Tumor necrosis factor-alpha converting enzyme in the human placenta throughout gestation

Ectodomain shedding of epidermal growth factor receptor ligands such as transforming growth factor- alpha (TGF-alpha), heparin-binding epidermal growth factor-like growth factor (HBEGF), and amphiregulin (AREG) is considered to be important during implantation. Tumor necrosis factor-alpha converting enzyme (TACE) has been suggested as the major sheddase for these molecules. The objectives of this study are (1) to characterize the expression of TACE in the human placenta throughout gestation; (2) to determine the association between the expression of TACE with TGF-alpha, HBEGF, and AREG; (3) to ascertain whether TACE mediates TGF-alpha, HBEGF, and AREG shedding; and (4) to examine the effect of hypoxia on the expression of TACE. By analyzing a total of 55 villous samples representing different gestational ages, the authors found that TACE was continuously expressed in the placentas throughout gestation and that the levels of TACE were positively correlated with the levels of TGF-alpha, HBEGF, and AREG. Preadministration of a TACE inhibitor in villous explant cultures or transfection of cytotrophoblastic cells with TACE-specific small interference RNA decreased the shedding of HBEGF and AREG. Moreover, hypoxia (2% O(2)) caused an increase in the levels of TACE mRNA and protein in villous explants and primary cytotrophoblastic cells in vitro. These results indicate that oxygen regulates the expression of TACE and that TACE may be important for placental development during human pregnancy.     

Antenatal fetal testing in pregnancies complicated by gestational diabetes mellitus

Most obstetricians adapt some form of strategy for antenatal fetal testing in pregnancies complicated by gestational diabetes mellitus (GDM). There are, however, wide differences of opinion among providers as to the preferred protocol for such testing. The optimal method of fetal surveillance, the gestational age at which to start testing, the frequency of testing, and even whether all patients with GDM require antenatal testing are all controversial, unresolved issues. Indeed, in the absence of prospective, randomized clinical trials, it is impossible to determine whether antenatal fetal testing is beneficial in uncomplicated GDM. Moreover, it appears that even with the use of well-defined antenatal testing protocols, it is unavoidable that some women with GDM will experience an unexplained third trimester stillbirth. Pending the availability of solid data based on prospective trials, it is prudent to incorporate antenatal fetal testing in the management scheme of women with gestational diabetes.     

Calcium sensing receptor in pregnancies complicated by gestational diabetes mellitus

Introduction

Infants born from mothers with Gestational diabetes mellitus (GDM) experience several complications, including a higher rate of postnatal hypocalcemia. In this study, we investigated the association between calcium sensing receptor (CaSR) and neonatal hypocalcemia observed in GDM pregnancies.

Methods

Our study consisted of 58 pregnant women with GDM and 40 healthy women and their neonates. CaSR placental expression was evaluated with immunohistochemistry and Western Blot. Three CaSR single nucleotide polymorphisms, A986S, R990G, Q1011E, were evaluated in neonate's genomic DNA. Serum Ca, P, Mg, 25(OH)D and PTH were measured in cord blood and at 2nd day of life.

Results

GDM neonates had lower mean cord blood Ca levels than controls (2.47 ± 0.21 mmol/l vs 2.59 ± 0.13 mmol/l, p = 0.001) while 15.5% developed postnatal hypocalcemia. CaSR expression was lower in GDM than in healthy placentas (p < 0.001). In the GDM group, reduced CaSR immunostaining in the syncytiotrophoblast (p = 0.042) and extravillous cytotrophoblasts (p = 0.002) was associated with lower Ca cord blood levels. Moreover, the absence of the S allele of the A986S polymorphism was associated with lower serum Ca levels both at birth (AA:2.41 ± 0.23 mmol/l, AS + SS: 2.57 ± 0.12 mmol/l, p = 0.002) and at 2nd day of life (AA:2.05 ± 0.22 mmol/l, AS + SS: 2.20 ± 0.18 mmol/l, p = 0.019).

Conclusions

Our results showed that CaSR is under-expressed in GDM compared with healthy placentas and this alteration may be associated with the lower Ca levels measured in cord blood of GDM infants. Placental CaSR seems to exert a local effect in fetal Ca homeostasis, which is dissociated from its contribution to the regulation of Ca homeostasis in postnatal life.     

Scavenger receptor for hemoglobin in preterm prelabor rupture of membranes pregnancies complicated by histological chorioamnionitis

Objective: We sought to evaluate the distribution of scavenger receptor for hemoglobin positive (CD163⁺) cells in the placenta and fetal membranes from pregnancies complicated by preterm prelabor rupture of membranes with respect to the presence and absence of histological chorioamnionitis. Methods: Sixty-two women with singleton pregnancies with a gestational age between 24+0 and 36+6 weeks were included in a prospective cohort study. CD163 was evaluated by immunohistochemistry in the placenta and fetal membranes. The number of CD163⁺ cells and neutrophils was counted in the following locations: fetal membranes’ amnion, chorion, and decidua, as well as the placenta’s amnion, chorionic plate, subchorionic fibrin, stem villi, terminal villi, and decidua. Results: CD163⁺ cells were found in all compartments of the placenta and the fetal membranes regardless of the inflammatory status. A positive correlation between the number of CD163⁺ cells and neutrophils in the subchorionic fibrin and the chorionic plate was found. The number of CD163⁺ cells was higher in the placental subchorionic fibrin and chorionic plate when histological chorioamnionitis was present. Conclusion: The presence of histological chorioamnionitis affected the number of CD163⁺ cells in the placental chorionic plate and in the subchorionic fibrin but not in the fetal membranes.     

Histologic chorioamnionitis in pregnancies of various gestational ages. II: Implications in preterm labor

A retrospective review of placental materials (membranes, chorionic plate, umbilical cord) derived from preterm birth is reported. All those studied had intact membranes on admission and did not have spontaneous rupture. Those with preterm labor unresponsive to tocolysis, including those with brief and more prolonged labors, were compared with those delivered preterm because of maternal or fetal indications without labor. Those with labor had inflammatory changes in all three sites of greater frequency than those without labor. Those with longer labors had significantly higher rates of inflammation than those without labor. In this population, removing the influence of spontaneous rupture and labor over 6 hours long greatly diminished the likelihood of inferring that inflammation of the choriamniotic environment is a cause of preterm labor unresponsive to tocolysis.     

Histologic chorioamnionitis in pregnancies of various gestational ages: implications in preterm rupture of membranes

A retrospective review of placental material derived primarily from preterm deliveries was conducted and inflammatory changes graded on a scale of 0-3. Reviewers were blind as to the clinical outcomes. Other reviewers, unaware of the pathologic results, surveyed the clinical data, and results were combined for analysis. The findings suggest that placental and membrane inflammation probably precedes preterm spontaneous rupture of membranes in 8-30% of cases without labor. The duration of ruptured membranes and labor enhance the frequency of inflammation. Inflammation is not associated with significant puerperal infection unless cesarean delivery occurs. Perinatal morbidity and mortality were not significantly enhanced nor associated with conservative management of spontaneous preterm rupture of membranes in this population beyond the influence of fetal weight and gestational age.     

Maternal and neonatal outcomes in pregnancies complicated by gestational diabetes. a nation-wide study

Objective: To estimate the association between gestational diabetes mellitus (GDM) and adverse pregnancy and neonatal outcomes in Denmark.

Methods: A population-based cohort study including all singleton pregnancies in Denmark from 2004 to 2010 (n?=?403?092). Maternal complications during pregnancy and delivery and fetal complications were classified according to the International Classification of Diseases 10th Revision.

Results: The final study population consisted of 398?623 women. Of these, 9014 (2.3%) had GDM. Data were adjusted for maternal age, parity, smoking, gestational age, birth weight, BMI, gender of the fetus and calendar year. The risk of preeclampsia, caesarean section (both planned and emergency) and shoulder dystocia was increased in women with GDM. In the unadjusted analysis, the risk of thrombosis was increased by a factor 2 in the GDM patients, but in the adjusted analysis this association disappeared. Post-partum hemorrhage was similar in the two groups. The GDM women had an increased risk of giving birth to a macrosomic neonate although the unadjusted analysis did not show any difference between the two groups. Low Apgar score was increased in the GDM, but this association disappeared in the adjusted analysis. Stillbirth was comparable in the two groups.

Conclusions: Women with GDM still have increased incidence of obstetric and neonatal complications, which could imply that treatment of women with GDM should be tightened.     

Decreased gestational sac volumes in pregnancies induced by human menopausal gonadotropin

Mean gestational sac volumes of 9 singleton pregnancies induced by human menopausal gonadotropin (hMG) measured by ultrasound were compared with mean gestational sac volumes obtained from 37 normal singleton pregnancies, 6 to 8 weeks from the last menstrual period. HMG-induced gestational sacs were smaller at 6 and 7 weeks of gestation, compared with normal pregnancies. Despite the initial lag in gestational sac volume, hMG-induced pregnancies subsequently demonstrated appropriate fetal growth as measured by crown-rump length measurements between 8 and 12 weeks. These pregnancies also demonstrated normal fetal growth patterns in the second and third trimesters of pregnancy, as assessed by clinical evaluation and ultrasound. These preliminary data suggest that early growth development in hMG-induced pregnancies may be different from that in spontaneously occurring pregnancies.     

Maternal obesity is a major risk factor for large-for-gestational-infants in pregnancies complicated by gestational diabetes

Objectives  Our aim was to evaluate the relative contribution of maternal weight, GDM severity and glycemic control in women with gestational diabetes (GDM) on the prevalence of LGA infants. Methods  A total of 233 women with GDM were classified according to the fasting and/or postprandial glucose levels as in “good” or “poor” glycemic control. Severity of GDM was categorized using fasting plasma glucose on the 3-h 100 g oral glucose tolerance test (OGTT). Results  The incidence of LGA infants was significantly higher in obese women than in those with lower BMI. There was no significant correlation between GDM severity or level of glycemic control and birth weight or proportion of LGA infants. On multivariate regression analyses, only maternal weight at delivery and fasting glucose level on OGTT were found to be independently and significantly associated with the birth weight, and only maternal weight at delivery was a significant and independent predictor of LGA infants. Conclusions  Both the GDM severity and maternal weight are independent predictors of infants’ birth weights. Maternal weight at delivery is a major risk factor for LGA infants. The study was presented at the SMFM 27th annual meeting on February, 2007.     

Management of late preterm and early-term pregnancies complicated by mild gestational hypertension/pre-eclampsia

Gestational hypertension/pre-eclampsia is the most frequent obstetrical complication, complicating 26%-29% of all gestations in nulliparous women. In general, the diagnosis of mild gestational hypertension/pre-eclampsia is made at 38 weeks or more in approximately 80% of cases. For many years, the optimal timing of delivery for patients with mild gestational hypertension/pre-eclampsia at 37-0/7 to 39-6/7 weeks was unclear. Recently, investigators of the HYPITAT (Pregnancy-induced hypertension and pre-eclampsia after 36 weeks: induction of labor versus expectant monitoring: A comparison of maternal and neonatal outcome, maternal quality of life and costs) randomized trial evaluated maternal and neonatal complications in patients at 36-40 weeks' gestation who were randomized to either induction of labor or expectant monitoring. The results of this trial revealed that induction of labor at or after 37-0 weeks was associated with lower rate of maternal complications without increased rates of either cesarean delivery or neonatal complications. In contrast, the optimum management for those with mild hypertension/pre-eclampsia with stable maternal and fetal conditions at 34-0/7 to 36-6/7 weeks remains uncertain. Therefore, there is urgent need for research to evaluate the reasons for late preterm birth in such women as well as for a randomized trial to evaluate the optimal timing for delivery in such patients.     

The human tumor-associated antigen RCAS1 in pregnancies complicated by pre-eclampsia

The human tumor-associated antigen RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) is considered to play a role in the escape of tumor cells from immune surveillance and, at the same time, participates in the inhibition of the maternal immune response during pregnancy. The aim of our study was to investigate the expression of tumor-associated RCAS1 protein in the placenta and amniotic membranes and to assess and compare its concentration in amniotic fluid, maternal and cord blood sera in pregnancies complicated by pre-eclampsia. Samples were obtained from women with pre-eclampsia (N=9), pre-eclampsia with IUGR (N=4), normotensive IUGR (N=7) and healthy term controls (N=25) after delivery. Placentas were studied by immunohistochemistry, Western blot analysis and real-time (RT)-PCR. For assessment of RCAS1 protein concentrations in biological fluids, ELISA was performed. RCAS1 mRNA expression in the placentas of pre-eclamptic patients was significantly lower than in controls (p<0.01). The maternal blood serum RCAS1 protein concentration in the pre-eclampsia cases was also significantly lower than in controls (p=0.0207). The other study groups did not differ significantly. This study reveals the possible role of the RCAS1 protein in the development of pre-eclampsia through an immunological pathway.     

Placental lipid contents in preterm labor complicated by chorioamnionitis

Fifteen decidua free placental samples from nine preterm deliveries without evidence of chorioamnionitis and six preterm deliveries with evidence of chorioamnionitis were analyzed for fatty acids contents. The percentage of arachidonic acid in phospholipids, in free fatty acids, in triglycerides and cholesterol esters were also measured in each sample. Arachidonic acid was found to be present in significantly increased amounts in the placentas of women with chorioamnionitis and preterm delivery, as compared to those of women with preterm delivery and the absence of chorioamnionitis.     

Doppler assessment of the fetal asphyxia in pregnancies complicated by gestational hypertension and intrauterine growth retardation

OBJECTIVES: Gestational hypertension is associated with a high morbidity for both mother and fetus. Doppler ultrasound has allowed the fetal circulation to be examined. Now it is possible to monitor the response of the fetal circulation to hypoxia. DESIGN: The aim of this study was to determine flow patterns in fetal circulation from pregnancies complicated by gestational hypertension and intrauterine growth restriction. MATERIALS AND METHODS: The investigation included 23 fetuses with signs of the gestational hypertension and intrauterine growth restriction. We evaluated cerebral-placental ratio (CPR) and pulsation index (PI) in the middle cerebral artery (MCA) and the umbilical artery (UA). We also evaluated flows in umbilical vein. RESULTS: We observed abnormal flow pattern in all cases of analyzing fetuses. The most common abnormal flow was vein pulsation (48%). CONCLUSIONS: All analyzing fetuses shown signs of the hypoxia. Present of the umbilical vein pulsation or decompensate of the brain sparing effect is closely related o increased perinatal mortality.