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Gestational diabetes mellitus (GDM) and preeclampsia (PE) are both characterized by endothelial dysfunction and GDM women have higher incidence of PE. The placenta plays a key role in PE pathogenesis but its contribution to PE during GDM remains unclear. Herein, we compared placental and maternal blood anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt1) and pro-angiogenic Placental Growth Factor (PlGF) expressions in GDM and GDM-PE pregnancies compared to controls (CTRL) and PE cases. Electrochemiluminescence immunoassays showed a significantly higher maternal blood sFlt1/PlGF values in GDM-PE relative to CTRL and GDM pregnancies. We reported that placental PlGF gene expression was significantly decreased in GDM, PE and GDM-PE relative to CTRL. However, PlGF protein levels were significantly increased in GDM and GDM-PE relative to CTRL and PE placentae. Finally, sFlt1 gene expression was significantly increased in PE relative to CTRL, GDM and GDM-PE placentae. In contrast, sFlt1 protein expression was significantly decreased in GDM-PE relative to CTRL, GDM and PE placentae. Finally, higher sFlt1/PlGF ratio in GDM-PE maternal blood suggest that sFlt1 overproduction is related to PE onset also in GDM pregnancies even though characterized by a less severe endothelial dysfunction in terms of angiogenic biomarkers.

Purpose: Depressive disorders are related to obstetrical and neonatal complications. The purpose of this study is to evaluate the outcomes of pregnancy in women suffering from depressive disorders, who are treated or not treated with pharmacotherapy during pregnancy. Methods: The maternal and neonatal outcomes of 281 pregnant women with depressive disorders (D group—DG), who delivered their babies at Sant’Anna Hospital of Turin, were compared with those of a control group of 200 depression-free, healthy, pregnant women, who were matched for maternal age (C group—CG). Of the depressed patients, those who received pharmacotherapy during pregnancy (DG-Tr, n = 199, 70.8%) were compared with those who did not (DG-Untr, n = 82, 29.2%). The comparisons were performed using χ2 tests for categorical variables and ANOVA for continuous variables. A linear regression analysis was run to examine the association between APGAR scores at 5 min and certain clinical variables. Results: The women in DG showed higher rates of cesarean section, preterm delivery, induction of labor and SGA babies, and low neonatal weights and 5-min APGAR scores, compared to the untreated patients. Those treated with psychotropic drugs showed lower rates of cesarean section, but lower 5-min APGAR scores, compared to those who were untreated. However, after controlling for confounding variables, the 5-min APGAR scores were linearly associated with neonatal weight and not with the use of psychotropic treatment. No significant differences were observed between the treated and untreated women, regarding the rates of preterm delivery, induction of labor, SGA and low neonatal weight. Conclusion: In pregnant patients with depressive disorders, poorer outcomes are expected vs. healthy controls. Pharmacological treatment is associated with a reduced rate of cesarean section, without inducing other complications for the mother and the newborn.

We tested the pro-angiogenic and anti-inflammatory effects of human placenta-derived mesenchymal stromal cells (hPDMSCs)-derived conditioned media (CM) on a mouse model of preeclampsia (PE), a severe human pregnancy-related syndrome characterized by maternal hypertension, proteinuria, endothelial damage, inflammation, often associated with fetal growth restriction (FGR). At d11 of pregnancy, PE was induced in pregnant C57BL/6N mice by bacterial lipopolysaccharide (LPS) intravenous injection. At d12, 300 μL of unconditioned media (control group) or 300 μL PDMSCs-CM (CM group) were injected. Maternal systolic blood pressure was measured from 9 to 18 days of pregnancy. Urine protein content were analyzed at days 12, 13, and 17 of pregnancy. At d19, mice were sacrificed. Number of fetuses, FGR, fetal reabsorption, and placental weight were evaluated. Placentae were analyzed for sFlt-1, IL-6, and TNF-α gene and protein expressions. No FGR and/or reabsorbed fetuses were delivered by PDMSCs-CM-treated PE mice, while five FGR fetuses were found in the control group accompanied by a lower placental weight. PDMSCs-CM injection significantly decreased maternal systolic blood pressure, proteinuria, sFlt-1, IL-6, and TNF-α levels in PE mice. Our data indicate that hPDMSCs-CM can reverse PE-like features during pregnancy, suggesting a therapeutic role for hPDMSCs for the treatment of preeclampsia.

Bisphenol A (BPA) is a synthetic phenol extensively used in the manufacture of polycarbonate plastics and epoxy resins and a component of liquid and food storages. Among health disorders potentially attributed to BPA, the effects on metabolism have been especially studied. BPA represents a hazard in prenatal life because of its presence in tissues and fluids during pregnancy. Our recent study in rats fed with BPA showed a placental increase in glucose type 1 transporter (GLUT-1), suggesting a higher uptake of glucose. However, the role of BPA on GLUT transporters in pregnant women with metabolic dysfunction has not yet been investigated. In this study, placental tissue from 26 overweight (OW) women and 32 age-matched normal weight (NW) pregnant women were examined for expression of GLUT1 and GLUT4. Placental explants from OW and NW mothers were exposed to BPA 1 nM and 1 μM and tested for GLUTs expression. The data showed a different response of placental explants to BPA in GLUT1 expression with an increase in NW mothers and a decrease in OW ones. GLUT4 expression was lower in the explants from OW than NW mothers, while no difference was showed between OW and NW in placental biopsies for any of the transporters.

Proinflammatory cytokines are produced in pregnancy in response to the invading pathogens and/or nonmicrobial causes such as damage-associated molecules and embryonic semi-allogenic antigens. While inflammation is essential for a successful pregnancy, an excessive inflammatory response is implicated in several pathologies including pre-eclampsia (PE). This review focuses on the proinflammatory cytokine macrophage migration inhibitory factor (MIF), a critical regulator of the innate immune response and a major player of processes allowing normal placental development. PE is a severe pregnancy-related syndrome characterized by exaggerated inflammatory response and generalized endothelial damage. In some cases, usually of early onset, it originates from a maldevelopment of the placenta, and is associated with intrauterine growth restriction (IUGR) (placental PE). In other cases, usually of late onset, pre-pregnancy maternal diseases represent risk factors for the development of the disease (maternal PE). Available data suggest that low MIF production in early pregnancy could contribute to the abnormal placentation. The resulting placental hypoxia in later pregnancy could produce high release of MIF in maternal serum typical of placental PE. More studies are needed to understand the role of MIF, if any, in maternal PE.

Endocrine-disrupting chemicals (EDCs) are exogenous substances able to mimic or to interfere with the endocrine system, thus altering key biological processes such as organ development, reproduction, immunity, metabolism and behavior. High concentrations of EDCs are found in several everyday products including plastic bottles and food containers and they could be easily absorbed by dietary intake. In recent years, considerable interest has been raised regarding the biological effects of EDCs, particularly Bisphenol A (BPA) and phthalates, on human pregnancy and fetal development. Several evidence obtained on in vitro and animal models as well as by epidemiologic and population studies strongly indicated that endocrine disruptors could negatively impact fetal and placental health by interfering with the embryonic developing epigenome, thus establishing disease paths into adulthood. Moreover, EDCs could cause and/or contribute to the onset of severe gestational conditions as Preeclampsia (PE), Fetal Growth Restriction (FGR) and gestational diabetes in pregnancy, as well as obesity, diabetes and cardiovascular complications in reproductive age. Therefore, despite contrasting data being present in the literature, endocrine disruptors must be considered as a therapeutic target. Future actions aimed at reducing or eliminating EDC exposure during the perinatal period are mandatory to guarantee pregnancy success and preserve fetal and adult health.

Objective: To determine whether maternal serum concentrations of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a cytokine with anti-inflammatory activity, also involved in cardiovascular morbidity, differ between women with early preeclampsia (

Preeclampsia (PE) is a multifactorial pregnancy-induced syndrome and infection could have a role in its etiopathogenesis. Hepcidin, central regulator of iron homeostasis, is an antimicrobial peptide induced by inflammatory/infective stimuli. Therefore, hepcidin could be a good nonspecific marker of infection in PE. In a cross-sectional study, we assessed maternal serum levels (ELISA) and placental expression (Real-Time PCR and ELISA) of hepcidin in PE and normal pregnancies. In a prospective study, hepcidin maternal serum levels were assessed in early pregnancy before PE onset and in age matched controls. Hepcidin protein and gene expressions were significantly decreased in PE placentae with normal fetal growth compared to controls and PE with Fetal Growth Restriction (FGR), respectively. In contrast, we did not find significant differences in maternal serum hepcidin levels in PE vs gestational age-matched controls. Hepcidin serum levels in the first half of pregnancy were found significantly higher in women who subsequently developed PE compared to mothers having a physiological pregnancy until term. Altered hepcidin expression in PE placentae could be explained by direct infective/inflammatory stimuli. Furthermore, high hepcidin levels in maternal serum could be an early marker of PE, further emphasizing the role of inflammatory status before symptoms onset in PE.

Background To evaluate whether sonographic (US) diagnosis of the fetal spine position could increase the success rate of manual rotation of the fetal occiput (MRFO) in second-stage arrest in persistent occiput posterior position (OPP). Methods In this randomized controlled parallel single-center trial, 58 nulliparous in second-stage arrest of labor with fetus in cephalic presentation and OPP diagnosed by US were randomly assigned to group A where the fetal spine position was not known by the operator or to group B where the operator knew it. The main outcome was the success of MRFO in the two groups. Secondary outcomes were perineal injuries, blood loss, duration of expulsive period, and neonatal APGAR at 5 minutes. Results A priori knowledge of the spine position improves the success of the MRFO (41.4% group A versus 82.8% group B, p value < 0.001), the percentage of spontaneous deliveries (27.6% group A versus 69% group B, p value = 0.01), and maternal outcome (intact perineum and blood loss). No differences were detected on the neonatal side. Conclusions MRFO is a safe and useful procedure that should be performed in second-stage arrest in OPP. A better performance was observed when supported by the US knowledge of the spine position. © 2017 Wiley Periodicals, Inc. J Clin Ultrasound, 2017

Herein, we evaluated whether Placental Mesenchymal Stromal Cells (PDMSCs) derived from normal and Preeclamptic (PE) placentae presented differences in the expression of G1/S-phase regulators p16INK4A, p18INK4C, CDK4 and CDK6. Finally, we investigated normal and PE-PDMSCs paracrine effects on JunB, Cyclin D1, p16INK4A, p18INK4C, CDK4 and CDK6 expressions in physiological term villous explants. PDMSCs were isolated from physiological (n = 20) and PE (n = 24) placentae. Passage three normal and PE-PDMSC and conditioned media (CM) were collected after 48h. Physiological villous explants (n = 60) were treated for 72h with normal or PE-PDMSCs CM. Explants viability was assessed by Lactate Dehydrogenase Cytotoxicity assay. Cyclin D1 localization was evaluated by Immuofluorescence (IF) while JunB, Cyclin-D1 p16INK4A, p18INK4C, CDK4 and CDK6 levels were assessed by Real Time PCR and Western Blot assay. We reported significantly increased p16INK4A and p18INK4C expression in PE- relative to normal PDMSCs while no differences in CDK4 and CDK6 levels were detected. Explants viability was not affected by normal or PE-PDMSCs CM. Normal PDMSCs CM increased JunB, p16INK4 and p18INK4C and decreased Cyclin-D1 in placental tissues. In contrast, PE-PDMSCs CM induced JunB downregulation and Cyclin D1 increase in placental explants. Cyclin D1 IF staining showed that CM treatment targeted mainly the syncytiotrophoblast. We showed Cyclin D1-p16INK4A/p18INK4C altered pathway in PE-PDMSCs demonstrating an aberrant G1/S phase transition in these pathological cells. The abnormal Cyclin D1-p16INK4A/p18INK4C expression in explants conditioned by PE-PDMSCs media suggest a key contribution of mesenchymal cells to the altered trophoblast cell cycle regulation typical of PE pregnancies with fetal-placental compromise.

Purpose: To estimate the impact of increasing pre-pregnancy Body Mass Index (BMI) on the risk of adverse maternal and perinatal outcomes, in patients who delivered in an Italian tertiary care Obstetric department. Methods: Data, related to women who delivered at Sant’Anna Hospital, Turin, between 2011 and 2015, were collected retrospectively from the hospital database. According to BMI, women were considered as normal weight, overweight, and class 1, 2 and 3 obese (WHO criteria). Logistic regression analysis studied the impact of BMI on maternal and neonatal outcomes, adjusting results for maternal age and parity. Adjusted absolute risks of each outcome were reported according to incremental values in pre-pregnancy BMI. Results: A total of 27,807 women were included. 75.8% of pregnancies occurred among normal-weight women, whereas 16.7% were overweight, and 7.5% obese women (5.4% class 1, 1.7% class 2 and 0.4% class 3). A 10% decrease in pre-pregnancy BMI was associated with a reduction of at least 15% of Gestational diabetes mellitus (GDM), preeclampsia, maternal admission to intensive care unit (ICU), macrosomia, APGAR 5′ < 6 and neonatal admission to ICU. GDM and preeclampsia resulted in the highest reduction being almost 30%. Larger differences in BMI (20–25%) corresponded to at least a 10% in reduction of risk of preterm and very preterm delivery and emergency cesarean section. Differences in maternal pre-pregnancy BMI had no impact on the frequency of shoulder dystocia and stillbirth. Conclusions: This study offers a quantitative estimation of negative impact of pre-pregnancy obesity on the most common pregnancy and perinatal complications.

Key points Exposure to chronic hypoxia during gestation influences long‐term health and development, including reproductive capacity, across generations.If the peri‐conceptual environment in the developing oviduct is affected by gestational hypoxia, then this could have implications for later fertility and the health of future generations.In the present study, we show that the oviducts of female rats exposed to chronic hypoxia in utero have reduced telomere length, decreased mitochondrial DNA biogenesis and increased oxidative stressThe results of the present study show that exposure to chronic gestational hypoxia leads to accelerated ageing of the oviduct in early adulthood and they help us understand how exposure to hypoxia during development could influence reproductive health across generations. Abstract Exposure to chronic hypoxia during fetal development has important effects on immediate and long‐term outcomes in offspring. Adverse impacts in adult offspring include impairment of cardiovascular function, metabolic derangement and accelerated ovarian ageing. However, it is not known whether other aspects of the female reproductive system may be similarly affected. In the present study, we examined the impact of chronic gestational hypoxia on the developing oviduct. Wistar rat dams were randomized to either normoxia (21%) or hypoxia (13%) from day 6 post‐mating until delivery. Post‐delivery female offspring were maintained in normoxia until 4 months of age. Oviductal gene expression was assayed at the RNA (quantitative RT‐PCR) and protein (western blotting) levels. Oviductal telomere length was assayed using Southern blotting. Oviductal telomere length was reduced in the gestational hypoxia‐exposed animals compared to normoxic controls (P, Key points Exposure to chronic hypoxia during gestation influences long‐term health and development, including reproductive capacity, across generations.If the peri‐conceptual environment in the developing oviduct is affected by gestational hypoxia, then this could have implications for later fertility and the health of future generations.In the present study, we show that the oviducts of female rats exposed to chronic hypoxia in utero have reduced telomere length, decreased mitochondrial DNA biogenesis and increased oxidative stressThe results of the present study show that exposure to chronic gestational hypoxia leads to accelerated ageing of the oviduct in early adulthood and they help us understand how exposure to hypoxia during development could influence reproductive health across generations.

This prospective observational study aimed to evaluate whether women with SARS-CoV-2 infection during the first trimester of pregnancy are at higher risk of noninvasive prenatal screening test alterations and/or of congenital fetal anomalies at the second-trimester fetal anatomy scan. Maternal symptoms were secondly investigated. The study was carried out on 12-week pregnant women admitted for noninvasive prenatal testing (16 April and 22 June 2020). The cohort had seromolecular tests for SARS-CoV-2, after which they were divided into a positive case group and a negative control group. Both groups had 20-week ultrasound screening. Seventeen out of the 164 women tested positive for SARS-CoV-2 (10.3%). There were no significant differences in mean nuchal translucency thickness or biochemical markers (pregnancy-associated plasma protein A, alpha-fetoprotein, human chorionic gonadotropin, unconjugated estriol) between cases and controls (p = 0.77, 0.63, 0.30, 0.40, 0.28) or in the fetal incidence of structural anomalies at the second-trimester fetal anatomy scan (p = 0.21). No pneumonia or hospital admission due to COVID-19-related symptoms were observed. Asymptomatic or mildly symptomatic SARS-CoV-2 infection during the first trimester of pregnancy did not predispose affected women to more fetal anomalies than unaffected women. COVID-19 had a favorable maternal course at the beginning of pregnancy in our healthy cohort.

Matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) need to be finely modulated in physiological processes. However, oxygen tension influences MMP/TIMP balances, potentially leading to pathology. Intriguingly, new 2H,3H-decafluoropentane-based oxygen-loaded nanodroplets (OLNDs) have proven effective in abrogating hypoxia-dependent dysregulation of MMP and TIMP secretion by single cell populations. This work explored the effects of different oxygen tensions and dextran-shelled OLNDs on MMP/TIMP production in an organized and multicellular tissue (term human placenta). Chorionic villous explants from normal third-trimester pregnancies were incubated with/without OLNDs in 3 or 20% O2. Explants cultured at higher oxygen tension released constitutive proMMP-2, proMMP-9, TIMP-1, and TIMP-2. Hypoxia significantly altered MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios enhancing TIMP-2 and reducing proMMP-2, proMMP-9, and TIMP-1 levels. Intriguingly, OLNDs effectively counteracted the effects of low oxygen tension. Collectively, these data support OLND potential as innovative, nonconventional, and cost-effective tools to counteract hypoxia-dependent dysregulation of MMP/TIMP balances in human tissues.

Context The von Hippel Lindau (VHL) protein is a key executor of the cellular hypoxic response that is compromised in preeclampsia, a serious disorder complicating 5% to 7% of pregnancies. To date, the mechanisms controlling VHL gene expression in the human placenta remain elusive. Objective We examined VHL epigenetic regulation in normal pregnancy and in preeclampsia, a pathology characterized by placental hypoxia. Design, Setting, and Participants Placentae were obtained from early-onset preeclampsia (n = 56; Main Outcome Measure(s) We measured the activity of Jumonji domain containing protein 6 (JMJD6), a ferrous iron (Fe2+)– and oxygen-dependent histone demethylase, and examined its function in the epigenetic control of VHL. Results JMJD6 regulates VHL gene expression in the human placenta. VHL downregulation in preeclampsia is dependent on decreased JMJD6 demethylase activity due to hypoxia and reduced Fe2+ bioavailability. Chromatin immunoprecipitation assays revealed decreased association of JMJD6 and its histone targets with the VHL promoter. Findings in preeclampsia were corroborated in a murine model of pharmacological hypoxia using FG-4592. Placentae from FG-4592–treated mice exhibited reduced VHL levels, accompanied by placental morphological alterations and reduced pup weights. Notably, Fe2+ supplementation rescued JMJD6 histone demethylase activity in histone from E-PE and FG-4592–treated mice. Conclusions Our study uncovers epigenetic regulation of VHL and its functional consequences for altered oxygen and iron homeostasis in preeclampsia.

Background The correlation between advanced or proteinuric chronic kidney disease (CKD) and adverse pregnancy outcomes is intuitive, although how early CKD affects pregnancy remains unknown. Glomerular hyperfiltration is a physiological response to pregnancy, correlated with outcomes in hypertension or collagen diseases. The aim of the study was to correlate first trimester hyperfiltration with pregnancy outcomes in stage 1 CKD patients. Methods A historical prospective study was conducted on the database of our Unit, gathering all pregnant CKD patients referred since 1 January 2000. From 383 pregnancies referred in 2000–2013, 75 patients were selected (stage 1 CKD, referred within the 14th gestational week, singleton deliveries, absence of diabetes, hypertension or nephrotic proteinuria at referral, body mass index [BMI]

Preeclampsia (PE), an hypertensive disorder of pregnancy, exhibits increased circulating levels of a short form of the auxillary TGF-beta (TGFB) receptor endoglin (sENG). Until now, its release and functionality in PE remains poorly understood. Here we show that ENG selectively interacts with sphingomyelin(SM)-18:0 which promotes its clustering with metalloproteinase 14 (MMP14) in SM-18:0 enriched lipid rafts of the apical syncytial membranes from PE placenta where ENG is cleaved by MMP14 into sENG. The SM-18:0 enriched lipid rafts also contain type 1 and 2 TGFB receptors (TGFBR1 and TGFBR2), but not soluble fms-like tyrosine kinase 1 (sFLT1), another protein secreted in excess in the circulation of women with PE. The truncated ENG is then released into the maternal circulation via SM-18:0 enriched exosomes together with TGFBR1 and 2. Such an exosomal TGFB receptor complex could be functionally active and block the vascular effects of TGFB in the circulation of PE women.

Introduction In the present study, we characterized the expression of Activating Protein 1 (AP-1) factors, key cell cycle regulators, in primary placental mesenchymal stromal cells (PDMSCs) derived from normal and preeclamptic (PE) pregnancies with fetal-placental compromise. Methods PDMSCs were isolated from control ( n = 20) and preeclamptic ( n = 24) placentae. AP-1 expression was determined by semi-quantitative RT-PCR (sqRT-PCR), Real Time PCR and Western Blot assay. PDMSCs were plated and JunB siRNA was performed. JunB and Cyclin-D1 expression were assessed by Real Time and Western Blot analyses. Results JunB expression was significantly increased while Cyclin-D1 expression was significantly down-regulated in PE relative to control PDMSCs. JunB siRNA was accompanied by JunB down-regulation and increased Cyclin-D1 in normal PDMSCs. Conclusions We described, for the first time, AP-1 expression in PDMSCs derived from physiological and PE placentae. Importantly, we demonstrated that JunB over-expression in PE-PDMSCs affects Cyclin-D1 regulation. Our data suggest a possible contribution of these pathological placental cells to the altered cell cycle regulation typical of preeclamptic placentae.

Macrophage migration inhibitory factor (MIF) plays a pivotal role in pregnancy-related proinflammatory processes, such as placentation and labor. Differential MIF concentrations have been correlated with pathological events during pregnancy, such as recurrent miscarriages and severe pre-eclampsia (PE). The aim of this study was to prospectively investigate whether maternal MIF serum levels are already altered in early pregnancy before PE onset. Women (n=2,821) before 20 weeks of gestational age were recruited for a prospective study on early markers of PE. Forty-eight consecutive pregnancies that developed PE and 79 normotensive pregnancies that delivered at term were chosen. Maternal MIF serum levels were assessed by ELISA. We found significantly lower MIF serum levels in women who developed PE (4,967 ± 3,119 pg/mL) compared to controls (7,640 ± 5,519 pg/mL) (mean ± standard deviation, P0.001). Our findings indicate that low maternal MIF serum levels in early pregnancy may contribute to abnormal placental development.

To determine whether normal human amnion-derived mesenchymal stromal cells (hAMSCs) secrete trophic mediators able to inhibit human prostate cancer cell lines growth.Human prostate cancer and normal cell lines were used. Mesenchymal stromal cells (MSC) were isolated through mechanical and enzymatic digestion from amniotic membranes and were evaluated for specific mesenchymal stromal cells antigens. Cell proliferation was examined by MTT assay. Staining with propidium iodide (PI) followed by flow cytometry was used to detect cell cycle phase.hAMSC showed proper mesenchymal stem cells phenotype. We found that hAMSC conditioned media (CM) inhibited prostate cancer cells proliferation. Indeed, we demonstrated that hAMSC CM treatment increased percentage of G1 cancer cells and decreased percentage of cancer cells in S and G2M phases, suggesting that the hAMSC factors slow progression of prostate cancer cells through cell cycle inhibition.Our study provide evidences that hAMSC microenvironment secretes soluble factors able to inhibit prostate cancer cells growth. This may represent a novel strategy to control proliferation of prostate cancer through modulation of the host microenvironment.

BACKGROUND: In the last decade, significant improvements have been achieved in maternal-fetal and diabetic care which make pregnancy possible in an increasing number of type 1 diabetic women with end-organ damage. Optimal counseling is important to make the advancements available to the relevant patients and to ensure the safety of mother and child. A systematic review will help to provide a survey of the available methods and to promote optimal counseling. OBJECTIVES: To review the literature on diabetic nephropathy and pregnancy in type 1 diabetes. METHODS: Medline, Embase, and the Cochrane Library were scanned in November 2012 (MESH, Emtree, and free terms on pregnancy and diabetic nephropathy). Studies were selected that report on pregnancy outcomes in type 1 diabetic patients with diabetic nephropathy in 1980-2012 (i.e. since the detection of microalbuminuria). Case reports with less than 5 cases and reports on kidney grafts were excluded. Paper selection and data extraction were performed in duplicate and matched for consistency. As the relevant reports were highly heterogeneous, we decided to perform a narrative review, with discussions oriented towards the period of publication. RESULTS: Of the 1058 references considered, 34 fulfilled the selection criteria, and one was added from reference lists. The number of cases considered in the reports, which generally involved single-center studies, ranged from 5 to 311. The following issues were significant: (i) the evidence is scattered over many reports of differing format and involving small series (only 2 included over 100 patients), (ii) definitions are non-homogeneous, (iii) risks for pregnancy-related adverse events are increased (preterm delivery, caesarean section, perinatal death, and stillbirth) and do not substantially change over time, except for stillbirth (from over 10% to about 5%), (iv) the increase in risks with nephropathy progression needs confirmation in large homogeneous series, (v) the newly reported increase in malformations in diabetic nephropathy underlines the need for further studies. CONCLUSIONS: The heterogeneous evidence from studies on diabetic nephropathy in pregnancy emphasizes the need for further perspective studies on this issue.

BACKGROUND: Diabetes and nephropathy are important challenges during pregnancy, increasingly encountered because of the advances in maternal-fetal care. AIM: To evaluate the maternal and fetal outcomes recorded in "severe" diabetic nephropathy in type 1 diabetic patients referred to nephrological healtcare. METHODS: The study was performed in an outpatient unit dedicated to kidney diseases in pregnancy (with joint nephrological and obstetric follow-up and strict cooperation with the diabetes unit). 383 pregnancies were referred to the outpatient unit in 2000-2012, 14 of which were complicated by type 1 diabetes. The report includes 12 deliveries, including 2 pregnancies in 1 patient; one twin pregnancy; 2 spontaneous abortions were not included. All cases had long-standing type 1 diabetes (median of 21 (15-31) years), relatively high median age (35 (29-40) years) and end-organ damage (all patients presented laser-treated retinopathy and half of them clinical neuropathy). Median glomerular filtration rate (GFR) at referral was 67 ml/min (48-122.6), proteinuria was 1.6 g/day (0.1-6.3 g/day). RESULTS: Proteinuria steeply increased in 11/12 patients, reaching the nephrotic range in nine (6 above 5 g/day). One patient increased by 2 chronic kidney disease (CKD) stages. Support therapy included blood pressure and diabetes control, bed rest, and moderate protein restriction. All children were preterm (7 early preterm); early spontaneous labor occurred in 4/12 patients. All singletons were appropriate for gestational age and developed normally after birth. The male twin child died 6 days after birth (after surgery for great vessel transposition). CONCLUSIONS: Diabetic patients with severe diabetic nephropathy are still present a considerable challenge. Therefore, further investigations are required, particularly on proteinuria management and the occurrence of spontaneous labor.

Background Pre-eclampsia (PE) is a major cause of maternal and perinatal morbidity and mortality worldwide. It is defined by new onset of hypertension and proteinuria after the 20th week of gestation and characterized by systemic exaggerated inflammatory response. D6 is a chemokines scavenger receptor that binds with high affinity CC chemokines, internalizes and targets the ligands for degradation. It is expressed in trophoblast-derived tissues and prevents excessive placenta leukocyte infiltration.The aim of this study was to investigate the expression and function of D6 in human placentae from pre-eclamptic and healthy pregnant women. Methods and Results Plasma levels of D6-binding CC chemokines (CCL-2, CCL-3, CCL-4, CCL-7, CCL-11) and pro-inflammatory cytokines (IL-6, TNF-α, CRP) were analyzed in 37 healthy pregnant women and 38 patients with PE by multiplex bead assay. Higher circulating levels of CCL7, CCL11, IL-6, (p

Pre‐eclampsia (PE) is one of the most severe syndromes in human pregnancy, and the underlying mechanisms of PE have yet to be determined. Pre‐eclampsia is characterized by the alteration of the immune system's activation status, an increase in inflammatory Th1/Th17/APC cells, and a decrease in Th2/Treg subsets/cytokines. Moreover, inflammatory infiltrates have been detected in the amniotic membranes of pre‐eclamptic placentae, and to this date limited data are available regarding the role of amniotic membrane cells in PE. Interestingly, we and others have previously shown that human amniotic mesenchymal stromal cells (hAMSC) possess anti‐inflammatory properties towards almost all immune cells described to be altered in PE. In this study we investigated whether the immunomodulatory properties of hAMSC were altered in PE. We performed a comprehensive study of cell phenotype and investigated the in vitro immunomodulatory properties of hAMSC isolated from pre‐eclamptic pregnancies (PE‐hAMSC), comparing them to hAMSC from normal pregnancies (N‐hAMSC). We demonstrate that PE‐hAMSC inhibit CD4/CD8 T‐cell proliferation, suppress Th1/Th2/Th17 polarization, induce Treg and block dendritic cells and M1 differentiation switching them to M2 cells. Notably, PE‐hAMSC generated a more prominent induction of Treg and higher suppression of interferon‐γ when compared to N‐hAMSC, and this was associated with higher transforming growth factor‐β1 secretion and PD‐L2/PD‐L1 expression in PE‐hAMSC. In conclusion, for the first time we demonstrate that there is no intrinsic impairment of the immunomodulatory features of PE‐hAMSC. Our results suggest that amniotic mesenchymal stromal cells do not contribute to the disease, but conversely, could participate in offsetting the inflammatory environment which characterizes PE.

There is evidence that alpha-smooth muscle actin (alpha-SMA) is a protein that plays a pivotal role in the production of contractile forces and it is induced by transforming growth factor-beta1 (TGF-beta1). We have analysed the expression of alpha-SMA, TGF-beta1, its receptor RI and the activator phospho-Smad2 in (a) fetal growth restriction pre-eclamptic placentae characterised by early onset and absence of end diastolic velocities in the umbilical arteries (FGR-AED) and (b) control placentae accurately matched for gestational age. The study was performed by immunohistochemical, quantitative Western blotting, ELISA, RT-PCR and in vitro analyses. We found that TGF-beta1 stimulates alpha-SMA production in chorionic villi cultured in vitro. In addition, we observed that in vivo TGF-beta1 concentration is significantly higher in FGR-AED placental samples than in control placentae and that this growth factor could have a paracrine action on villous stroma myofibroblasts expressing TGF-beta1 receptors and phospho-Smad2. Indeed, we report that alpha-SMA undergoes a redistribution in FGR-AED placental villous tree, i.e. we show that alpha-SMA is enhanced in medium and small stem villi and significantly decreased in the peripheral villi. Our data allow us to consider TGF-beta1 and alpha-SMA as key molecules related to FGR-AED placental villous tree phenotypic changes responsible for increased impedance to blood flow observable in this pathology.

Objective. Chronic kidney disease (CKD) and preeclampsia (PE) may both present with hypertension and proteinuria in pregnancy. Our objective is to test the possibility of distinguishing CKD from PE by means of uteroplacental flows and maternal circulating sFlt-1/PlGF ratio.Design. Prospective analysis.Population. Seventy-six patients (35 CKD, 24 PE, and 17 other hypertensive disorders), with at least one sFlt-1/PlGF and Doppler evaluation after the 20th gestational week.Methods. Maternal sFlt-1-PlGF were determined by immunoassays. Abnormal uterine artery Doppler was defined as resistance index ≥ 0.58. Umbilical Doppler was defined with gestational-age-adjusted Pulsatility Index. Clinical diagnosis was considered as reference. Performance of Doppler study was assessed by sensitivity analysis; sFlt-1/PlGF cut-off values were determined by ROC curves.Results. The lowest sFlt-1/PlGF ratio (8.29) was detected in CKD, the highest in PE (317.32) (P<0.001). Uteroplacental flows were mostly preserved in CKD patients in contrast to PE (P<0.001). ROC analysis suggested two cut-points: sFlt-1/PlGF ≥ 32.81 (sensitivity 82.93%; specificity 91.43%) and sFlt-1/PlGF ≥ 78.75 (sensitivity 62.89%, specificity 97.14%). Specificity reached 100% at sFlt-1/PlGF ≥ 142.21 (sensitivity: 48.8%). Early-preterm delivery was associated with higher sFlt-1/PlGF ratio and abnormal uteroplacental flows relative to late-preterm and term deliveries.Conclusions. sFlt-1/PlGF ratio and uteroplacental flows significantly correlated with PE or CKD and preterm delivery.

BACKGROUND Advances have been made in the management of pregnancies in women receiving dialysis; however, single-centre studies and small numbers of cases have so far precluded a clear definition of the relationship between dialysis schedules and pregnancy outcomes. The aim of the present systematic review was to analyse the relationship between dialysis schedule and pregnancy outcomes in pregnancies in chronic dialysis in the new millennium. METHODS Medline-PubMed, Embase and the Cochrane library were searched (1 January 2000-31 December 2014: MESH, Emtree, free terms on pregnancy and dialysis). A separate analysis was performed for case series (more than five cases) and case reports. Meta-regression was performed in case series dealing with the larger subset of haemodialysis (HD) patients; case reports were analysed separately [according to peritoneal dialysis (PD) versus HD; conception before or during dialysis]. RESULTS We obtained 190 full texts and 25 congress abstracts from 2048 references. We selected 101 full papers and 25 abstracts (36 series; 90 case reports), for a total of 681 pregnancies in 647 patients. In the case series (574 pregnancies in 543 patients), preterm delivery was extremely frequent (83%). Meta-regression analysis showed a relationship between hours of dialysis per week in HD and preterm delivery, and was significant for preterm deliveries (

Human placental mesenchymal stromal cells (pMSCs) have never been investigated in intrauterine growth restriction (IUGR). We characterized cells isolated from placental membranes and the basal disc of six IUGR and five physiological placentas. Cell viability and proliferation were assessed every 7 days during a 6-week culture. Expression of hematopoietic, stem, endothelial, and mesenchymal markers was evaluated by flow cytometry. We characterized the multipotency of pMSCs and the expression of genes involved in mitochondrial content and function. Cell viability was high in all samples, and proliferation rate was lower in IUGR compared with control cells. All samples presented a starting heterogeneous population, shifting during culture toward homogeneity for mesenchymal markers and occurring earlier in IUGR than in controls. In vitro multipotency of IUGR-derived pMSCs was restricted because their capacity for adipocyte differentiation was increased, whereas their ability to differentiate toward endothelial cell lineage was decreased. Mitochondrial content and function were higher in IUGR pMSCs than controls, possibly indicating a shift from anaerobic to aerobic metabolism, with the loss of the metabolic characteristics that are typical of undifferentiated multipotent cells. Significance This study demonstrates that the loss of endothelial differentiation potential and the increase of adipogenic ability are likely to play a significant role in the vicious cycle of abnormal placental development in intrauterine growth restriction (IUGR). This is the first observation of a potential role for placental mesenchymal stromal cells in intrauterine growth restriction, thus leading to new perspectives for the treatment of IUGR.

Apelin peptide is a ligand of the G protein coupled receptor (GPCR) APJ. Apelin-13 (Ape) is the most active isoform on the cardiovascular system, where it exerts positive inotropy and vasodilation. It also mimics ischemic postconditioning (IPost) against ischemia–reperfusion (I/R) injury. Protection is caused by NO after phosphatidylinositol 3-kinase (PI3K)-Akt activation. Various GPCRs activate PI3K-Akt via epidermal growth factor receptor (EGFR) transactivation by ligand-dependent and -independent pathways, the former due to the shedding of epidermal growth factor (EGF)-like ligands by matrix metalloproteinase (MMP), the latter to the nonreceptor tyrosine kinase Src. We investigated the main steps of the pathway of Apeinduced cardioprotection focusing the attention on a possible role of EGFR transactivation.

Chronic kidney disease (CKD) is increasingly encountered in pregnancy because of greater diagnostic awareness, which is a reflection of the newer, broader definitions (i.e., any changes in blood or urine composition or at imaging, or a glomerular filtration rate (GFR) of60 mL/min lasting at least 3 months) and of increased incidence (higher maternal age and better outcomes of several kidney diseases). CKD is extremely heterogeneous and may be described by the degree of GFR reduction (CKD stages), the presence of proteinuria and hypertension and the type of kidney disease; the risk of adverse pregnancy-related events increases as GFR decreases and it is affected by proteinuria and hypertension. Specific risks are reported in various diseases such as lupus nephropathy or diabetic nephropathy. While transplantation at least partially restores fertility in end-stage kidney disease, pregnancy on dialysis is increasingly reported. This chapter deals with the available evidence on the management of CKD patients in pregnancy.

OBJECTIVES Pre-eclampsia (PE) is characterized by an excess of inflammation and endothelial dysfunction. Helicobacter pylori (H. pylori) causes chronic inflammatory changes and endothelial damage. We investigated the prevalence of seropositivity for IgG against H. pylori and cytotoxin-associated antigen A (CagA) in PE patients and the presence of H. pylori DNA in their placentas. METHODS We tested 47 pregnant women with PE and 47 with uneventful pregnancies for serum antibodies against H. pylori (enzyme immunoassays) and CagA protein (immunoblot assays). In 20 of them (10 normal and 10 PE) we assessed the presence, in the placenta, of H. pylori DNA by means of nested polymerase chain reaction (PCR). The odds ratios (OR) and 95% confidence intervals (CI), adjusted for parity, were calculated using logistic regression analysis to assess the risk of PE associated with H. pylori infection. RESULTS Helicobacter pylori seropositivity frequency was higher in mothers with PE (51.1%) compared to women with uneventful pregnancy (31.9%) (OR, 2.668; 95% CI, 1.084-6.566; P = 0.033). The difference was even greater for CagA seropositivity (80.9 and 14.9%, respectively) (OR, 26.035; 95% CI, 8.193-82.729; P < 0.001). All placentas were negative for H. pylori DNA. CONCLUSIONS Helicobacter pylori, and especially strains carrying the CagA gene, may contribute to the inflammatory mechanisms involved in the pathogenesis of PE.