Biochemical and Anthropometric Parameters for the Early Recognition of the Intrauterine Growth Restriction and Preterm Neonates at Risk of Impaired Neurodevelopment.

BACKGROUND: S100B and Tau are implicated with both brain growth and injury. Their urinary levels in 30-to-40-day-old full-term, preterm, IUGR, and preterm-IUGR subjects were measured to investigate their possible relationship with future delayed neurodevelopment. METHODS: Values were related to the neuro-behavioral outcome at two years of age, as well as to brain volumes and urinary NGF assessed at the same postnatal time point. RESULTS: Using the Griffiths III test, cognitive and motor performances were determined to establish subgroups characterized by either normal or impaired neuro-behavior. The latter included preterm, IUGR, and preterm-IUGR individuals who exhibited significantly higher and lower S100B and Tau levels, respectively, along with markedly reduced cerebral volumes and urinary NGF, as previously demonstrated. Contrary to NGF, however, Tau and S100B displayed a weak correlation with brain volumes. CONCLUSIONS: Delayed cognitive and motor performances observed in two-year-old preterm and IUGR-born individuals were also found to be associated with anomalous urinary levels of S100B and Tau, assessed at 30-40 days of the postnatal period, and their changes did not correlate with brain growth. Thus, our data suggests that, in addition to cerebral volumes and NGF, urinary S100B and Tau can also be considered as valuable parameters for the early detection of future neurodevelopmental abnormalities.

Urinary Cystatin-C, a marker to assess and monitor neonatal kidney maturation and function: validation in twins.

BACKGROUND: Nephrogenesis is a complex process of nephron formation and maturation that can be compromised by preterm delivery and intrauterine growth restriction. This study aimed to evaluate and compare urinary Cys-C levels with renal volume in a cohort of preterm and term twins, adequate for gestational age or intrauterine growth restricted, to investigate their values in different conditions of nephrogenesis. METHODS: The study was performed on twins at 30-40 days of postnatal corrected age: renal volumes were measured by 3D ultrasound technology and urine samples were analyzed for Cystatin-C. A follow-up was performed by Cystatin-C. RESULTS: Renal volumes in preterm and intrauterine growth-restricted twins showed values significantly lower than those observed in term twins and were inversely correlated to urinary Cystatin-C levels. During the follow-up, intrauterine growth-restricted twins showed amplified levels of urinary Cystatin-C; in contrast, invariable or decreased levels were observed in adequate for gestational age twins. CONCLUSIONS: Urinary Cystatin-C, evaluated when intrauterine/extrauterine nephrogenesis could be considered completed, concurrently with renal volume assessment can improve the identification of neonates with initial kidney impairment. Its potential value as a useful marker in monitoring physiological/pathological renal conditions could be considered, mainly for neonates at elevated risk of developing long-term renal diseases. IMPACT: Urinary Cys-C levels are inversely correlated to renal volumes and reflect nephrogenesis conditions. No data in literature are reported regarding: (a) the concurrent assessment of renal volumes and urinary levels of Cystatin-C in preterm and term twins with different conditions of gestational life, i.e., AGA and IUGR and (b) the follow-up of IUGR and preterm neonates using the urinary Cys-C determination. The variations of urinary Cys-C levels, observed in the follow-up of preterm and/or IUGR neonates, support the usefulness of monitoring those neonates with altered nephrogenesis, who are later at risk for renal impairment and for long-term renal diseases.

Biochemical parameters of renal impairment/injury and surrogate markers of nephron number in intrauterine growth-restricted and preterm neonates at 30-40 days of postnatal corrected age.

BACKGROUND: Premature and/or intrauterine growth-restricted neonates have an increased risk of developing postnatal renal injuries in later life. Studies on renal physiology in these neonates at a corrected age of 30-40 days are scarce and mostly relate to preterm infants. The data from these studies often lack the results of correlation analyses between biochemical parameters and nephron number-data which could provide additional insight and/or improve recognition of individuals at higher risk of renal failure. METHODS: Urinary total protein and albumin levels and N-acetyl-ß-D-glucosaminidase and cathepsin B activity were evaluated in preterm and intrauterine growth-restricted infants at a corrected age of 30-40 days and compared to data from a healthy control neonate population. The data were then associated with predominant susceptibility factors of renal damage related to low nephron number, such as gestational age, birth weight, total renal volume and renal cortex volume. RESULTS: Compared to the control neonate population, we found significantly increased levels of all biochemical parameters tested in the intrauterine growth-restricted neonates, whereas in the preterm infants we observed a significant increase in cathepsin B activity, total protein level and, to a lesser extent, albumin level. Cathepsin B activity showed a significant, strong and inverse correlation with all surrogate markers of nephron number and was also strongly and positively correlated with urinary albumin level. CONCLUSIONS: At this postnatal age, we found that lower nephron number in low birth weight neonates was associated to tubular impairment/injury that could be concurrent with a dysfunction of glomerular permeability. Urinary cathepsin B activity may be a candidate marker for the early prediction of renal susceptibility to damage in low birth weight neonates.

Body mass index associated to rs2021966 ENPP1 polymorphism increases the risk for gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is a condition of impaired glucose tolerance occurring in 1-14% of all pregnancies. This wide range reflects pathological involvement of single nucleotide polymorphisms (SNPs) and maternal weight as risk factors. This study evaluated the association of genetic component and maternal factors to identify women with higher risk of developing GDM. About 240 pregnant women characterized by negative Oral Glucose Tolerance Test (-OGTT) and 38 with positive OGGT (+OGTT) were enrolled. SNPs for ENPP1, NRF1, VEGFA, CEBPA, and PIK3R1 were analyzed by SNP genotyping. An association study was performed and differences in genotype and allele frequencies between cases and controls were analyzed by χ(2) test. +OGTT was associated to high values of pre-gestational body mass index (BMI) and age. SNP for ENPP1 gene was associated to +OGTT, while genetic variants for other genes did not correlate to GDM. ENPP1 homozygous for A allele and heterozygous showed altered frequencies in +OGTT when compared with -OGTT. Association of both pre-gestational BMI and age with AA homozygous genotype increased significantly the risk to +OGTT. Our results demonstrate that correlation of age and pre-gestational BMI with homozygous for A allele increased significantly the risk of impaired glucose tolerance and GDM.

Brain 3D-echographic early predictors of neuro-behavioral disorders in infants: a prospective observational study.

BACKGROUND: Prematurity, low birth weight (LBW), very low birth weight (VLBW), and intrauterine growth restriction (IUGR) are risk factors of long-term poor neuro-development outcomes and associate with reduction of regional brain volumes. OBJECTIVE: To evaluate the possible role of 3D ultrasound sonography (3DUS) regional brain volumes, measured at 30-40 days of postnatal period, as early predictors of long-term risk of neuro-behavioral disorders. METHODS: A highly selected population, which included: full-term, preterm, IUGR, and preterm-IUGR born individuals, was followed longitudinally from 30 to 40 days of postnatal period to the second year of life. The population was mostly composed of bichorionic twins to ensure a, theoretically, major intracategory homogeneity. Preterm and IUGR subjects were characterized by a gestational age (GA) and birth weight (BW)>32 weeks and >1500 g, respectively, whereas the full-term neonates were of 37 weeks GA. At enrollment, the assessment of the volumetric measurements was performed using the 3DUS. The evaluation of neuro-development was performed at 2 years using the Griffiths Mental Development Scales. RESULTS: The 3DUS measurements of whole brain, thalamus, frontal cortex, and cerebellum volumes, assessed at 30-40 days of postnatal period, were significantly reduced in infants characterized by negative outcome. In addition, the respective areas of the ROC curves, made by comparing values of normal and abnormal neuro-development groups, were indicative of a strong diagnostic accuracy. CONCLUSION: Data found suggest that the 3DUS regional brain volumes may assume a significant role as early indicators of neonates at major risk of neuro-behavioral disorders in later life. Further and larger studies in this direction are needed to validate this significant perspective.

3D evaluation of fetal brain structures: reference values and growth curves.

BACKGROUND: The development of the fetal central nervous system is one of the most important fields of research in perinatology. Since the early 1980s, 3 D ultrasound has become one of the major research tools in obstetrics and gynecology. OBJECTIVE: The aim of this study was to reconstruct thalamus, cerebellum and Cortex volumes of fetal brain and generate, for these volumes, growth curves related to gestational age. METHODS: We enrolled 344 pregnant women. Using "Tomographic Ultrasound Imaging" (TUI), in all cases we obtained a satisfying 3 D acquisition of fetal brain. We reconstructed offline thalamus, cerebellum and cortex volumes using "Virtual Organ Computer-Aided AnaLysis" (VOCAL) or 4 D View (GE Healthcare). RESULTS: Among the 344 fetuses examined, we obtained 314 thalamus volumes, 252 cerebellum volumes and 261 cortex volumes and we constructed the reference growth curves. CONCLUSION: Our study confirms the reliability of cerebral volumes evaluation using 3 D technology and how these cerebral structures grow through gestation.

3-D Echo Brain Volumes to Predict Neurodevelopmental Outcome in Infants: A Prospective Observational Follow-up Study.

Prematurity and intra-uterine growth restriction (IUGR) are risk factors for long-term poor neurodevelopmental outcomes and are associated with reductions in regional brain volumes. In this study, the aim was to determine the possible role of 3-D ultrasonography (3-DUS) volumes of whole brain, thalamus, frontal cortex and cerebellum, measured at postnatal days 30-40, as early predictors of long-term risk for neurobehavioral disorders. To this purpose, a heterogeneous population of full-term, preterm, IUGR and preterm IUGR (pre-IUGR) born individuals (n = 334), characterized by gestational age and birth weight in the ranges 24-41 wk and 860-4000 g, respectively, was followed from postnatal days 30-40 to the second year of life. At enrollment, brain volumes were measured using 3-DUS, whereas neurodevelopment was assessed at 2 y using the Griffiths III test. Cerebral volumes were strictly and significantly lower in infants characterized by a negative outcome and had excellent diagnostic accuracy. The 3-DUS volume of whole brain, thalamus, frontal cortex or cerebellum may be an early predictor of neonates at major risk for neurobehavioral disorders in later life.

Urinary Nerve Growth Factor in full-term, preterm and intra uterine growth restriction neonates: Association with brain growth at 30-40 days of postnatal period and with neuro-development outcome at two years. A pilot study.

Nerve Growth Factor (NGF) and Brain Derived Neurotrophic Factor (BDNF) are crucial for the peripheral and central nervous system development, respectively, and differential brain and blood levels in Intra Uterine Growth Restriction (IUGR) and prematurity have been found. As reduced growth of brain regions, measured at 30-40 days of postnatal period, has been demonstrated in preterm and IUGR neonates who showed impaired neuro-development at two years of age, in this study, the levels of NGF and BDNF were evaluated in the urine samples of 30-40 day-old subjects who were full-term, preterm and IUGR and showed a normal or an abnormal neuro-development at follow up after two years. Neurotrophins were measured concurrently with volumes of whole brain, thalamus, frontal cortex and cerebellum. Values were then correlated with later neuro-developmental outcome. Biochemical parameters and cerebral volumes were assessed using colorimetric ELISA kits and three-dimensional ultra-sonography (3DUS), respectively. Neuro-development was estimated using the Griffiths-II test. Urinary NGF and brain volumes significantly correlated and were lower in preterm and IUGR subjects characterized by poor neuro-development. No differences were seen in the case of BDNF. The present investigation demonstrates, for the first time, the strong and direct association of NGF with brain growth at the initial phase of the postnatal period and with neuro-developmental outcome in later life. Remarkably, urinary NGF may be suggested as an early prognostic indicator of high long-term risk of motor and cognitive impairment in IUGR and preterm neonates.

Renal Consequences of Gestational Diabetes Mellitus in Term Neonates: A Multidisciplinary Approach to the DOHaD Perspective in the Prevention and Early Recognition of Neonates of GDM Mothers at Risk of Hypertension and Chronic Renal Diseases in Later Life.

Fetal exposure to gestational diabetes mellitus (GDM) seems to stimulate a negative impact on the kidneys. Renal volumes and urinary biomarkers of renal function and tubular impairment and injury were evaluated in 30⁻40-day old newborns of GDM mothers (n = 139) who needed insulin therapy during pregnancy. We found that neonates of mothers who maintained strict control over normoglycemia (n = 65) during pregnancy and fulfilled the other criteria of the GDM management program showed no differences compared to control (n = 55). Conversely, those (n = 74), whose mothers did not maintain glycemic control and were not compliant to the management program, exhibited significantly lower levels of renal volumes and higher activity of N-acetyl-ß-D-glucosaminidase and cathepsin B. Differences due to maternal pre-gestational and gestational body mass index (BMI) as well as to maternal weight gain were demonstrated. Our findings indicate that a multidisciplinary approach, which involves an appropriate management of GDM, prevents the negative effects of GDM on the kidneys at 30⁻40 days of postnatal age, indicating the fundamental role of glycemic control, as well as of an adequate range of maternal weight gain. Total renal volume, cortical volume, and urinary activity of N-acetyl-ß-D-glucosaminidase and cathepsin B may be suggested as indicators for the early recognition of GDM neonates at long-term risk of hypertension and kidney disease.

Intrapartum test for detection of Group B Streptococcus colonization during labor.

PURPOSE: The purpose of this study was to evaluate the potential improvement of introducing an intrapartum test for the detection of Group B Streptococcus (GBS) during labor and to estimate its cost-effectiveness versus antepartum GBS screening culture. MATERIALS AND METHODS: Three hundred and thirteen women at beginning of labor, with unknown GBS status or with antepartum GBS screening culture were enrolled. A vaginal-rectal specimen was collected from each woman for GBS detection by real-time PCR. Results of intrapartum test and antepartum GBS screening culture were compared. RESULTS: Antepartum culture results did not always reflect the intrapartum maternal GBS colonization status since in 15.1% of the cases it was not concordant with intrapartum test. However, selecting only women, who underwent antepartum culture and intrapartum test at the same time, the percentage of concordance was 96.6%. Based on intrapartum test results, 74.9% of the total number of intrapartum antibiotic prophylaxis (IAP) was administered uselessly, while 1.9% of women did not receive IAP although they were positive to intrapartum test. Intrapartum test resulted less cost-effective than antepartum culture but it became more cost-effective at a cost threshold of about 16.00 €. CONCLUSIONS: The clinical introduction of intrapartum test could be a valuable mean for identification of GBS colonization during labor, allowing an appropriate management of mothers and neonates with consequent benefit for their health and with limited costs for Healthcare System.

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.