Maria De Bonis

Changes in Placental CRH, Urocortins, and CRH-Receptor mRNA Expression Associated with Preterm Delivery and Chorioamnionitis

CONTEXT The pathogenesis of preterm delivery (PTD) is not clear, although inflammation/infection play a major role. Corticotropin releasing-hormone (CRH) and Urocortins (Ucns) are involved in the pathophysiology of PTD. OBJECTIVE This study evaluates trophoblast mRNA expression of CRH, Ucn, Ucn2, Ucn3, and their receptors [CRH-type 1 receptor (CRH-R1), CRH-R2] in infective conditions. To determine whether infection or glucocorticoids contribute to change their placental mRNA expression, the effects of lipopolysaccharide or dexamethasone was evaluated. DESIGN Placentas were obtained from spontaneous PTD; premature rupture of membranes (pPROM) and pPROM with chorioamnionitis. SETTING Placental specimens were collected from women receiving perinatal care at our Division of Obstetrics and Gynecology. PATIENTS OR OTHER PARTICIPANTS Pregnant women delivered preterm were enrolled. INTERVENTIONS mRNA expression was evaluated by RT-PCR. MAIN OUTCOME MEASURE Because CRH and Ucns are involved in immunological functions we evaluated their involvement in PTD with or without infection. RESULTS CRH, Ucn2, and CRH-R1 mRNA expression were higher, while Ucn and CRHR-2 were lower in pPROM with chorioamnionitis than in PTD and pPROM. Ucn3 mRNA expression was lower in pPROM with and without chorioamnionitis than in PTD. The addition of lipopolysaccharide in trophoblast explants decreased Ucn, Ucn3, and CRH-R2 and increased CRH, Ucn2, and CRH-R1 mRNA expression in a dose-dependent manner. Dexamethasone increased CRH and decreased Ucn2 mRNA expression in a dose dependent manner. CONCLUSIONS Our findings showed a significant impact of pPROM with chorioamnionitis on placental CRH peptides and receptors, suggesting that placental expression of stress-related pathways is activated in infective process.

Urocortin increases IL-4 and IL-10 secretion and reverses LPS-induced TNF-alpha release from human trophoblast primary cells.

Problem  As urocortin (Ucn) is a placental peptide belonging to the corticotrophin‐releasing hormone (CRH) family that modulates immune function in other biological models, this study evaluated Ucn effects on cytokines secretion from cultured human trophoblast cells.

ORIGINAL ARTICLE: Urocortin Increases IL-4 and IL-10 Secretion and Reverses LPS-induced TNF-α Release from Human Trophoblast Primary Cells

Problem  As urocortin (Ucn) is a placental peptide belonging to the corticotrophin‐releasing hormone (CRH) family that modulates immune function in other biological models, this study evaluated Ucn effects on cytokines secretion from cultured human trophoblast cells.

Changes of Placental Kiss-1 mRNA Expression and Maternal/Cord Kisspeptin Levels at Preterm Delivery

Kisspeptin, a placental polypeptide secreted throughout pregnancy, is suggested to play a role at parturition. Here we evaluated whether its placental mRNA expression and maternal/fetal plasma levels change at term and preterm delivery, and its effect on oxytocin secretion from placental explants. Samples were collected from 40 women with singleton pregnancies who underwent elective cesarean section at term (TNL), term vaginal delivery (TD), and preterm vaginal delivery (PTD). Plasma Kisspeptin and oxytocin levels were assessed by ELISA; placental mRNA expression by Real-time quantitative RT-PCR analysis. Placental expression was significantly (P < 0.0001) higher in PTD than TNL and TD and significantly (P < 0.001) higher in TD than TNL. Maternal/fetal plasma concentrations did not differ among the groups, and maternal were significantly higher than fetal levels (P < 0.05). In placental explants increasing doses of kisspeptin did not modify oxytocin secretion. In conclusion, labor is associated with increased placental KiSS-1 expression without changes in maternal/fetal circulation.

Carbetocin versus oxytocin after caesarean section: similar efficacy but reduced pain perception in women with high risk of postpartum haemorrhage

Objective: To compare the effectiveness of carbetocin with oxytocin with respect to maintain adequate uterine tone and to reduce the incidence and severity of postpartum haemorrhage. Moreover safety, adverse effects and the need of additional medications were evaluated. Methods: Prospective controlled clinical trial. We compared the effect of a single dose of carbetocin (n = 55) with oxytocin infusion (n = 55) in a women population undergoing to elective caesarean section with regional subarachnoid anaesthesia with at least one risk factor for postpartum haemorrhage. Results: The mean ± SD of postoperative pain in the day of surgery in carbetocin group was significantly lower than in oxytocin group and remained significant till the third day after caesarean section. In the day of surgery and the first day after surgery, women of carbetocin group who needed analgesic drugs were significantly lower than women of oxytocin group. The differences of diuresis and of diuretic drugs need were not statistically significant between the two groups. Conclusions: A single carbetocin injection is efficacious and safe on the maintenance of uterine tone and on the limitation of blood losses, in peri- and in postoperative period. In addition, carbetocin was able to reduce pain perception during postoperative days improving quality life of women.

Neuroendocrine aspects of placenta and pregnancy

Placenta plays a central role in the regulation of physiological mechanisms of pregnancy, and in particular is the organ of communication between mother and fetus. This action is also related to its ability to produce hormones, growth factors and cytokines during the progression of pregnancy, and in response to stimuli such as stress and inflammation/infection. In the last years the understanding of the physiological and pathological functions of human placenta revealed the hypersecretion of hormones in presence of gestational diseases and raised the question whether this mechanism is cause of disorders of pregnancy, or part of an adaptive response of placenta to resolve adverse conditions. However, there are evidences indicating that changes of placental hormone secretion may have clinical usefulness, since they are measurable in biological fluids, and may be used as predictive markers or prognostic tools. Of particular interest is the role of corticotropin releasing hormone, urocortins and activins in the maintaining physiological pregnancy and in the pathogenesis of diseases (preterm birth and preeclampsia).

Amniotic fluid urocortin, CRF, oestriol, dehydroepiandrosterone sulfate and cortisol concentrations at mid-trimester: putative relationship with preterm delivery

OBJECTIVE Stress-related peptide and steroid hormones are involved in the pathogenesis of preterm delivery, even though their clinical usefulness as predictive markers of preterm delivery remains unclear. The present study evaluated whether mid-trimester amniotic fluid concentrations of stress-related peptides, that is corticothophin-releasing factor (CRF) and urocortin (Ucn) and feto-placental steroids (oestriol, DHEA-S and cortisol) correlated with preterm delivery. STUDY DESIGN It is a retrospective case-control study. Healthy women (n=130) undergoing amniocentesis at mid-gestation for genetic indications, of whom 15 had a preterm delivery (cases) and 115 delivered at term (controls). CRF, urocortin, cortisol, DHEA-S and oestriol concentrations were measured by specific and sensitive immunoenzymatic assays. RESULTS Amniotic fluid urocortin concentrations in the cases (0.50+/-0.07 ng/ml) (M+/-SD) were significantly lower (P<0.0001) than in the control group (0.90+/-0.26 ng/ml), while CRF concentrations did not differ between the cases (1.52+/-0.39 ng/ml) and control group (1.64+/-0.68 ng/ml). Amniotic fluid cortisol (17.71+/-3.72 ng/ml vs. 17.32+/-3.17 ng/ml), DHEA-S (0.16+/-0.06 ng/ml vs. 0.17+/-0.09 ng/ml) and oestriol (4.68+/-1.95 ng/ml vs. 4.79+/-1.84 ng/ml) concentrations were similar in the two groups. CONCLUSIONS The low amniotic fluid concentrations of urocortin at mid-trimester may be a signal of predisposition to preterm delivery, while the unchanged CRF and steroid hormones concentrations in women delivering preterm suggest that this mechanisms are not yet activated at mid-trimester.

Levels of antibodies against protein C and protein S in pregnancy and in preeclampsia

Objectives. The clinical relevance of antibodies anti-protein C and anti-protein S in pregnancy remains controversial. We evaluate whether, in the absence of thrombophilic diseases, maternal plasma levels of antibodies (IgM and IgG) change during pregnancy and in preeclampsia (PE), with and without superimposed fetal growth restriction (FGR). Methods. A retrospective cohort of 50 women with PE (n = 30) and PE + FGR (n = 20) and 70 controls [first trimester (n = 20); second trimester (n = 20); third trimester (n = 30)] were enrolled in the study. Results. In healthy pregnant women, plasma levels of anti-protein C antibodies decreased from first to third trimester and were below the range of positivity. IgM anti-protein-C and anti-protein-S were significantly higher (P < 0.001) in both PE (23.88 ± 10.65 MoM and 43.90 ± 20.45 MoM, respectively) and PE + FGR group (15.95 ± 12.62 MoM and 36.02 ± 27.43 MoM, respectively) than in control group (2.23 ± 3.23 MoM and 1.68 ± 4.075 MoM, respectively), in the presence of unchanged levels of IgG isotype. Conclusions. In this study, we first found that the production of anti-protein C and anti-protein S antibodies decreases throughout healthy pregnancies, while they circulate in high levels in women with PE and PE/FGR.

The identification of high risk pregnancy: a new challenge in obstetrics

Preterm delivery (PTD) and pre-eclampsia (PE) represent the main “obstetric syndromes,” caused by multiple conditions, and characterized by complex pathogenesis. Nonetheless, recent evidences attest that deregulation of the immune system and exaggeration of inflammatory processes, taking place in the feto-placental unit, represent common central mechanisms occurring in both diseases. Tertiary prevention represents the only intervention to prevent PTD, but its incidence is still increasing. Advances in secondary prevention, focusing on risk factors and possible markers, are necessary.

Correlation With Placental Kisspeptin in Postterm Pregnancy and Apoptosis

Postterm pregnancy represents a condition associated with trophoblast apoptosis. Kisspeptin is a peptide able to induce apoptosis by a specific receptor, GPR54, through the upregulation of proapoptotic genes. The aims of the study were to evaluate (1) the messenger RNA (mRNA) expression of kisspeptin, GPR54, Bax/Bcl2, and p21 in postterm placentas and (2) kisspeptin ability to act on apoptosis in the third trimester placental explants. Placental specimens were collected from spontaneous term and postterm delivery and kisspeptin, GPR54, Bax/Bcl2, and p21 mRNA expression levels were analyzed by real-time polymerase chain reaction. Placental explants, collected from elective term cesarean sections, treated with different doses of kisspeptin were analyzed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). The expression levels of all the genes studied in postterm placentas were significantly higher than in-term placentas. Kisspeptin-induced apoptosis in placental explants with a dose-dependent effect, and TUNEL assay demonstrated the kisspeptin involvement in the apoptotic placental processes. Our present findings led us to hypothesize that kisspeptin may represent a placental proapoptotic agent acting in physiological and/or pathological pregnancy conditions in which placental apoptosis mechanisms are increased.