anthropometric (body weight, body length, HC and HFL) weekly increment was made for all infants according to their respective group. No statistical difference in any of these parameters between these 5 groups emerged. This study showed that, at an anatomical level, and provided that nutrition is normal, HC is as sensitive as HFL to assess brain growth; when the whole body is growing normally, cerebral growth in preterm infants who experienced IUGR, ICH, VD, is comparable to that observed in preterm babies who did not.

Leucocyte and serum lysosomal enzymes in intrauterine growth retarded newborn infants

Activities of B-Glucuronidase, acid phosphatase and Hexosaminidase were determined in cord blood of neonates with Intrauterine growth retardation (IUGR). The serum lysosomal enzyme activities were not significantly different from those of the well-grown control neonates. However, there were observed changes which suggest that the alterations in the activity of the enzymes reflect the severity or chronicity of malnutrition. Leucocyte enzyme activities were significantly elevated in small-for-gestational age, dysma ture neonates. It is possible that the increased susceptibility of IUGR neonates to infection may be related to the high concentration of leucocyte acid hydrolases which result from stabilization of lysosomal membranes theraby preventing the fusion of lysosome with phagocytosed microorganisms.