Explore the vast range of titles available.

Miscarriage is generally defined as the loss of a pregnancy before viability. An estimated 23 million miscarriages occur every year worldwide, translating to 44 pregnancy losses each minute. The pooled risk of miscarriage is 15·3% (95% CI 12·5–18·7%) of all recognised pregnancies. The population prevalence of women who have had one miscarriage is 10·8% (10·3–11·4%), two miscarriages is 1·9% (1·8–2·1%), and three or more miscarriages is 0·7% (0·5–0·8%). Risk factors for miscarriage include very young or older female age (younger than 20 years and older than 35 years), older male age (older than 40 years), very low or very high body-mass index, Black ethnicity, previous miscarriages, smoking, alcohol, stress, working night shifts, air pollution, and exposure to pesticides. The consequences of miscarriage are both physical, such as bleeding or infection, and psychological. Psychological consequences include increases in the risk of anxiety, depression, post-traumatic stress disorder, and suicide. Miscarriage, and especially recurrent miscarriage, is also a sentinel risk marker for obstetric complications, including preterm birth, fetal growth restriction, placental abruption, and stillbirth in future pregnancies, and a predictor of longer-term health problems, such as cardiovascular disease and venous thromboembolism. The costs of miscarriage affect individuals, health-care systems, and society. The short-term national economic cost of miscarriage is estimated to be £471 million per year in the UK. As recurrent miscarriage is a sentinel marker for various obstetric risks in future pregnancies, women should receive care in preconception and obstetric clinics specialising in patients at high risk. As psychological morbidity is common after pregnancy loss, effective screening instruments and treatment options for mental health consequences of miscarriage need to be available. We recommend that miscarriage data are gathered and reported to facilitate comparison of rates among countries, to accelerate research, and to improve patient care and policy development.

Background: Recurrent miscarriage (RM) remains unsolved in > 50% of patients and causes physical and psychological problems in women without specific risk factors for miscarriage. For a successful pregnancy, acceptance of the endometrium and invasion of trophoblast cells into the endometrium is necessary. Objective: This study aimed to use computational analysis to identify key genes and related pathways in endometrial and trophoblast cells derived from RM samples. Materials and Methods: In this bioinformatics study, we explored the differential expression of genes in endometrial and trophoblast cells by analyzing the GSE165004 and GSE76862 datasets, respectively with the limma package in R software. Subsequently, overlapped genes between 2 datasets were selected, gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed. The overlapped genes were integrated to construct a protein-protein interaction network and hub genes selection. Results: We observed 41 overlapped genes between endometrial and trophoblast cells, and future analysis was accomplished in overlapped and nonoverlapped genes. Kyoto Encyclopedia of Genes and Genomes analysis indicated that overlapped genes were significantly enriched in the complement and coagulation cascades, pluripotency of stem cells, and synthesis and degradation of ketone bodies. Gene ontology analysis suggested that the genes were enriched in the cell cycle, apoptosis, and cell division. The top 10 genes included: IRS1, FGF2, MAPK6, MAPK1, MAPK3, MAPK8, MAPK9, PLK1, PRKACA, and PRKCA were identified from the PPI network. Conclusion: This study identified the key genes and potential molecular pathways underlying the development of RM. This could provide novel insights to determine the possible mechanisms and interventional strategies associated with miscarriage. Key words: Recurrent miscarriage, Transcriptome profile, Gene ontology, Bioinformatics.

The way in which a balanced vaginal microbiome helps prevent gynecological diseases in women and maintain health remains to be fully elucidated. In the present study, the potential effect of aberrations in the vaginal flora on unexplained recurrent miscarriage (RM) was investigated. The vaginal bacterial communities of 10 patients with unexplained RM and 10 healthy volunteers were sampled and subjected to sequencing analysis of the V3-V4 regions of the bacterial 16S ribosomal RNA gene using the Illumina MiSeq platform. Beta diversity analysis/principal component analysis indicated that bacterial community structures were different between the RM and control groups. A lower microbiota diversity in samples from RM patients was revealed by alpha diversity estimation. Taxonomic analysis demonstrated that abundance of three types of phyla (Firmicutes, Actinobacteria and Bacteroidetes) was significantly different between the RM and the normal control group. Furthermore, at the genus level, Lactobacillus was the most dominant genus in the two groups. Statistically significant differences were observed in 5 genera between the two groups. In the RM group, 3 bacterial taxa (Atopobium, Prevotella and Streptococcus) were significantly more abundant, while only 2 taxa were overrepresented in the control group (Lactobacillus and Gardnerella). In conclusion, the present results provide experimental evidence supporting dysbiosis of the vaginal flora in women with RM.

It is well known that progesterone plays a major role in the maintenance of pregnancy, particularly during the early stages, as it is responsible for preparing the endometrium for implantation and maintenance of the gestational sac. The management of pregnant women at risk of a threatened or idiopathic recurrent miscarriage is complex and critical. Therefore, a group of obstetricians and gynecologists practicing in Saudi Arabia gathered to update the 2014 Saudi guidelines for threatened and recurrent miscarriage management. In preparation, a literature review was conducted to explore the role of oral, vaginal, and injectable progestogens: this was used as a basis to develop position statements to guide and standardize practice across Saudi Arabia.

The present study was undertaken to: i) Determine the levels of oxidative stress (OS) markers, malondialdehyde (MDA), superoxide anions (SOA) and hydrogen peroxide (H2O2), in both plasma and placental tissues of recurrent miscarriage (RM) patients in comparison with those of healthy pregnant (HP) and non-pregnant (NP) women; ii) determine the levels of enzymatic antioxidants [glutathione peroxidase (GPx), glutathione reductase (GSR), superoxide dismutase (SOD) and catalase (CAT)], and non-enzymatic antioxidant micronutrients [selenium (Se), zinc (Zn), copper (Cu) and manganese (Mn)] in both plasma and placental tissues of RM patients, in comparison with those of HP and NP women; iii) profile differential expression levels of selected antioxidant and apoptosis-related genes in the placental tissues of RM cases, in relation to those of HP women of matched gestational age, using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The results revealed highly significant increases of all investigated OS markers in plasma and placental tissues of RM patients compared with those of HP women. Moderate, but significant, increases of OS markers were observed in the plasma of HP patients in relation to those of NP women. The activities of antioxidant enzymes exhibited statistically significant decreases in both plasma and placental tissues of RM patients compared with those of HP women. The significantly reduced level of antioxidant enzymes was also evident in the plasma of HP women as compared with those of NP women. Results of RT-qPCR assays clearly indicated that the expression level of apoptosis-related genes [tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and S100A8], and pro-inflammatory cytokine genes [tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-8] were significantly upregulated in placental tissue of RM cases in relation to those of HP subjects. By contrast, mRNA transcriptional levels of key antioxidant genes (GPx, SOD, GSR and CAT) were found to be significantly reduced in placental tissue of RM patients in comparison to those of HP women. In conclusion, our data highlight a plausible cause-effect association between the observed increase in placental OS level and depletion of the activity of antioxidant enzymes. This suggests that OS is a contributing factor in the pathogenesis of idiopathic RM.

A considerable proportion of recurrent miscarriage (RM) cases are caused by recurrent chromosomally abnormal conceptions. However, in younger patients and patients with multiple miscarriages, maternal causes seem to dominate. No single biomarker with a high predictive value of maternally caused RM has been identified. Non-genetic biomarkers in RM may not reflect conditions in the pregnant uterus and we rarely know whether they are causes or consequences of miscarriage. Studies of genetic biomarkers are probably the best way to reveal the pathophysiological mechanisms behind RM. Epidemiological and genetic studies suggest that RM due to maternal causes has a multifactorial background. The risk of RM in each patient is probably determined by the interaction of many genetic variants and environmental factors but only few of these have so far been identified. The genetic biomarkers for RM can probably be classified into three groups: (1) variants associated with excessive inflammatory responses and autoimmunity; (2) variants of importance for insulin and androgen sensitivity and turn-over, and (3) variants associated with thrombophilia. Identification of these markers will require whole genome association studies comprising thousands of individuals. Acknowledgement of the multifactorial background for RM has important implications for the management of patients in clinical practice.

Background Previously, we demonstrated up-regulated activated CD4+ and CD8+ T lymphocytes as well as up-regulated cytotoxic NK cells in the blood of patients with idiopathic recurrent miscarriage. In the present study, we tried to identify deficiencies in counter-regulating immune mechanisms of these patients. Method Cytokines were determined in NK cells and in plasma samples of 35 healthy controls, 33 patients with idiopathic recurrent miscarriage, 34 patients with end stage renal disease, 10 transplant patients early and 37 transplant patients late post-transplant using flow-cytometry and luminex. In addition, cytokines were studied in supernatants of cell cultures with peripheral blood mononuclear cells stimulated in-vitro with tumor cell line K562. Results Patients with idiopathic recurrent miscarriage exhibited the highest absolute cell counts of circulating TGFß1+ NK, NKT and T lymphocytes and the lowest TGFß1 plasma levels of all study groups (for all p  < 0.050). In-vitro, peripheral blood mononuclear cells of patients with idiopathic recurrent miscarriage showed high spontaneous TGFß1 production that could not be further increased by stimulation with K562, indicating increased consumption of TGFß1 by activated cells in the cell culture. Moreover, patients with idiopathic recurrent miscarriage had abnormally high IL4+ as well as abnormally high IFNy+ NK cells ( p  < 0.010) but similar IL10+ NK cell numbers as female healthy controls and showed the lowest plasma levels of IL10, TGFß3, IL1RA, IL1ß, IL5, IL6, IL8, IL17, TNFα, GM-CSF, TPO and VEGF and the highest plasma levels of G-CSF, FGF-basic, CCL3 and CXCL5 as compared to female HC and female transplant recipients (for all p < 0.050). Conclusions Patients with idiopathic recurrent miscarriage show an activated immune system that can hardly be stimulated further and cannot be efficiently down-regulated by up-regulated TGFß1+ and IL4+ NK, NKT and T lymphocytes which are present concomitantly in these patients. The strongly decreased TGFß and IL10 plasma levels indicate deficient down-regulation and reflect a dysbalance of the immune system in patients with idiopathic recurrent miscarriage. These findings may be relevant for explaining the pathogenesis of idiopathic recurrent miscarriage.

A higher frequency of spontaneous miscarriage has been observed in infertile couples, and there is a higher prevalence of infertility among patients with a history of recurrent spontaneous miscarriages (RSMs; ≥2 miscarriages). This study aimed to determine the proportion of infertile patients with RSM and examine risk factors associated in patients with RSM being treated with assisted reproductive technologies. This cross-sectional observational study was conducted at six reproductive medicine centers in three cities of China. Data of 751 patients with at least one spontaneous miscarriage were analyzed. Demographic data and etiological factors associated with infertility were compiled and compared between patients with a single spontaneous miscarriage (SSM) and those with RSM. Two hundred (26.6%, 95% confidence interval [CI]: 23.50-29.95%) patients experienced RSMs and 551 (73.4%) had a single miscarriage. The odds of RSM increased with increasing age (odds ratio [OR] = 1.06), uterine disorders (OR = 2.09), endocrine disorders (OR = 2.48), and immune disorders (OR = 2.98). Higher education level, masters or above, and a pelvic cavity disorder were associated with lower risk of RSM (OR = 0.27 and 0.46, respectively). Late spontaneous miscarriages were more frequent in patients with RSM than in those with a SSM (31.5% vs. 14.2%, respectively, P< 0.001) and were associated with a history of uterine cavity procedures (OR = 2.095) and cervical factors related to infertility (OR = 4.136, 95% CI: 1.012-16.90). Compared to patients with only a SSM, the conditions of patients with RSM are more complicated. To increase the success rate of assisted reproductive technology, factors including uterus cavity adhesion, cervical relaxation, endocrine disorders, and immune disorders should be treated before assisted reproduction is initiated. These data may provide treatment guidance for infertile patients with a history of RSM.

Abstract STUDY QUESTION What are the updates for the recommended management of women with recurrent pregnancy loss (RPL) based on the best available evidence in the literature from 2017 to 2022? SUMMARY ANSWER The guideline development group (GDG) updated 11 existing recommendations on investigations and treatments for RPL, and how care should be organized, and added one new recommendation on adenomyosis investigation in women with RPL. WHAT IS KNOWN ALREADY A previous ESHRE guideline on RPL was published in 2017 and needs to be updated. STUDY DESIGN, SIZE, DURATION The guideline was developed and updated according to the structured methodology for development and update of ESHRE guidelines. The literature searches were updated, and assessments of relevant new evidence were performed. Relevant papers published between 31 March 2017 and 28 February 2022 and written in English were included. Cumulative live birth rate, live birth rate, and pregnancy loss rate (or miscarriage rate) were considered the critical outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS Based on the collected evidence, recommendations were updated and discussed until consensus was reached within the GDG. A stakeholder review was organized after the updated draft was finalized. The final version was approved by the GDG and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE The new version of the guideline provides 39 recommendations on risk factors, prevention, and investigation in couples with RPL, and 38 recommendations on treatments. These includes 62 evidence-based recommendations—of which 33 were formulated as strong recommendations and 29 as conditional—and 15 good practice points. Of the evidence-based recommendations, 12 (19.4%) were supported by moderate-quality evidence. The remaining recommendations were supported by low (34 recommendations; 54.8%), or very low-quality evidence (16 recommendations; 25.8%). Owing to the lack of evidence-based investigations and treatments in RPL care, the guideline also clearly mentions those investigations and treatments that should not be used for couples with RPL. LIMITATIONS, REASONS FOR CAUTION The guidelines have been updated; however, several investigations and treatments currently offered to couples with RPL have not been well studied; for most of these investigations and treatments, a recommendation against using the intervention or treatment was formulated based on insufficient evidence. Future studies may require these recommendations to be revised. WIDER IMPLICATIONS OF THE FINDINGS The guideline provides clinicians with clear advice on best practice in RPL, based on the best and most recent evidence available. In addition, a list of research recommendations is provided to stimulate further studies in RPL. Still, the absence of a unified definition of RPL is one of the most critical consequences of the limited scientific evidence in the field. STUDY FUNDING/COMPETING INTEREST(S) The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the dissemination of the guideline. The guideline group members did not receive payment. O.B.C. reports being a member of the executive board of the European Society for Reproductive Immunology and has received payment for honoraria for giving lectures about RPL in Australia in 2020. M.G. reports unconditional research and educational grant received by the Centre for Reproductive Medicine, Amsterdam UMC from Guerbet, Merck and Ferring, not related to the presented work. S.L. reports position funding from EXAMENLAB Ltd. and ownership interest by stock or partnership of EXAMENLAB Ltd (CEO). S.Q. reports being a deputy director of Tommy’s National centre for miscarriage research, with payment received by the institution for research, staff time, and consumables for research. H.S.N. reports grants with payment to institution from Freya Biosciences ApS, Ferring Pharmaceuticals, BioInnovation Institute, the Danish ministry of Education, Novo Nordic Foundation, Augustinus Fonden, Oda og Hans Svenningsens Fond, Demant Fonden, Ole Kirks Fond, and Independent Research Fund Denmark and speakers’ fees for lectures from Ferring Pharmaceuticals, Merck A/S, Astra Zeneca, IBSA Nordic and Cook Medical. She also reports to be an unpaid founder and chairman of a maternity foundation. M.-L.v.d.H. received small honoraria for lectures on RPL care. The other authors have no conflicts of interest to declare. DISCLAIMER This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type. ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines.)

Background： The management of patients with recurrent miscarriage （RM） and antiphospholipid antibody syndrome （APS） includes prolonged treatment with heparin and aspirin, starting from the confirmation of pregnancy and continuing until 6 weeks after birth. This study was conducted to determine the relationship between changes in antiphospholipid antibody titers and clinical outcomes. The effect of a shortened treatment regimen was also evaluated. Methods： A prospective study of 123 patients with RM and APS between March 2012 and May 2014 was conducted. Patients were pretreated with a low dose of prednisone plus aspirin before pregnancy, and heparin was added after conception. The levels of antiphospholipid antibodies and pregnancy outcomes were evaluated. Results： All patients were positive for anti-β2-glycoprotein 1 （anti-β2-GP 1） IgM. Atier prepregnancy treatment with low-dose prednisone plus aspirin, 99 of 123 patients became pregnant, and 87 of those pregnancies resulted in successful live births, while 12 resulted in miscarriage, showing a success rate of 87.9%. In the live birth group, levels of anti-β2-GP1 were 56.8±49.0 RU/ml before the pretreatment regimen, 32. 1± 26.0 RU/ml after 2 months of pretreatment, and 24.1 ± 23. IRU/ml during early pregnancy （P 〈 0.05）. In the miscarriage group, antiphospholipid antibody titers were 52.8 ±30.7 RU/ml before pretreatment, 38.5 ±34.2 RU/ml after pretreatment, and 33.9 ±24.7 RU/ml during early pregnancy; the decrease in antiphospholipid antibodies was lower in the miscarriage group than in the live birth group （P 〈 0.05）. Of the 24 inferthe patients, the average antibody titer did not decline after pretreatment （P = 0.802）. Conclusions： Anti-[32-GP1 IgM was the predominant form of antibody in patients with RM and APS. The decreases in antiphospholipid antibody titers correlated with better pregnancy outcomes. The shorter treatment regimen was effective and economical.