A Novel Predictive Machine Learning Model Integrating Cytokines in Cervical-Vaginal Mucus Increases the Prediction Rate for Preterm Birth.

Preterm birth (PB) is a leading cause of perinatal morbidity and mortality. PB prediction is performed by measuring cervical length, with a detection rate of around 70%. Although it is known that a cytokine-mediated inflammatory process is involved in the pathophysiology of PB, none screening method implemented in clinical practice includes cytokine levels as a predictor variable. Here, we quantified cytokines in cervical-vaginal mucus of pregnant women (18-23.6 weeks of gestation) with high or low risk for PB determined by cervical length, also collecting relevant obstetric information. IL-2, IL-6, IFN-γ, IL-4, and IL-10 were significantly higher in the high-risk group, while IL-1ra was lower. Two different models for PB prediction were created using the Random Forest machine-learning algorithm: a full model with 12 clinical variables and cytokine values and the adjusted model, including the most relevant variables-maternal age, IL-2, and cervical length- (detection rate 66 vs. 87%, false positive rate 12 vs. 3.33%, false negative rate 28 vs. 6.66%, and area under the curve 0.722 vs. 0.875, respectively). The adjusted model that incorporate cytokines showed a detection rate eight points higher than the gold standard calculator, which may allow us to identify the risk PB risk more accurately and implement strategies for preventive interventions.

Regulation of MMP-2 by IL-8 in Vascular Endothelial Cells: Probable Mechanism for Endothelial Dysfunction in Women with Preeclampsia.

Endothelial dysfunction (ED) in preeclampsia (PE) results from the convergence of oxidative stress, inflammation, and alterations in extracellular matrix components, affecting vascular tone and permeability. The molecular network leading to ED includes IL-8 and MMP-2. In vitro, IL-8 regulates the concentration and activity of MMP-2 in the trophoblast; this interaction has not been studied in endothelial cells during PE. We isolated human umbilical vein endothelial cells (HUVECs) from women with healthy pregnancies (NP, n = 15) and PE (n = 15). We quantified the intracellular concentration of nitric oxide and reactive oxygen species with colorimetric assays, IL-8 with ELISA, and MMP-2 with zymography and using an ELISA-type system. An IL-8 inhibition assay was used to study the influence of this cytokine on MMP-2 concentration and activity. HUVECs from women with PE showed significantly higher oxidative stress than NP. IL-8 and MMP-2 were found to be significantly elevated in PE HUVECs compared to NP. Inhibition of IL-8 in HUVECs from women with PE significantly decreased the concentration of MMP-2. We demonstrate that IL-8 is involved in the mechanisms of MMP-2 expression in HUVECs from women with PE. Our findings provide new insights into the molecular mechanisms regulating the ED distinctive of PE.

Critical windows of perinatal particulate matter (PM2.5) exposure and preadolescent kidney function.

Air pollution exposure, especially particulate matter ≤2.5 µm in diameter (PM2.5), is associated with poorer kidney function in adults and children. Perinatal exposure may occur during susceptible periods of nephron development. We used distributed lag nonlinear models (DLNMs) to examine time-varying associations between early life daily PM2.5 exposure (periconceptional through age 8 years) and kidney parameters in preadolescent children aged 8-10 years. Participants included 427 mother-child dyads enrolled in the PROGRESS birth cohort study based in Mexico City. Daily PM2.5 exposure was estimated at each participant's residence using a validated satellite-based spatio-temporal model. Kidney function parameters included estimated glomerular filtration rate (eGFR), serum cystatin C, and blood urea nitrogen (BUN). Models were adjusted for child's age, sex and body mass index (BMI) z-score, as well as maternal education, indoor smoking report and seasonality (prenatal models were additionally adjusted for average first year of life PM2.5 exposure). We also tested for sex-specific effects. Average perinatal PM2.5 was 22.7 µg/m3 and ranged 16.4-29.3 µg/m3. Early pregnancy PM2.5 exposures were associated with higher eGFR in preadolescence. Specifically, we found that PM2.5 exposure between weeks 1-18 of gestation was associated with increased preadolescent eGFR, whereas exposure in the first 14 months of life after birth were associated with decreased eGFR. Specifically, a 5 µg/m3 increase in PM2.5 during the detected prenatal window was associated with a cumulative increase in eGFR of 4.44 mL/min/1.732 (95%CI: 1.37, 7.52), and during the postnatal window we report a cumulative eGFR decrease of -10.36 mL/min/1.732 (95%CI: -17.68, -3.04). We identified perinatal windows of susceptibility to PM2.5 exposure with preadolescent kidney function parameters. Follow-up investigating PM2.5 exposure with peripubertal kidney function trajectories and risk of kidney disease in adulthood will be critical.

Markers of oxidative stress in postmenopausal women with metabolic syndrome.

During the postmenopausal period, there are metabolic alterations that predispose individuals to metabolic syndrome (MS), oxidative stress (OS), and the risk of developing cardiovascular diseases. We aimed to compare the concentrations of OS markers in postmenopausal women with and without MS. Malondialdehyde, carbonyl groups, and total antioxidant capacity (TAC) were quantified. We conducted a cross-sectional study: Group 1 (n = 42) included women without MS, and Group 2 (n = 58) comprised women with MS. Participants' age was similar between groups. Glucose, insulin, the homeostasis model assessment of insulin resistance, triglycerides, uric acid, and body mass index were significantly lower in postmenopausal women without MS. OS markers were significantly lower in Group 1 vs. Group 2: malondialdehyde, 31.32 ± 14.93 vs. 40.27 ± 17.62 pmol MDA/mg dry weight (p = .01); protein carbonylation, 6325 ± 1551 vs. 7163 ± 1029 pmol PC/mg protein (p = .0003); and TAC, 1497 ± 297.3 vs. 1619 ± 278.8 pmol Trolox equivalent/mg protein (p = .041). OS markers were significantly higher in postmenopausal women with MS. Impact statementWhat is already known on this subject? Oxidative stress has been implicated in numerous disease processes; however, information on the relationship between oxidative stress and metabolic syndrome among postmenopausal women remains limited.What do the results of this study add? Our results indicate that in postmenopausal Mexican women, oxidative stress markers were significantly lower in those without metabolic syndrome, whereas total antioxidant capacity was higher in those with metabolic syndrome, which could be explained as an antioxidant defense mechanism capable of neutralising excess oxidative damage markers.What are the implications of these findings for clinical practice and/or further research? This study is of interest to a broad audience because it compares the concentrations of oxidative stress markers in postmenopausal women with and without metabolic syndrome. Our study could support intervention with supplements or foods rich in antioxidants as lifestyle modifications in postmenopausal women with metabolic syndrome.

Oxidative stress biomarkers and their relationship with cytokine concentrations in overweight/obese pregnant women and their neonates.

BACKGROUND: Oxidative damage present in obese/overweight mothers may lead to further oxidative stress conditions or inflammation in maternal and cord blood samples. Thirty-four pregnant women/newborn pairs were included in this study to assess the presence of oxidative stress biomarkers and their relationship with serum cytokine concentrations. Oxidative stress biomarkers and antioxidant enzymes were compared between the mother/offspring pairs. The presence of 27 cytokines was measured in maternal and cord blood samples. Analyses were initially performed between all mothers and newborns and later between normal weight and mothers with overweight and obesity, and diabetic/non-diabetic women. RESULTS: Significant differences were found in biomarker concentrations between mothers and newborns. Additionally, superoxide-dismutase activity was higher in pre-pregnancy overweight mothers compared to those with normal weight. Activity for this enzyme was higher in neonates born from mothers with normal pregestational weight compared with their mothers. Nitrites in overweight/obese mothers were statistically lower than in their offspring. Maternal free fatty acids, nitrites, carbonylated proteins, malondialdehyde and superoxide dismutase predicted maternal serum concentrations of IL-4, IL-13, IP-10 and MIP-1ß. Arginase activity in maternal plasma was related to decreased concentrations of IL-4 and IL-1ß in cord arterial blood. Increased maternal malondialdehyde plasma was associated with higher levels of IL-6 and IL-7 in the offspring. CONCLUSIONS: Oxidative stress biomarkers differ between mothers and offspring and can predict maternal and newborn cytokine concentrations, indicating a potential role for oxidative stress in foetal metabolic and immunologic programming. Moreover, maternal obesity and diabetes may affect maternal microenvironments, and oxidative stress related to these can have an impact on the placenta and foetal growth.

Decidualization Mediated by Steroid Hormones Modulates the Innate Immunity in Response to Group B Streptococcal Infection in vitro.

BACKGROUND: Decidual cells play a role in the modulation of the innate immune response to protect pregnancy against infection. Steroid hormones regulate the innate immune response in different tissues, and they are involved in several biological processes like decidualization. The aim of this study was to assess if steroid hormones modulate the innate immunity in endometrial stromal cells (ESCs) and decidual stromal cells (DSCs) in response to group B streptococcus (GBS) infection in vitro. METHODS: Primary cultures of ESC were differentiated into DSC using 36 nM estradiol + 300 nM progesterone, and both were infected with GBS overnight. Concentrations of pro- and anti-inflammatory mediators (interleukin [IL]-1ß, IL-6, tumor necrosis factor [TNF]-α, IL-10, and TGF-ß), chemokines (IL-8 and GCP-2), and human ß-defensins (HBD-1, HBD-2, and HBD-3) were measured in the culture supernatants. RESULTS: DSCs showed a significant increase in IL-6 (p < 0.05), TNF-α (p < 0.05), IL-10 (p < 0.01), and TGF-ß (p < 0.05) secretion after GBS infection, while these changes were not observed in infected ESCs. IL-8 and GCP-2 increased after GBS infection, regardless of decidualization. ß-Defensins 1-3 decreased (p < 0.05) in ESCs after GBS infection, and hormone decidualization preserved the secretion of these antimicrobial peptides. CONCLUSIONS: Decidualization mediated by steroid hormones balance the pro- and anti-inflammatory response at the maternal-fetal interface under infection conditions.

New Insights into the Role of Matrix Metalloproteinases in Preeclampsia.

Preeclampsia is a severe pregnancy complication globally, characterized by poor placentation triggering vascular dysfunction. Matrix metalloproteinases (MMPs) exhibit proteolytic activity implicated in the efficiency of trophoblast invasion to the uterine wall, and a dysregulation of these enzymes has been linked to preeclampsia. A decrease in MMP-2 and MMP-9 interferes with the normal remodeling of spiral arteries at early pregnancy stages, leading to the initial pathophysiological changes observed in preeclampsia. Later in pregnancy, an elevation in MMP-2 and MMP-9 induces abnormal release of vasoactive factors conditioning hypertension. Although these two enzymes lead the scene, other MMPs like MMP-1 and MMP-14 seem to have a role in this pathology. This review gathers published recent evidence about the implications of different MMPs in preeclampsia, and the potential use of these enzymes as emergent biomarkers and biological therapeutic targets, focusing on studies involving human subjects.

An increase in IL-1ß concentrations in embryo culture-conditioned media obtained by in vitro fertilization on day 3 is related to successful implantation.

PURPOSE: This study aimed to evaluate interleukin (IL)-1ß concentrations in maternal serum and in embryo-cultured conditioned media and to correlate these findings with success of implantation. METHODS: A total of 70 infertile women who underwent in vitro fertilization treatment were studied. IL-1ß concentrations were quantified in maternal serum and in embryo culture-conditioned media on days 1 and 3. The findings were compared between those who achieved pregnancy and those who did not. RESULTS: No significant differences were found in IL-1ß serum concentrations between the groups. IL-1ß was not detected in day 1 culture-conditioned medium. On day 3, IL-1ß was quantified in 27 patients, and IL-1ß concentrations were significantly higher in women who achieved pregnancy than in those who did not (p < 0.001). CONCLUSIONS: High IL-1ß concentrations in day 3 culture-conditioned medium in patients who achieve pregnancy after in vitro fertilization treatment indicate a possible role of embryonic IL-1ß in the implantation process.

Isolation of Primary Human Decidual Cells from the Fetal Membranes of Term Placentae.

The maternal decidua is a transient and dynamic tissue that functions as an immunoprivileged matrix related to nutritional and endocrine processes. The function of decidual cells is key to the success of embryo implantation and the maintenance of pregnancy with a positive maternal-fetal outcome. Therefore, establishing a method to optimize the isolation of primary decidual cells is essential. Our protocol described here provides a good yield of decidual cells in an optimized time.

Optimizing perinatal wellbeing in pregnancy with obesity: a clinical trial with a multi-component nutrition intervention for prevention of gestational diabetes and infant growth and neurodevelopment impairment.

Pregnancy complicated by obesity represents an increased risk of unfavorable perinatal outcomes such as gestational diabetes mellitus (GDM), hypertensive disorders in pregnancy, preterm birth, and impaired fetal growth, among others. Obesity is associated with deficiencies of micronutrients, and pregnant women with obesity may have higher needs. The intrauterine environment in pregnancies complicated with obesity is characterized by inflammation and oxidative stress, where maternal nutrition and metabolic status have significant influence and are critical in maternal health and in fetal programming of health in the offspring later in life. Comprehensive lifestyle interventions, including intensive nutrition care, are associated with a lower risk of adverse perinatal outcomes. Routine supplementation during pregnancy includes folic acid and iron; other nutrient supplementation is recommended for high-risk women or women in low-middle income countries. This study is an open label randomized clinical trial of parallel groups (UMIN Clinical Trials Registry: UMIN000052753, https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000060194) to evaluate the effect of an intensive nutrition therapy and nutrient supplementation intervention (folic acid, iron, vitamin D, omega 3 fatty acids, myo-inositol and micronutrients) in pregnant women with obesity on the prevention of GDM, other perinatal outcomes, maternal and newborn nutritional status, and infant growth, adiposity, and neurodevelopment compared to usual care. Given the absence of established nutritional guidelines for managing obesity during pregnancy, there is a pressing need to develop and implement new nutritional programs to enhance perinatal outcomes.

Comparative Infections of Zika, Dengue, and Yellow Fever Viruses in Human Cytotrophoblast-Derived Cells Suggest a Gating Role for the Cytotrophoblast in Zika Virus Placental Invasion.

The Zika virus (ZIKV) is teratogenic and considered a TORCH pathogen (toxoplasmosis [Toxoplasma gondii], rubella, cytomegalovirus, herpes simplex virus [HSV], and other microorganisms capable of crossing the blood-placenta barrier). In contrast, the related flavivirus dengue virus (DENV) and the attenuated yellow fever virus vaccine strain (YFV-17D) are not. Understanding the mechanisms used by ZIKV to cross the placenta is necessary. In this work, parallel infections with ZIKV of African and Asian lineages, DENV, and YFV-17D were compared for kinetics and growth efficiency, activation of mTOR pathways, and cytokine secretion profile using cytotrophoblast-derived HTR8 cells and monocytic U937 cells differentiated to M2 macrophages. In HTR8 cells, ZIKV replication, especially the African strain, was significantly more efficient and faster than DENV or YFV-17D. In macrophages, ZIKV replication was also more efficient, although differences between strains were reduced. Greater activation of the mTORC1 and mTORC2 pathways in HTR8 cells infected with ZIKV than with DENV or YFV-17D was observed. HTR8 cells treated with mTOR inhibitors showed a 20-fold reduction in ZIKV yield, versus 5- and 3.5-fold reductions for DENV and YFV-17D, respectively. Finally, infection with ZIKV, but not DENV or YFV-17D, efficiently inhibited the interferon (IFN) and chemoattractant responses in both cell lines. These results suggest a gating role for the cytotrophoblast cells in favoring entry of ZIKV, but not DENV and YFV-17D, into the placental stroma. IMPORTANCE Zika virus acquisition during pregnancy is associated with severe fetal damage. The Zika virus is related to dengue virus and yellow fever virus, yet fetal damage has not been related to dengue or inadvertent vaccination for yellow fever during pregnancy. Mechanisms used by the Zika virus to cross the placenta need to be deciphered. By comparing parallel infections of Zika virus strains belonging to the African and Asian lineages, dengue virus, and the yellow fever vaccine virus strain YFV-17D in placenta-derived cytotrophoblast cells and differentiated macrophages, evidence was found that Zika virus infections, especially by the African strains, were more efficient in cytotrophoblast cells than dengue virus or yellow fever vaccine virus strain infections. Meanwhile, no significant differences were observed in macrophages. Robust activation of the mTOR signaling pathways and inhibition of the IFN and chemoattractant response appear to be related to the better growth capacity of the Zika viruses in the cytotrophoblast-derived cells.

AI-Enhanced Analysis Reveals Impact of Maternal Diabetes on Subcutaneous Fat Mass in Fetuses without Growth Alterations.

Pregnant women with diabetes often present impaired fetal growth, which is less common if maternal diabetes is well-controlled. However, developing strategies to estimate fetal body composition beyond fetal growth that could better predict metabolic complications later in life is essential. This study aimed to evaluate subcutaneous fat tissue (femur and humerus) in fetuses with normal growth among pregnant women with well-controlled diabetes using a reproducible 3D-ultrasound tool and offline TUI (Tomographic Ultrasound Imaging) analysis. Additionally, three artificial intelligence classifier models were trained and validated to assess the clinical utility of the fetal subcutaneous fat measurement. A significantly larger subcutaneous fat area was found in three-femur and two-humerus selected segments of fetuses from women with diabetes compared to the healthy pregnant control group. The full classifier model that includes subcutaneous fat measure, gestational age, fetal weight, fetal abdominal circumference, maternal body mass index, and fetal weight percentile as variables, showed the best performance, with a detection rate of 70%, considering a false positive rate of 10%, and a positive predictive value of 82%. These findings provide valuable insights into the impact of maternal diabetes on fetal subcutaneous fat tissue as a variable independent of fetal growth.

Impact of Protease Inhibitor-Based Highly Active Antiretroviral Therapy on Fetal Subcutaneous Fat Tissue in HIV-Pregnant Women in a Middle-Income Country.

BACKGROUND: HIV infection continues to be a global public health challenge, affecting approximately 1.7 million reproductive-aged women. Protease inhibitor-based highly active antiretroviral therapy (PI-HAART) has significantly reduced the risk of vertical transmission of HIV from mother to child. Nevertheless, concerns linger regarding the long-term effects, particularly on body composition, notably subcutaneous fat tissue (SFT). Although HIV-associated lipodystrophy syndrome (LS) has been well documented in adults and older children, its impact on fetuses exposed to PI-HAART remains underexplored. This study aims to evaluate SFT in the fetuses of HIV-pregnant women exposed to PI-HAART, assessing the potential clinical implications. METHODS: We conducted a comparative study between HIV-pregnant women receiving PI-HAART and an HIV-negative control group. Fetometry measurements were obtained via 3D ultrasound. SFT in the fetal arm and thigh segments was assessed. Data were analyzed using lineal multivariate regression and receiver-operating characteristics (ROC)-curve analysis. RESULTS: Fetuses exposed to PI-HAART exhibited a significant reduction in subcutaneous fat, particularly in the proximal third-middle union of the femur (coefficient: -2.588, p = 0.042). This reduction was correlated with lower newborn serum glucose levels (65.7 vs. 56.1, p = 0.007; coefficient: -1.277, p = 0.045). CONCLUSIONS: Our study sheds light on the connection between PI-HAART, fetal subcutaneous fat, and neonatal health. These findings might reveal the long-lasting effects of PI-HAART on newborns and children's well-being. Our results emphasize the need for a more balanced approach to managing pregnant women with HIV in developing countries and open new venues for research on the impact of intrauterine PI-HAART exposure on energy metabolism and fetal programming.

Cervicovaginal Cytokines to Predict the Onset of Normal and Preterm Labor: a Pseudo-longitudinal Study.

Inflammatory processes associated with human parturition are still not completely understood, not only because the gap between inflammation and the onset of labor has been difficult to study but also because of the limited knowledge about the role of cervicovaginal fluid (CVF) cytokines during the sequence of labor. We aimed to determine whether CVF cytokines could predict the onset of normal and preterm labor. Chemokines and proinflammatory and anti-inflammatory cytokines in CVF were measured in a pseudo-longitudinal manner in healthy women between 12 and 41 weeks gestation with intact fetal membranes before and during the first stage of labor. Women were grouped into five stages, from the absence of uterine activity and cervical changes to regular uterine contractions with cervix dilation > 3 cm (active phase of labor). Of 144 women with spontaneous labor, 96 gave birth at term, 48 gave birth preterm, and both groups displayed similar cytokine concentrations. We found positive correlations between proinflammatory cytokines and the initial sequence of labor, using individual cytokines and score-based data by principal component analysis (IFN-γ, TNF-α, IL-1ß, IL-6) as dependent variables. The risk of labor onset increased as the concentrations of IL-6 increased (hazard ratio = 202.09, 95% confidence interval = 24.57-1662.49, P < 0.001). The IL-6 concentration predicted the onset of labor within 12 days of sampling (area under the time-dependent ROC curve = 0.785, 95% confidence interval = 0.693-0.877). Here, we showed that regardless of gestational age, the onset of labor could be predicted by the IL-6 concentration in the CVF, since the initial sequence of spontaneous labor displayed an inflammatory response expressed by the increase in proinflammatory cytokines.

Prenatal and early childhood critical windows for the association of nephrotoxic metal and metalloid mixtures with kidney function.

INTRODUCTION: As renal development and maturation processes begin in utero and continue through early childhood, sensitive developmental periods arise during which metal exposures can program subclinical nephrotoxicity that manifests later in life. We used novel dentine biomarkers of established nephrotoxicants including arsenic (As), cadmium (Cd), lead (Pb), chromium (Cr), and lithium (Li), and their mixtures, to identify critical windows of exposure-associated kidney function alterations in preadolescents. METHODS: Participants included 353 children in the Programming Research in Obesity Growth, Environment and Social Stressors (PROGRESS) longitudinal birth cohort study based in Mexico City. Estimated glomerular filtration rate (eGFR) was assessed in 8-12 year old children using serum cystatin C measures. Pre- and postnatal metal(loid) concentrations were assessed in weekly increments by analyzing deciduous teeth with laser ablation-inductively coupled plasma-mass spectrometry. We used reverse distributed lag models (rDLMs) and lagged Weighted Quantile Sum (L-WQS) regression to examine time-varying associations between weekly perinatal metal(loid) exposure or metal(loid) mixtures and preadolescent eGFR while adjusting for age, sex, BMI z-score, SES and prenatal tobacco smoke exposure. RESULTS: We identified a critical window of susceptibility to Pb exposure, in the late 3rd trimester (5 weeks prior to birth) during which higher Pb exposure was associated with children's increased eGFR. When all elements were assessed as a mixture, we identified late 2nd/early 3rd trimester (weeks 8-17 of gestation) as a window of vulnerability associated with decreased eGFR, with Li and Cr contributing the greatest weights to the association. When stratified by sex, we observed stronger effects among boys than girls. CONCLUSIONS: Using tooth-matrix biomarkers, we identified discrete developmental exposure windows wherein Pb and metal(loid) mixtures were associated with altered preadolescent kidney function.

miR-21 differentially regulates IL-1ß and IL-10 expression in human decidual cells infected with streptococcus B.

Intrauterine infections caused by bacteria like group B streptococcus (GBS) and the subsequent activation of the maternal inflammatory response have been long suspected to be the underlying cause of preterm labor. The inflammatory network triggered by maternal decidua has been widely described and includes the secretion of pro- and anti-inflammatory cytokines as IL-1ß and IL-10; however, the mechanisms that regulate their secretion have not been completely elucidated. MicroRNAs (miRNAs) are critical modulators of the inflammatory response by regulating cytokine expression in several cell types. Here, we explored the role of miR-21 in the expression of IL-1ß and IL-10 in human decidual stromal cells (DSCs) exposed in vitro to GBS. We observed that IL1B and IL10 expression at the mRNA level was increased in DSCs after GBS infection. IL-10 but not IL-1ß secretion was detected in the culture supernatants. We found a higher miR-21 expression (22-fold) in infected DSCs as compared with non-infected cells. miR-21 functional analysis revealed that DSCs transfected with an antagomiR vs. miR-21 significantly increased the secretion of IL-1ß but decreased that of IL-10 in DSCs cells infected with GBS. Our results suggest that miR-21 participates in balancing the inflammatory response in infected decidua through at least IL-1ß and IL-10 regulation. This is the first study attributing a functional role of miR-21 in the regulation of key molecules involved in the inflammatory response in infected DSCs, providing new insights into the epigenetic control of human decidual inflammation.

Resveratrol Supplementation in Obese Pregnant Rats Improves Maternal Metabolism and Prevents Increased Placental Oxidative Stress.

Maternal obesity (MO) causes maternal and fetal oxidative stress (OS) and metabolic dysfunction. We investigated whether supplementing obese mothers with resveratrol improves maternal metabolic alterations and reduces OS in the placenta and maternal and fetal liver. From weaning through pregnancy female Wistar rats ate chow (C) or a high-fat diet (MO). One month before mating until 19 days' gestation (dG), half the rats received 20 mg resveratrol/kg/d orally (Cres and MOres). At 19dG, maternal body weight, retroperitoneal fat adipocyte size, metabolic parameters, and OS biomarkers in the placenta and liver were determined. MO mothers showed higher body weight, triglycerides and leptin serum concentrations, insulin resistance (IR), decreased small and increased large adipocytes, liver fat accumulation, and hepatic upregulation of genes related to IR and inflammatory processes. Placenta, maternal and fetal liver OS biomarkers were augmented in MO. MOres mothers showed more small and fewer large adipocytes, lower triglycerides serum concentrations, IR and liver fat accumulation, downregulation of genes related to IR and inflammatory processes, and lowered OS in mothers, placentas, and female fetal liver. Maternal resveratrol supplementation in obese rats improves maternal metabolism and reduces placental and liver OS of mothers and fetuses in a sex-dependent manner.

Inflammatory-Metal Profile as a Hallmark for COVID-19 Severity During Pregnancy.

Pregnancy makes women more susceptible to infectious agents; however, available data on the effect of SARS-CoV-2 on pregnant women are limited. To date, inflammatory responses and changes in serum metal concentration have been reported in COVID-19 patients, but few associations between metal ions and cytokines have been described. The aim of this study was to evaluate correlations between inflammatory markers and serum metal ions in third-trimester pregnant women with varying COVID-19 disease severity. Patients with severe symptoms had increased concentrations of serum magnesium, copper, and calcium ions and decreased concentrations of iron, zinc, and sodium ions. Potassium ions were unaffected. Pro-inflammatory cytokines IL-6, TNF-α, IL-8, IL-1α, anti-inflammatory cytokine IL-4, and the IP-10 chemokine were induced in the severe presentation of COVID-19 during pregnancy. Robust negative correlations between iron/magnesium and zinc/IL-6, and a positive correlation between copper/IP-10 were observed in pregnant women with the severe form of the disease. Thus, coordinated alterations of serum metal ions and inflammatory markers - suggestive of underlying pathophysiological interactions-occur during SARS-CoV-2 infection in pregnancy.

Novel Ratio Soluble Fms-like Tyrosine Kinase-1/Angiotensin-II (sFlt-1/ANG-II) in Pregnant Women Is Associated with Critical Illness in COVID-19.

BACKGROUND: In healthy pregnancies, components of the Renin-Angiotensin system (RAS) are present in the placental villi and contribute to invasion, migration, and angiogenesis. At the same time, soluble fms-like tyrosine kinase 1 (sFlt-1) production is induced after binding of ANG-II to its receptor (AT-1R) in response to hypoxia. As RAS plays an essential role in the pathogenesis of COVID-19, we hypothesized that angiogenic marker (sFlt-1) and RAS components (ANG-II and ACE-2) may be related to adverse outcomes in pregnant women with COVID-19; Methods: Prospective cohort study. Primary outcome was severe pneumonia. Secondary outcomes were ICU admission, intubation, sepsis, and death. Spearman's Rho test was used to analyze the correlation between sFlt-1 and ANG-II levels. The sFlt-1/ANG-II ratio was determined and the association with each adverse outcome was explored by logistic regression analysis and the prediction was assessed using receiver-operating-curve (ROC); Results: Among 80 pregnant women with COVID-19, the sFlt-1/ANG-II ratio was associated with an increased probability of severe pneumonia (odds ratio [OR]: 1.31; p = 0.003), ICU admission (OR: 1.05; p = 0.007); intubation (OR: 1.09; p = 0.008); sepsis (OR: 1.04; p = 0.008); and death (OR: 1.04; p = 0.018); Conclusion: sFlt-1/ANG-II ratio is a good predictor of adverse events such as pneumonia, ICU admission, intubation, sepsis, and death in pregnant women with COVID-19.

Molecular Insights into the Thrombotic and Microvascular Injury in Placental Endothelium of Women with Mild or Severe COVID-19.

Clinical manifestations of coronavirus disease 2019 (COVID-19) in pregnant women are diverse, and little is known of the impact of the disease on placental physiology. Severe acute respiratory syndrome coronavirus (SARS-CoV-2) has been detected in the human placenta, and its binding receptor ACE2 is present in a variety of placental cells, including endothelium. Here, we analyze the impact of COVID-19 in placental endothelium, studying by immunofluorescence the expression of von Willebrand factor (vWf), claudin-5, and vascular endothelial (VE) cadherin in the decidua and chorionic villi of placentas from women with mild and severe COVID-19 in comparison to healthy controls. Our results indicate that: (1) vWf expression increases in the endothelium of decidua and chorionic villi of placentas derived from women with COVID-19, being higher in severe cases; (2) Claudin-5 and VE-cadherin expression decrease in the decidua and chorionic villus of placentas from women with severe COVID-19 but not in those with mild disease. Placental histological analysis reveals thrombosis, infarcts, and vascular wall remodeling, confirming the deleterious effect of COVID-19 on placental vessels. Together, these results suggest that placentas from women with COVID-19 have a condition of leaky endothelium and thrombosis, which is sensitive to disease severity.