Serum fetuin-A/alpha2-HS-glycoprotein in human pregnancies with normal and restricted fetal growth

Objective. To investigate circulating concentrations of human fetuin-A (important fetal glycoprotein, involved in vascular pathology and bone metabolism) in mothers, fetuses and neonates from intrauterine-growth-restricted (IUGR, associated with low bone mass at birth and metabolic syndrome in adult life) and appropriate-for-gestational-age (AGA) pregnancies.

Methods. Serum fetuin-A concentrations were prospectively measured in 40 mothers, the doubly-clamped umbilical cords (representing fetal state) and their 20 IUGR and 20 AGA full-term neonates on postnatal day 1 (N1) and 4 (N4).

Results. No significant differences in fetuin-A concentrations were observed between groups, or between maternal, fetal and neonatal samples in both groups. In the AGA group, maternal fetuin-A concentrations positively correlated with fetal and N1 ones (r = 0.599, p = 0.005 and r = 0.469, p = 0.037, respectively). In the IUGR group, maternal fetuin-A concentrations positively correlated with N4 ones (r = 0.541, p = 0.014).

Conclusion. Serum fetuin-A concentrations do not differ between IUGR cases and AGA controls. Maternal and fetal fetuin-A concentrations are similar and positively correlated, indicating the likelihood of passive transplacental transfer of this substance.     

Cord blood netrin-1 and -4 concentrations in term pregnancies with normal,restricted and increased fetal growth

Abstract

Objective: To determine levels of the possible angioregulatory molecules netrin-1 and -4, in intrauterine-growth-restricted (IUGR), large for gestational age (LGA) (both groups characterized by altered angiogenic mechanisms) and appropriate-for-gestational-age (AGA) pregnancies.

Methods: Cord blood (UC) netrin-1 and -4 concentrations were measured in 30 IUGR, 30 LGA and 20 AGA infants and their mothers (MS).

Results: Netrin-1 and -4 concentrations did not differ in all groups. UC netrin-4 increased with gestational age (b?=?0.075, 95% CI 0.029–0.121, p?=?0.002). In the IUGR group, MS netrin-4 decreased as birth-weight centiles increased [b?=??0.058, 95% CI ?0.112 to ?0.004, p?=?0.036]. In the LGA group, MS netrin-1 decreased with advanced gestational age [b?=??0.063, 95% CI ?0.105 to ?0.022, p?=?0.004]. In all cases, MS netrin-1 positively correlated with MS netrin-4 (r?=?0.299, p?=?0.007), while UC netrin-1 negatively correlated with UC netrin-4 (r?=??0.239, p?=?0.033).

Conclusions: Increased UC netrin-4 levels with advancing gestational age may reflect its effect on fetal development. Decreased maternal netrin-1 levels in the LGA group possibly represent a negative feedback mechanism against increased angiogenesis. Increased maternal netrin-4 levels in IUGR neonates may reflect in utero hypoxia, while the negative correlations between fetal netrin-1 and -4 levels may exert the dynamic balance between their angio- and anti-angiogenic properties.     

The potential role of the lectin pathway of complement in the host defence of full-term intrauterine growth restricted neonates at birth

Objective: To prospectively investigate the potential role of the lectin pathway of complement in intrauterine-growth-restriction (IUGR, associated with impaired immunocompetence and increased risk for neonatal infections), by determining cord blood concentrations of mannose-binding lectin (MBL), H-ficolin and L-ficolin (important mediators of neonatal innate immunity) in IUGR and appropriate for gestational age (AGA) pregnancies. Furthermore, we aimed to describe correlations among cord blood MBL, H- and L-ficolin concentrations and with several demographic parameters of the infants at birth. Methods: Serum MBL, H- and L-ficolin concentrations were determined by ELISA in 154 mixed arteriovenous cord blood samples from IUGR (n?=?50) and AGA (n?=?104) singleton full-term infants. Results: Cord blood MBL concentrations were significantly lower in IUGR cases than AGA controls (p?=?0.029). No differences in cord blood H- and L-ficolin concentrations were observed between groups. In the IUGR group, cord blood MBL concentrations negatively correlated with respective L-ficolin ones (r?=??0.442, p?=?0.001). Conclusions: The relatively decreased MBL expression in IUGR fetuses at term could possibly contribute to IUGR-associated neonatal immunodeficiency, predisposing to increased susceptibility to infections. The negative correlation between MBL and L-ficolin concentrations in the IUGR group might suggest an underlying immune variation and needs to be further investigated.     

Feeding preterm neonates with patent ductus arteriosus (PDA): intestinal blood flow characteristics and clinical outcomes

Objective: To evaluate the effects of patent ductus arteriosus (PDA) on postprandial superior mesenteric artery blood flow velocities (SMA BFV)s and feeding tolerance in extremely low birth weight (ELBW) neonates.

Methods: Appropriate for gestational age, ELBW preterm neonates, tolerating bolus enteral feedings were eligible to participate in this prospective observational study. Pulsed Doppler was used to measure preprandial and postprandial (at 30 and 60?min) time-averaged mean velocity (TAMV), peak systolic velocity (PSV) and end diastolic velocity (EDV) once during the day of life 5–7; at the same time, PDA size was estimated using the PDA: left pulmonary artery (LPA) ratio.

Results: A total of 38 infants were studied, 16 in small, 13 in moderate and 9 in large PDA groups. The postprandial SMA BFVs were lower in the large PDA group, although not reaching statistical significance. Importantly, infants in the large PDA group reached full enteral intake later (p?=?0.02) and had higher incidence of death secondary of necrotizing enterocolitis (NEC; p?=?0.04).

Conclusions: ELBW preterm neonates with large PDA may have attenuated intestinal blood flow responses to feedings. There was also an association with higher rates of necrotizing enterocolitis and feeding intolerance in the large PDA group.     

Packed red blood cell transfusion (PRBC) attenuates intestinal blood flow responses to feedings in pre-term neonates with normalization at 24 hours

Objective: To determine whether packed red blood cell (PRBC) transfusion affects post-prandial superior mesenteric artery blood flow velocities (SMA BFVs) in very-low birth weight (VLBW) neonates and if so, at what time point after transfusion restoration of previous SMA BFV patterns occurs.

Design/Methods: VLBW pre-term neonates, older than 14 days and tolerating bolus enteral feedings administered every 3?h were enrolled in this prospective observational study. Pulsed Doppler ultrasound was used to measure pre- and post-prandial (at 45?min) time-averaged mean, peak and end diastolic velocities (TAMV, PSV, EDV) immediately before and after 15?ml/kg of PRBC transfusion was given over 3?h; patent ductus arteriosus (PDA) status was also evaluated. Subsequent pre- and post-prandial SMA BFVs were recorded 24 and 48?h after the transfusion.

Results: Pre- and post-prandial measurements were obtained for 21 out of 25 enrolled infants. Post-prandial SMA BFVs were attenuated during the feedings immediately after transfusion; at 24 and 48?h after transfusion, changes in post-prandial SMA BFVs were similar to those measured prior to transfusion; the presence of the PDA did not affect results.

Conclusions: PRBC transfusion blunted SMA BFV responses to feedings immediately after the transfusion with normalization observed 24?h post-transfusion.     

Uterine artery blood flow volume in pregnant women with an abnormal pulsatility index of the uterine arteries delivering normal or intrauterine growth restricted newborns

The aim of this study was to assess and compare uterine artery (UtA) blood flow volume in pregnant patients with an abnormal uterine Doppler pulsatility index (PI) who delivered fetuses with an appropriate weight for gestational age (AGA) or with intrauterine growth restricted (IUGR).We prospectively recruited singleton pregnancies with abnormal uterine arteries P.I. between 18 and 38 weeks of gestation regardless of estimated fetal weight (EFW). Vessel diameter and blood flow velocity were measured along the UtA upstream to the vessel bifurcation in both the right and left UtAs. Uterine blood flow volumes measured in these pregnancies were compared to historical Control-pregnancies. Forty-three patients delivered at term a normal weight newborn (AGA-pregnancies). Thirty patients delivered growth restricted newborns at 32 weeks (i.r. 29-36w) with a median weight of 1160 gr (i.r. 1000-2065 gr) (IUGR-pregnancies).At mid-gestation (18 + 0 − 25 + 6 weeks + days of gestation) a significantly lower uterine blood flow volume per unit weight was observed between the two study groups and compared to controls: 142 ml/min/kg in IUGR-pregnancies, 217 ml/min/kg in AGA-pregnancies and 538 ml/min/kg in Control-pregnancies. These striking differences in blood flow volume were already present at mid-gestation, at a time when EFW was still normal. In late gestation (27 + 0 − 37 + 6 weeks + days of gestation), pregnancies with an abnormal uterine P.I. showed persistently low UtA flow (<50% of controls) even when corrected for fetal weight: 81 ml/min/kg in IUGR-pregnancies, 105 ml/min/kg in AGA-pregnancies, and 193 ml/min/kg in Control-pregnancies; p < 0.0001.Our findings are consistent with other recent studies regarding the association between reduced uterine blood flow volume and fetal growth restriction. However, the study brings new insight into the finding of abnormal uterine P.I. in normally grown fetuses typically dismissed as “falsely abnormal” or “false positive” findings. Our study suggests that blood flow volume measurement may serve as a new tool to assess this group of patients and possibly those with ischemic placental diseases that may provide some basis for therapeutic interventions.     

Placental glucose transporter 3 (GLUT3) is up-regulated in human pregnancies complicated by late-onset intrauterine growth restriction

Introduction

Transport of glucose from maternal blood across the placental trophoblastic tissue barrier is critical to sustain fetal growth. The mechanism by which GLUTs are regulated in trophoblasts in response to ischemic hypoxia encountered with intrauterine growth restriction (IUGR) has not been suitably investigated.

Objective

To investigate placental expression of GLUT1, GLUT3 and GLUT4 and possible mechanisms of GLUT regulation in idiopathic IUGR.

Methods

We analyzed clinical, biochemical and histological data from placentas collected from women affected by idiopathic full-term IUGR (n = 10) and gestational age-matched healthy controls (n = 10).

Results

We found increased GLUT3 protein expression in the trophoblast (cytotrophoblast greater than syncytiotrophoblast) on the maternal aspect of the placenta in IUGR compared to normal placenta, but no differences in GLUT1 or GLUT4 were found. No differential methylation of the GLUT3 promoter between normal and IUGR placentas was observed. Increased GLUT3 expression was associated with an increased nuclear concentration of HIF-1α, suggesting hypoxia may play a role in the up-regulation of GLUT3.

Discussion

Further studies are needed to elucidate whether increased GLUT3 expression in IUGR is a marker for defective villous maturation or an adaptive response of the trophoblast in response to chronic hypoxia.

Conclusions

Patients with IUGR have increased trophoblast expression of GLUT3, as found under the low-oxygen conditions of the first trimester.     

Decreased expression of phosphorylated placental heat shock protein 27 in human and ovine intrauterine growth restriction (IUGR)

Introduction

Intrauterine growth restriction (IUGR) has been documented to increase placental apoptosis at term. HSP27 has been shown to be involved in the control of apoptosis. Our objective is to determine the expression of phosphorylated HSP27 (p-HSP27) in human IUGR, and to determine the role of HSP27 during gestation in an ovine hyperthermia induced model of IUGR.

Methods

Human placenta tissue samples were collected at term to quantify p-HSP27. Pregnant sheep were placed in hyperthermic (HT) conditions to induce IUGR. Placental tissues were collected at 55 (early), 95 (mid-gestation) and 130 (near-term) days gestational age (dGA) to determined phosphorylated and total HSP27 across the development of IUGR.

Results

Phosphorylated HSP27 was significantly reduced in human placenta IUGR compared to controls at term. HSP27 was increased throughout gestation during the development of IUGR in the sheep. P-HSP27 was increased in early gestation (55 dGA), and decreased near term (130 dGA). The near term decrease was localized to the trophoblast cells of the placenta.

Discussion and conclusion

We conclude that decreased p-HSP27 at term is present when placental apoptosis is increased during IUGR. This could be a factor leading to the decreased placental weight observed during IUGR.     

Intrauterine growth restriction and absent or reverse end-diastolic blood flow in umbilical artery (Doppler class II or III): A retrospective study of short- and long-term fetal morbidity and mortality

OBJECTIVE: Absent or reverse end-diastolic flow (Doppler II/III) in umbilical artery is correlated with poor perinatal outcome, particularly in intrauterine growth restricted (IUGR) fetuses. The optimal timing of delivery is still controversial. We studied the short- and long-term morbidity and mortality among these children associated with our defined management. STUDY DESIGN: Sixty-nine IUGR fetuses with umbilical Doppler II/III were divided into three groups; Group 1, severe early IUGR, no therapeutic intervention (n = 7); Group 2, fetuses with pathological biophysical profile, immediate delivery (n = 35); Group 3, fetuses for which expectant management had been decided (n = 27). RESULTS: In Group 1, stillbirth was observed after a mean delay of 6.3 days. Group 2 delivered at an average of 31.6 weeks and two died in the neonatal period (6%). In Group 3 after a mean delay of 8 days, average gestational age at delivery was 31.7 weeks; two intra uterine and four perinatal deaths were observed (22%). Long-term follow-up revealed no sequelae in 25/31 (81%) and 15/18 (83%), and major handicap occurred in 1 (3%) and 2 patients (11%), respectively, for Groups 2 and 3. CONCLUSION: Fetal mortality was observed in 22% of this high risk group. After a mean period of follow-up of 5 years, 82% of infants showed no sequelae. According to our management, IUGR associated with umbilical Doppler II or III does not show any benefit from an expectant management in term of long-term morbidity.