Objectives: To develop a multivariate model for risk factors specific to early onset preeclampsia (EOP) and late onset preeclampsia (LOP) in our entire population (singleton and twin pregnancies). Material and methods: 20 year-observational population-based historical cohort study (2001-2020). All consecutive births delivered at the Centre Hospitalier Universitaire Hospitalier Sud Reunion’s maternity. A standardized validated epidemiological perinatal data base. Results: During the 20-year period, there were 81,834 pregnancies and 83,555 infants born, 1232 dichorionic and 350 monochorionic twin pregnancies. There were 2120 cases of preeclampsia, of which 2001preeclamptic singleton pregnancies and 119 twin pregnancies (incidence 7.5% in twin pregnancies vs 2.5% singletons, OR 3.0, p<0.001). Independent risk factors for EOP and LOP in a multivariate model (controlling for the two major confounders: namely maternal ages -both risks for EOP and LOP- and maternal pre-pregnancy BMI – specific risk factor for LOP) were: history of preeclampsia (aOR 11.7 for EOP, 7.8 for LOP, p < 0.0001), chronic hypertension (aOR 7.3 for EOP, 3.9 for LOP, p < 0.0001), history of perinatal death (aOR 2.2 for EOP, p < 0.0001 and 1.48 for LOP, p= 0.007), primipaternity (aOR 3.0 for EOP and 3.6 for LOP, p = 0.001), dizygotic twin pregnancies (aOR 3.7 for EOP, p < 0.0001 and 2.1 for LOP, p = 0.003), monozygotic twin pregnancies (aOR 3.98 for EOP, p = 0.003 and NS for LOP), ovulation induction (aOR 5.6 for EOP, p = 0.004 and NS for LOP), and in vitro fertilization (aOR 2.8 for EOP, p = 0.05 and NS for LOP). Specific to LOP and NS for EOP: renal diseases (aOR for LOP 2.9, p= 0.007) and gestational diabetes mellitus (aOR 1.2, p= 0.04). Conclusions: Maternal ages over 35 years, chronic hypertension , history of preeclampsia, ovulation induction, in vitro fertilizations, history of perinatal deaths and twin pregnancy (in our experience, especially mono zygotic twin pregnancies) are significant risk factors for EOP. New paternity is an independent factor for both EOP and LOP.

Preeclampsia (PE) is a serious complication of pregnancy with a pathogenesis that is not fully understood, though it involves the impaired invasion of extravillous trophoblasts (EVTs) into the decidual layer during implantation. Recently, others have found that diverse cell types, including EVTs, produce exosomes filled with molecular cargo (mainly proteins and RNAs) that can be transported to other cells and organs both locally and long-range. The cargo delivered by exosomes can signal to and modify the receiving cells and their environment, and EVT-derived exosomes may influence the pathogenesis of PE. Because the risk of PE is actually decreased by cigarette smoking, we considered the possibility that nicotine, a critical component of tobacco smoke, might protect against PE by modifying the content of exosomes from EVTs. In this study, we applied nicotine stimulation to cultured EVTs and subjected their secreted exosomes to proteomic analysis. We identified many proteins whose abundance in exosomes was modified by nicotine treatment of the donor EVTs, and we used bioinformatic annotation and network analysis to select five key hub proteins with potential roles in the pathogenesis or prevention of PE.

Despite prophylaxis and attempts to select a therapy, the frequency of preeclampsia does not decrease, and it still takes the leading position in the structure of maternal mortality and morbidity worldwide. In this review, we present a new theory of the etiology and pathogenesis of preeclampsia which is based on the interaction of Na/K-ATPase and its endogenous ligands including marinobufagenin. The signaling pathway of marinobufagenin involves an inhibition of transcriptional factor Fli1, a negative regulator of collagen synthesis, followed by deposition of collagen in the vascular tissues and altered vascular functions. Moreover, in vitro and in vivo neutralization of marinobufagenin is associated with restoration of Fli1. The inverse relationship between marinobufagenin and Fli1 opens new possibilities in the treatment of cancer: since Fli1 is a proto-oncogene, a hypothesis on suppression of Fli1 by cardiotonic steroids as potential anti-tumor therapeutic strategy is discussed as well. We propose a novel therapy of preeclampsia which is based on immunoneutralization of the marinobufagenin by monoclonal antibodies, which is capable to impair marinobufagenin-Na/K-ATPase interactions.

Preeclampsia (PE) continues to be a significant cause of maternal and neonatal morbidity and mortality. Angiotensin II type I receptor autoantibody (AT1-AA) has been reported accompanied by PE women in numerous studies. Therefore, detecting the mechanism of AT1-AA production is the key breakthrough in understanding PE. Deficiency in MFG-E8 has been verified can lead to autoimmune diseases due to dysfunction in macrophage phagocytosis and the production of autoantibodies. In the present study, we examined the expression of MFG-E8 in PE patients. Compared with the control, PE patients had a lower expression of placental MFG-E8 and a higher expression of placental AT1R. Then, we tested the effect of MFG-E8 on AT1-AA production and macrophage phagocytosis of trophoblast apoptosis in PE rats induced by low-dose endotoxin(LPS) and trophoblast model. In vivo, experiments results showed that systolic blood pressure, 24h urinary protein, serum TNF-α,sLFt-1 and AT1-AA levels, and placental trophoblast apoptosis caused by LPS were all significantly alleviated by MFG-E8. Moreover, administrated with MFG-E8 has shown decreased trophoblast apoptosis and AT1R exposure in vitro, and enhanced the phagocytosis of dead trophoblasts by macrophages. That supports the idea that MFG-E8 could be a potential therapeutic target for attenuating AT1-AA and protecting patients from AT1-AA and PE.

(1) Background: Preeclampsia (PE) prediction in the first trimester of pregnancy is a challenge for the clinicians. The aim of this study was to evaluate and compare the predictive performances of machine-learning based models for the prediction of preeclampsia, and its subtypes; (2) Methods: This prospective case-control study evaluated pregnancies that occurred in women who attended a tertiary maternity hospital in Romania between November 2019 and September 2022. The patients’ clinical and paraclinical characteristics were evaluated in the first trimester, and were included in 4 machine learning based models: decision tree (DT), naïve Bayes (NB), support vector machine (SVM), and random forest (RF), and their predictive performance was assessed; (3) Results: early-onset PE was best predicted by DT (accuracy: 94.1%), and SVM (accuracy: 91.2%) models, while NB (accuracy: 98.6%), and RF (accuracy: 92.8%) models had the highest performance when used to predict all types of PE. The predictive performance of these models was modest for moderate and severe types of PE, with accuracies ranging from 70.6% and 82.4%; (4) The machine learning-based models could be useful tools for PE prediction in the first trimester of pregnancy.

Preeclampsia (PE) is characterized by a series of clinical features such as hypertension and proteinuria associated with endothelial dysfunction and the impairment of placenta vascular endothelial integrity. This study aimed to investigate the effect of serum copper (Cu) level on some angiogenesis-related factors including vascular endothelial growth factor-A (VEGF-A), soluble Fms-like tyrosine kinase-1 (sVEGF-R1), soluble endoglin (sEng) and cerruloplasmin (Cp) in Iraqi women with preeclampsia (PE) and control pregnant women. Therefore, 60 women with PE in addition to 30 healthy pregnant women were enrolled in the study. Serum concentration of sEng, VEGF-A, sVEGF-R1, and Cu in PE group significantly increased (p<0.05) in the PE group compared with that in the control group. Increased production of antiangiogenic factors, soluble VEGF-A and sEng contribute to the pathophysiology of PE, indicating the involvement of these parameters in the angiogenic balance in patients with PE. Tests for between-subject effects showed that the circulating angiogenesis factors and Cu were significantly associated with the presence of PE. Serum Cu level was significantly correlated with VEGF- A and VEGF-R1 levels but not with sEng. Multiple regression analysis revealed that only Cp and BP can significantly predict the complications in women with PE. In conclusion, serum Cu has a role in the angiogenesis in women with PE and may be a new drug target in the prevention or treatment of PE.

1) Background: The screening of preeclampsia (PE) and intrauterine growth restriction (IUGR) represents a constant challenge for obstetricians. The aim of this study was to determine and compare the predictive performance of 4 machine learning-based algorithms for the prediction of PE, IUGR, and their association in a cohort of singleton pregnancies; (2) Methods This prospective study was conducted at a tertiary maternity hospital in Romania, and included 210 pregnancies that underwent first trimester screening. We included clinical and paraclinical data into 4 machine learning-based algorithms decision tree (DT), naïve Bayes (NB), support vector machine (SVM), and random forest (RF), and calculated their predictive performance; (3) Results: RF performed the best when used to predict PE, IUGR, and its subtypes, as well as the association between PE and IUGR. The overall predictive performance of DT for all these disorders was inferior to RF, NB, and SVM. Both SVM and NB had similar accuracy for the prediction of PE, while NB performed better than SVM for the prediction of IUGR; (4) Conclusions: Machine-learning-based algorithms could be useful for the prediction of ischemic placental disease and need to be validated on large cohorts of patients.

Preeclampsia (PE) is associated with an increased risk of cardiovascular disease (CVD) in later life. Postpartum cardiovascular risk screening could identify patients who would benefit most from lifestyle interventions. However, there are no readily available methods to identify these high-risk women. We propose that placental lesions may be useful in this regard. Here, we sought to determine the association between placental lesions and lifetime CVD risk. Placentas from 85 PE women were evaluated for histopathological lesions. At 6 months postpartum, a lifetime cardiovascular risk score was calculated. Placental lesions were compared between CVD risk groups and the association was assessed using odds ratios. Multivariable logistic regression was used to develop prediction models for CVD risk with placental pathology. Placentas from high-risk women had more severe lesions of maternal vascular malperfusion (MVM) and resulted in a 3-fold increased risk of screening high-risk for CVD (OR 3.10[1.20-7.92]) compared to women without these lesions. MVM lesion severity was moderately predictive of high-risk screening (AUC 0.63[0.51,0.75]; sensitivity 71.8%[54.6,84.4]; specificity 54.7%[41.5,67.3]. When clinical parameters were added, the model’s predictive performance improved (AUC 0.73[0.62,0.84]; sensitivity 78.4%[65.4,87.5]; specificity 51.6%[34.8,68.0]. The results suggest that placenta pathology may provide a unique modality to identify women for cardiovascular screening.

Preeclampsia (PE) is a common pregnancy complication. It is associated with high maternal morbidity and mortality rates and intrauterine foetal growth restriction. This condition is characterised by high blood pressure and urinary protein levels. Apelin and galectin-3 (Gal- 3) are peptides involved in the regulation of body fluid homeostasis, inflammation and cardiovascular functions. This study aimed to determine the correlations amongst serum apelin and Gal-3 levels and insulin resistance (IR) in women with PE. Sixty patients with PE and 30 healthy controls participated in this study. The PE group had significantly lower apelin levels (p < 0.01) and higher Gal-3 levels (p < 0.05) than the control group. The PE group had higher serum glucose levels and β-cell functions than the control group. Moreover, patients with PE exhibited dyslipidaemia. Correlation analysis indicated that apelin and Gal-3 levels were not significantly correlated. Moreover, no correlation existed between the apelin levels and any measured parameters of the PE group. In conclusion, the elevations in serum Gal-3 levels with increments in IR-related parameters and lipid profiles reflect the possible contribution of Gal-3 to the harmful effects of IR and dyslipidemia levels on women with PE.

Hypertensive disorders of pregnancy (HDP), including preeclampsia (PE) and gestational hypertension (GH), are major causes of maternal and fetal morbidity and mortality. This review elucidates the role of regulatory T cells (Tregs) in the immunological aspects of HDP and explores their therapeutic potential. Tregs, known for maintaining immune tolerance, are crucial in pregnancy to prevent immune-mediated rejection of the fetus. In HDP, Treg numbers and function imbalance are observed, correlating with disease severity. The review highlights that Tregs contribute to immunological adaptation in normal pregnancy, ensuring fetal acceptance and placental development. In contrast, HDP is associated with Treg dysfunction, marked by decreased numbers and impaired regulatory capacity, leading to inadequate immune tolerance and abnormal placental development. This dysfunction is particularly evident in PE, where Tregs fail to adequately modulate the maternal immune response against fetal antigens, contributing to the pathophysiology of the disorder. Therapeutic interventions aiming to modulate Treg activity represent a promising avenue for HDP management. Studies in animal models and limited clinical trials suggest that enhancing Treg functionality could mitigate HDP symptoms and improve pregnancy outcomes. However, the review acknowledges the complexity of translating these findings into effective clinical therapies, given the multifactorial nature of HDP and the intricate regulatory mechanisms of Tregs. In conclusion, while the precise role of Tregs in HDP is still being unravelled, their central role in immune regulation during pregnancy is indisputable. Further research is needed to fully understand the mechanisms by which Tregs contribute to HDP and to develop targeted therapies that can safely and effectively harness their regulatory potential for treating hypertensive diseases of pregnancy.

Pregnancy-induced hypertension and preeclampsia are associated with significant maternal and fetal mortality. A better understanding of those diseases, delineation of molecular pathomechanism, and efficient treatment development are some of the most urgent tasks in obstetrics and gynecology. Recent findings indicate a crucial role of inflammation in the development of hypertension and preeclampsia. Although the mechanism is very complex and needs further explanation, it appears that high levels of cholesterol, urate, and glucose activates NLRP3 inflammasome, which produces IL-1β, IL-18 and gasdermin D. Production of these proinflammatory chemokines is a beginning of local and general inflammation, what results in sympathetic outflow, angiotensin II production, proteinuria, hemolysis, liver damage, immunothrombosis, and coagulopathy. NLRP3 inflammasome is a critical complex in the mediation of inflammatory response, which makes it crucial for the development of pregnancy-induced hypertension and preeclampsia, as well as its complications, such as placental abruption and HELLP syndrome. Herein presented the article delineate molecular mechanisms of those processes, indicating directions of future advance.

Background: It is known that Preeclampsia affects the lactogenesis. However, data on effects of this pathology on the human milk neurobiomarkers composition are not available. The aim of this study is to investigate the effects of this gestational pathology on Activin A levels, a neurobi-omarker known to play an important role in the development and protection of the central nerv-ous system. Methods: The women recruited were divided in two different study groups: preeclamptic or normotensive women. All the human milk samples were collected using the same procedure. Activin A was quantified using an ELISA test. To investigate the effect of Preeclampsia on the Activin A concentration in the 3 lactation phases, mixed linear model with unistructural covariance structure, mother as random effect, and fixed effects were performed. Results: Activin A was detected in all samples. There were no significant differences between Preeclamptic and Normotensive women. The only significant effect is related to the lactation phase: it is significant the difference between colostrum and mature milk (p<0.01). In conclusion these results allow us to affirm that breast milk beneficial properties are maintained even if preeclampsia occurs.

Background. Human Milk (HM) is a dynamic nourishment: its composition is influenced by several conditions such as gestational age, maternal diet and ethnicity. It appears important evaluate the impact that gestational diseases have on HM components and if their presence, as source of oxidative stress in the mother, influence milk’s redox homeostasis. To assess Preeclampsia (PE) and Gestational Diabetes Mellitus (GDM) effect on milk’s total oxidative load, we chose to investigate both oxidative and antioxidant aspects, with respectively Lipid hydrop-eroxides (LOOHs) and Glutathione (GSH)). Methods. GSH and LOOHs were quantified using an ELISA test. To investigate the effect of pathology on redox homeostasis, mixed linear model with unistructural covariance structure was performed. Results. A total of 120 mothers were re-cruited. The GSH concentration results significant lower in GDM women than in healthy only in colostrum (p<0.01). No other differences emerged. LOOHs was not detectable in almost all the samples. Discussion. Our study is the first to extensively evaluate these components in the HM of women with these gestational pathologies. The main observation is that GDM can alter the anti-oxidant composition of HM mainly in colostrum, but in case of PE, the composition of HM milk is preserved.

The placenta is a vital organ of pregnancy, regulating adaptation to pregnancy, gestational-parent/fetal exchange and ultimately fetal development and growth. Not surprisingly, in cases of placental dysfunction - where aspects of placental development or function become compromised - adverse pregnancy outcomes can result. One common placenta-mediated disorder of pregnancy is preeclampsia (PE), a hypertensive disorder of pregnancy with a highly heterogeneous clinical presentation. The wide array of clinical characteristics observed in pregnant individuals and neonates of a PE pregnancy are likely the result of distinct forms of placental pathology underlying the PE diagnosis, explaining why no one common intervention has proven effective in the prevention or treatment of PE. The historical paradigm of placental pathology in PE highlights an important role for utero-placental malperfusion, placental hypoxia and oxidative stress, and a critical role for placental mitochondrial dysfunction in the pathogenesis and progression of the disease. In the current review, the evidence of placental mitochondrial dysfunction in the context of PE will be summarized, highlighting how altered mitochondrial function may be a common feature across distinct PE subtypes. Further, advances in this field of study and therapeutic targeting of mitochondria as a promising intervention for PE will be discussed.

Objective: We previously provided evidence to confirm that soluble Fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and their ratio, are useful tools to direct the management of preeclampsia (PE), fetal growth restriction (FGR), and PE+FGR near delivery. In this study we examine the potential additive value of Inhibin-A, a hormone marker of the transforming growth factor family. Methods: We used a cohort of 125 pregnant women enrolled near delivery at clinics of the University Medical Center of Ljubljana, Slovenia. There were 31 cases of PE, 16 of FGR, 42 of PE+FGR, 15 iatrogenic preterm delivery (PTD), and 21 unaffected controls with delivery of a healthy baby at term. Cases delivered before 34 weeks’ gestation included 13 of PE, 12 of FGR, 22 of PE+FGR, and 6 of PTD. We recorded demographic characteristics and medical history and the levels of PlGF, sFlt-1 and Inhibin-A. The predictive accuracy of each biomarker, their ratios, and combinations was estimated from areas under the curve (AUC) of Receiver Operating Characteristics (ROC) curves. We estimated accuracy by the continuous marker model and a cut-off model. Results: Combining Inhibin-A with PlGF or with the sFlt-1 / PlGF ratio showed a 10-20% increase in AUCs and 5-15% increase in the detection rate, at 10% false positive rate, of PE, and a lower, but significant, increase for PE+FGR but not for FGR alone. The use of a cut-off model was adequate, although a bit higher accuracy was obtained from the continuous model. Highest correlation was found for PlGF with all three complications. Conclusion: Inhibin-A improves the accuracy of predicting PE and PE+FGR provided by the angiogenic markers alone, bringing the results to a diagnostic level, thus assisting in directing clinical management. Inhibin-A had no added value for the accuracy of predicting FGR alone.

Antiphospholipid syndrome (APS) is characterized by venous or arterial thrombosis and/or adverse pregnancy outcome in the presence of persistent laboratory evidence of antiphospholipid antibodies (aPL). Preeclampsia (PE) complicates about 10-17% of pregnancies with APS. However, only early onset PE (< 34 weeks of gestation) belongs to the clinical criteria of APS. The similarities in the pathophysiology of early onset PE and APS emphasize an association of these two syndromes. Overall, both are the result of a defective trophoblast invasion and decidual transformation at early gestation. Women with APS are at increased risk for prematurity; the reasons are mostly iatrogenic due to placental dysfunction, such as PE or FGR. Interestingly, women with APS have also an increased risk for preterm delivery, even in the absence of FGR and PE and therefore not indicated but spontaneous. The basic treatment of APS in pregnancy is low-dose-aspirin and low-molecular- weight-heparin. Nevertheless, up to 20-30% of women develop complications at early and late gestation despite basic treatment. Several additional treatment options have been proposed, with Hydroxychloroquine (HCQ) being one of the most efficient. Additionally, nutritional interventions, such as intake of vitamin D have shown promising beneficial effects. Curcumin, due to its antioxidant and anti-inflammatory properties, might be considered as additional intervention as well.

Preterm delivery can be precipitated by infection, and preterm infants are at heightened risk of postnatal infection. Little is known about the ontogeny of inflammatory biomarkers in extremely preterm infants. We hypothesized that suspected prenatal infection (chorioamnionitis or spontaneous preterm labor) and clinically diagnosed postnatal infection would be associated with unique biomarker signatures, and those patterns would be influenced by the degree of prematurity. Venous blood was collected daily for the first week and weekly for up to 14 additional weeks from 142 neonates born at 22-32 weeks gestation. A custom array was utilized to measure monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6). C-reactive protein (CRP) levels were obtained from the electronic medical record. 90 infants had suspected prenatal infection and 63 were diagnosed with postnatal infection. Independent of gestational age at delivery, MCP-1 was significantly increased (P &lt; 0.001) in association with maternal preeclampsia, but MCP-1 was decreased (P&lt;0.01) and CRP was increased (P&lt;0.05) in the presence of chorioamnionitis. IL-6 and CRP were both increased in infants diagnosed with postnatal infection with peak levels observed on days 2 and 3, respectively. In conclusion, suspected prenatal and postnatal infections and non-infectious complications of pregnancy are associated with unique biomarker profiles, independent of gestational age. In those clinically diagnosed with a postnatal infection in the absence of antenatal infection concerns, IL-6 increases before CRP, emphasizing a potential role for expanded biomarker screening if antibiotics are initially avoided in infants born exclusively for maternal indications.

Background. Pregnancy rates in women on dialysis have increased in the last decades, thus making it a topic of growing interest. The rarity of this event is predominantly due to fertility problems and to the high rates of pregnancy failure including stillbirth, fetal and neonatal deaths [1]. Methods. We conducted a narrative review of existent literature in order to analyse the major issues about pregnancy on dialysis to give the reader a full updated prospective about this topic which, even if not common, is becoming more and more frequent. Results. Even if recently acquired knowledge has improved diagnosis and treatment of dialysis pregnancies focusing on several aspects, pregnancy on dialysis remains a great challenge for obstetricians and should be managed by a multidisciplinary expertise team. Conclusion. Dialysis in pregnancy may be necessary for women previously affected by end stage renal disease (ESRD) becoming pregnant, or in case of acute renal injury presenting for the first time during gestation or, again in case of existent renal pathology worsening during pregnancy and requiring dialysis. Although some evidence suggests that more intensive dialysis regimens are correlated with better obstetric outcomes, the optimal therapeutic protocol still remains to be established.

In this study, we wanted to discuss the acute coronary syndromes in the pregnant womens which are very important for life ofthe fetus. Spontaneous coronary artery dissection and management, which is the most common cause of acute coronary syndrome in pregnant women is also discussed. About 300 articles were examined and 35 articles which published in high quality journals with high level of evidence were chosen and this review was prepared.

Sirtuins, especially SIRT1, play a significant role in the regulation of inflammatory response, autophagy, and cell response to oxidative stress. Since their discovery, sirtuins have been regarded as anti-aging and longevity-promoting enzymes. Sirtuin-regulated processes seem to take part in most prevalent placental pathologies, such as preeclampsia. Furthermore, more and more research studies indicate that SIRT1 may prevent pre-eclampsia development, or at least alleviate its manifestations. Having taken this into consideration, we have made a review of recent studies on the role of sirtuins, especially SIRT1, in the regulation of processes determining normal or abnormal development and functioning of the placenta.

Vitamin D plays an essential role in embryogenesis and the course of intra- and postnatal periods and is crucially involved in the functioning of the mother-placenta-fetus system. Low quantity of Vitamin D during pregnancy can lead to the elevated risk for preeclampsia occurence. Despite the numerous studies on the association of Vitamin D deficiency and preeclampsia development, the current research on this theme is contradictory. In this review we summarize and analyze study data on the effects of vitamin D deficiency and supplementation on pregnancy, labor, fetal and neonatal outcomes.

Preeclampsia is a multifactorial cardiovascular disorder diagnosed after 20 weeks of gestation that is the leading cause of death for both mothers and babies in pregnancy. The pathophysiology remains poorly understood due to variability and unpredictability of disease manifestation when studied in animal models. After preeclampsia, both mothers and offspring have a higher risk of cardiovascular disease (CVD) including myocardial infarction or heart attack and heart failure (HF). Myocardial infarction is an acute myocardial damage that can be treated through reperfusion, however, that therapeutic approach leads to ischemic/reperfusion injury (IRI) often leading to HF. In this review, we compared the current in vivo, in vitro and ex vivo model systems used to study preeclampsia, IRI and HF. Future studies aiming at evaluating CVD in preeclampsia patients could benefit from novel models that better mimic the complex scenario described in this article.

Background and Objectives: The purpose of this study was to assess the bleeding that occurs during the first weeks of gestation and its implications throughout pregnancy. Secondarily, we studied the associated complications that appeared and tried to identify possible risk factors that could serve to select women at a greater risk of adverse outcomes that could benefit from an early diagnosis and improved monitoring. Materials and Methods: We selected all the women who consulted for first trimester metrorrhagia in the Emergency Department of the Hospital QuirónSalud in Malaga over the year 2015. We refer to first trimester metrorrhagia as that which occurs until week 12+6. Once the pregnant women were identified, we studied certain risk factors already present prior to the gestation and others associated with the gestation and its evolution. Results: After reviewing the visits to the obstetrics and gynecology emergency department, we selected those patients that met the inclusion criteria, resulting in a sample of 696 patients that we followed up. The average age of our patients was 34.1 years, with an average number of visits to the hospital of 1.67, most of them between the 5th and 8th weeks of pregnancy. 45.3% of these pregnancies resulted in a first trimester miscarriage, mainly between weeks 6 and 8. We tried to establish associations in order to identify possible risk factors, finding a relationship between increased maternal age and a higher risk of first trimester pregnancy loss, which rises as maternal age increases (33,37 4,316 years vs 35,01 4,740 years). This increase in risk is proportional to the increase in age. We made subgroups of women over 35 and over 40 and confirmed that increased age led to worse outcomes. We also studied several gestational complications and concluded that they appeared more frequently among older women. These complications include prematurity (33.11 vs 34.48 years), gestational diabetes (33.11 vs 36.06 years) and preeclampsia (33.25 vs 35 years). We reviewed the obstetric history of pregnant women whose gestation resulted in miscarriage and found that 50.5% of them had previously had another loss. Conclusions: Comparing the results with data from the general population, we found that the rate of first trimester miscarriage is up to 3 times higher among women who present bleeding during the first weeks of gestation compared to those who do not develop this complication. Maternal age is a risk factor for first trimester pregnancy loss and for the development of complications associated with pregnancy.

Neutrophils are the principal trouper of innate immune system. Activated neutrophils undergo a noble cell death termed NETosis and release a mesh-like structure called neutrophil extracellular traps (NETs) as a part of their defensive strategy against microbial pathogen attack. This web-like architecture includes a DNA backbone embedded with antimicrobial proteins like myeloperoxidase (MPO), neutrophil elastase (NE), histones etc. and deploys in the entrapment and clearance of encountered pathogens. Thus NETs play an inevitable beneficial role in the host's protection. However, recent accumulated evidence shows that dysregulated and enhanced NET formation has various pathological aspects including promotion of sepsis, pulmonary, cardiovascular, hepatic, nephrological, thrombotic, autoimmune, pregnancy, cancer diseases etc. and the list is increasing gradually. In this review, we summarize NETs mediated pathophysiology of different diseases, focus on some updated potential therapeutic approaches against NETs and share our future perspectives.