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Recurrent pregnancy loss (RPL) refers to two or more miscarriages before 20 weeks gestation. Its prevalence is 1–2%; its pathogenesis remains unexplained in more than 50% of cases, in which the cause is thought to be abnormal immune activity during placentation leading to a lack of pregnancy-induced immune tolerance. It is unknown whether immune activity is deranged in the endometrium of women with RPL. We studied the gene expression and the quantitative tissue protein levels of three immune checkpoints (CD276, which enhances cytotoxic T-cell activity, cytotoxic T-lymphocyte-associated antigen-4 [CTL-4], which reduces Th1 cytokine production, and lymphocyte activation gene-3 [LAG-3], which shows suppressive activity on Tregs and CD4+ T-cells) in endometrial samples from 27 women with unexplained RPL and in 29 women with dysfunctional uterine bleeding and previous uneventful pregnancies as controls. RNA isolation, real-time PCR, protein isolation, and ELISA were performed. CD276 gene expression and protein tissue levels were significantly lower in the endometrium of the RPL group than in the controls, whereas both CTL-4 and LAG-3 were significantly higher. This difference suggests defective endometrial immune regulation and overactivation of immune response in women with a history of RPL, at least in relation to controls with dysfunctional uterine bleeding and previous normal reproductive history. [ABSTRACT FROM AUTHOR]

Despite Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) -induced Oxidative Stress (OxS) being well documented in different organs, the molecular pathways underlying placental OxS in late-pregnancy women with SARS-CoV-2 infection are poorly understood. Herein, we performed an observational study to determine whether placentae of women testing positive for SARS-CoV-2 during the third trimester of pregnancy showed redox-related alterations involving Catalase (CAT) and Superoxide Dismutase (SOD) antioxidant enzymes as well as placenta morphological anomalies relative to a cohort of healthy pregnant women. Next, we evaluated if placental redox-related alterations and mitochondria pathological changes were correlated with the presence of maternal symptoms. We observed ultrastructural alterations of placental mitochondria accompanied by increased levels of oxidative stress markers Thiobarbituric Acid Reactive Substances (TBARS) and Hypoxia Inducible Factor-1 α (HIF-1α) in SARS-CoV-2 women during the third trimester of pregnancy. Importantly, we found an increase in placental CAT and SOD antioxidant enzymes accompanied by physiological neonatal outcomes. Our findings strongly suggest a placenta-mediated OxS inhibition in response to SARS-CoV-2 infection, thus contrasting the cytotoxic profile caused by Coronavirus Disease 2019 (COVID-19). [ABSTRACT FROM AUTHOR]

In healthy pregnancy, glucose and oxygen availability are essential for fetal growth and well being. However, how substrate delivery and fetal uptake are affected in human pregnancy complicated by fetal growth restriction (FGR) is still unknown. Here, we show that the human FGR fetus has a strikingly reduced umbilical uptake of both oxygen and glucose. In 30 healthy term and 32 FGR human pregnancies, umbilical volume flow (Qumb) and parallel umbilical vein (uv) and artery (ua) blood samples were obtained at elective Cesarean section to calculate fetal glucose and oxygen uptake as Qumb · Δ (uv-ua) differences. Umbilical blood flow was significantly lower in FGR pregnancy (-63%; P<0.001) but not when normalized for fetal body weight. FGR pregnancy had significantly lower umbilical oxygen delivery and uptake, both as absolute values (delivery: -78%; uptake: -78%) and normalized (delivery: -50%; uptake: -48%) for fetal body weight (all P<0.001). Umbilical glucose absolute delivery and uptake were significantly reduced (delivery: -68%; uptake: -72%) but only glucose uptake was decreased when normalized for fetal body weight (-30%; P<0.05). The glucose/oxygen quotient was significantly increased (+100%; P<0.05) while glucose clearance was significantly decreased (71%; P<0.001) in FGR pregnancy (both P<0.05). The human fetus in FGR pregnancy triggers compensatory mechanisms to reduce its metabolic rate, matching the proportion of substrate consumption relative to oxygen delivery as a survival strategy during complicated pregnancy. [ABSTRACT FROM AUTHOR]

: The objective of the present study was to evaluate whether placental mesenchymal stromal cells (PDMSCs) derived from normal and preeclamptic (PE) chorionic villous tissue presented differences in their cytokines expression profiles. Moreover, we investigated the effects of conditioned media from normal and PE-PDMSCs on the expression of pro-inflammatory Macrophage migration Inhibitory Factor (MIF), Vascular Endothelial Growth Factor (VEGF), soluble FMS-like tyrosine kinase-1 (sFlt-1) and free β-human Chorionic Gonadotropin (βhCG) by normal term villous explants. This information will help to understand whether anomalies in PE-PDMSCs could cause or contribute to the anomalies typical of preeclampsia. Methods: Chorionic villous PDMSCs were isolated from severe preeclamptic (n = 12) and physiological control term (n = 12) placentae. Control and PE-PDMSCs’s cytokines expression profiles were determined by Cytokine Array. Control and PE-PDMSCs were plated for 72 h and conditioned media (CM) was collected. Physiological villous explants (n = 48) were treated with control or PE-PDMSCs CM for 72 h and processed for mRNA and protein isolation. MIF, VEGF and sFlt-1 mRNA and protein expression were analyzed by Real Time PCR and Western Blot respectively. Free βhCG was assessed by immunofluorescent. Results: Cytokine array showed increased release of pro-inflammatory cytokines by PE relative to control PDMSCs. Physiological explants treated with PE-PDMSCs CM showed significantly increased MIF and sFlt-1 expression relative to untreated and control PDMSCs CM explants. Interestingly, both control and PE-PDMSCs media induced VEGF mRNA increase while only normal PDMSCs media promoted VEGF protein accumulation. PE-PDMSCs CM explants released significantly increased amounts of free βhCG relative to normal PDMSCs CM ones. Conclusions: Herein, we reported elevated production of pro-inflammatory cytokines by PE-PDMSCs. Importantly, PE PDMSCs induced a PE-like phenotype in physiological villous explants. Our data clearly depict chorionic mesenchymal stromal cells as central players in placental physiopathology, thus opening to new intriguing perspectives for the treatment of human placental-related disorders as preeclampsia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]