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Recurrent pregnancy loss (RPL) affects approximately 15–20% of couples. Constitutional chromosomal abnormalities (CA) are an important cause of RPL because the gametes of carriers may have chromosomal imbalance which is lethal to the fetus. Therefore, the identification of CA helps to provide information about likely outcome of pregnancy in carriers. The objective of this study was to determine the frequency and types of CA in RPL. The study group consisted of individuals with RPL seen at a tertiary care center in South India from 2001 to 2019, whose karyotypes were reviewed retrospectively. Cytogenetic analysis was performed on peripheral blood using standard protocols. The number of metaphases analyzed per patient was 20 and extended up to 50 for confirmation of low-level mosaicism. There were 3488 individuals (1663 couples and 162 where only partner was tested of whom 104 were females). The frequency of CA was 3.6% (127/3488) (M:F ratio of 1:2.6). Structural aberrations were seen in 2.5% (90/3488) and numerical aberrations of sex chromosomes in 1.1% (37/3488) of patients. Structural aberrations included 68 balanced translocations including one three-way translocation, seven inversions, one insertion and duplication each, and 14 Robertsonian translocations. There was one patient each with Turner syndrome (TS) and 47,XYY syndrome. We had 37 mosaics, comprising 29 with mosaic TS and 6 with triple X mosaicism and 2 with mosaicism for balanced translocation. The frequency of CA is comparable to the literature. We have described a few less commonly seen aberrations as well as sex chromosomal aneuploidies, almost all of which were due to low-level mosaicism. [ABSTRACT FROM AUTHOR]

Introduction: Anti-b2-glycoprotein I (b2GPI)/human leukocyte antigen (HLA)-DR antibodies may be a risk factor for recurrent pregnancy loss (RPL). The therapeutic modality for women with RPL and anti-b2GPI/HLA-DR antibody positivity has not been evaluated. This prospective, multicenter, observational study aimed to assess whether low-dose aspirin (LDA) and/or heparin therapies improve pregnancy outcomes in women with RPL who tested positive for antib2GPI/HLA-DR antibodies. Methods: Between August 2019 and December 2021, 462 women with RPL underwent anti-b2GPI/HLA-DR antibody measurements and risk assessments for RPL. Each attending physician decided the treatment modality for women with RPL who tested positive for anti-b2GPI/HLA-DR antibodies, and their pregnancy outcomes were followed up until December 2023. Finally, 47 pregnancies in 47 women with RPL and anti-b2GPI/HLA-DR antibody positivity were included in the analysis and were divided into two groups regarding whether they were treated with LDA and/or unfractionated heparin (UFH) (LDA/UFH group, n = 39) or with neither of them (non-LDA/non-UFH group, n = 8). The rates of live birth and pregnancy complications (i.e., preeclampsia and preterm delivery before 34 gestational weeks due to placental insufficiency) were compared between the two groups. Results: The live birth rate in the LDA/UFH group was higher than that in the non-LDA/non-UFH group (87.2% vs 50.0%, p = 0.03). The pregnancy complication rate in the LDA/UFH group was significantly lower than that in the non-LDA/non-UFH group (5.9% vs 50.0%, p = 0.048). Among 21 women who tested positive for anti-b2GPI/HLA-DR antibodies and had no other risk factors for RPL, the live birth rate in the LDA/UFH group (n = 14) was much higher than that in the non-LDA/non-UFH group (n = 7) (92.9% vs 42.9%, p = 0.03). Discussion: This study, for the first time, demonstrated that LDA and/or UFH therapies are effective in improving pregnancy outcomes in women with RPL and ab2GPI/HLA-DR antibody positivity. [ABSTRACT FROM AUTHOR]

Background and aim: Recurrent pregnancy loss (RPL), also known as recurrent implantation failure (RIF), is a distressing condition affecting women characterized by two or more consecutive miscarriages or the inability to carry a pregnancy beyond 20 weeks. Immunological factors and genetic variations, particularly in Vit D Binding Protein (VDBP), have gained attention as potential contributors to RPL. This study aimed to provide insight into the immunological, genetic, and metabolic networks underlying RPL, placing a particular emphasis on the interactions between VDBP, HLA-G1, CTLA-4, ENTPD1, and adenosine-fetal-maternal conflict crosstalk. Methods: A retrospective study included 198 women with three or more consecutive spontaneous abortions. Exclusion criteria comprised uterine abnormalities, endocrine disorders, parental chromosomal abnormalities, infectious factors, autoimmune diseases, or connective tissue diseases. Immunological interplay was investigated in 162 female participants, divided into two groups based on their Vit D levels: normal Vit D-RPL and low Vit D-RPL. Various laboratory techniques were employed, including LC/MS/MS for Vit D measurement, ELISA for protein detection, flow cytometry for immune function analysis, and molecular docking for protein–ligand interaction assessment. Results: General characteristics between groups were significant regarding Vit D and glucose levels. Low Vit D levels were associated with decreased NK cell activity and downregulation of HLA-G1 and HLA-G5 proteins, while CTLA-4 revealed upregulation. VDBP was significantly downregulated in the low Vit D group. Our findings highlight the intricate relationship between Vit D status and adenosine metabolism by the downregulation of SGLT1, and NT5E, key components of adenosine metabolism, suggests that Vit D deficiency may disrupt the regulation of adenosine levels, leading to an impaired reproductive outcome. HNF1β, a negative regulator of VDBP, was upregulated, while HNF1α, a positive regulator, was downregulated in low Vit D women after RPL. Molecular docking analysis revealed crucial residues involved in the interaction between Vit D and HNF1β. Conclusion: Collectively, these findings underscore the importance of Vit D in modulating immune function and molecular pathways relevant to pregnancy maintenance, highlighting the need for further research to elucidate the mechanisms and potential therapeutic interventions for improving pregnancy outcomes in individuals with Vit D deficiency and RPL. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusion To evaluate the levels of serum rare earth elements (REEs): lutetium [Lu], praseodymium [Pr], samarium [Sm], dysprosium [Dy], and cerium [Ce] in pregnant women with recurrent pregnancy loss (RPL) and evaluate their relationship with total antioxidant capacity (TAC) and 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG), a marker of DNA damage.A case‐controlled study was conducted on a cohort of 60 female participants, with first‐trimester healthy pregnant women as the control group and pregnant women with a history of consecutive abortions as the recurrent pregnancy loss (RPL) group. Following blood collection, serum concentrations of Lu, Pr, Sm, Dy, and Ce were measured using an inductively coupled plasma mass spectrophotometer (ICP‐MS). Oxidative stress and DNA damage were evaluated through TAC and DNA damage marker (8‐OHdG).Serum levels of Lu, Pr, Sm, Dy, and Ce were higher in women with RPL compared with control (P < 0.001). Intriguingly, a strong significant negative correlation was observed between TAC and REEs (P < 0.05). Lu, Dy, and Ce demonstrated a significant positive correlation with increased DNA damage in the RPL group (P < 0.05). Contrary, there was no evidence of a correlation between 8‐OHdG and Pr and Sm.The study highlights a potential association between Lu, Sm, Dy, and Ce and an increased risk of RPL, highlighting REE‐induced toxicity as a major risk factor for RPL. The outcome of the study is to advance our understanding of the interplay between rare earth elements and RPL, with potential implications for reproductive medicine, environmental health, and the development of preventive strategies for individuals at risk of RPL. [ABSTRACT FROM AUTHOR]

Background: Recurrent pregnancy loss (RPL) affects women's reproductive health seriously, with immune dysfunction playing a key role in its cause, yet the exact mechanisms remain elusive. We aim to investigate potential mechanisms and identify biomarkers linked to RPL. Methods: Immune cytokine testing and metabolomic profiling were conducted on the serum of 34 RPL patients and 30 healthy individuals. The metabolic pathways of the differential metabolites were analyzed, and specific metabolites were validated through targeted profiling. Potential biomarkers were identified, and the relationships between immune cytokines and differential metabolites were explored. Results: In the RPL group, serum interleukin-6 and interleukin-10 levels were significantly higher, while interleukin-2 and interferon-g were significantly lower. A total of 296 differential metabolites were detected by untargeted metabolomic profiling between the RPL and control groups, with most linked to amino acid metabolism. Targeted metabolomic profiling of amino acid metabolism revealed upregulation of indole-3-acetic acid, tyrosine, glycine, isoleucine, tryptophan, lysine, aspartic acid, arginine, leucine, threonine, glutamic acid, cystine, and phenylpyruvic acid (PPA) in the RPL group. Moreover, PPA and 5-hydroxy-Ltryptophan showed great potential in predicting RPL in a diagnostic model. Cystine and tyrosine were associated with immune cytokines in correlation analysis. Conclusion: The study highlights the role of amino acid metabolism in RPL pathogenesis, suggesting that PPA and 5-HTP may be potential predictive indicators, while cystine and tyrosine may potentially regulate immune responses related to RPL. Further investigation into the molecular mechanisms underlying these findings could potentially result in the creation of novel diagnostic and therapeutic approaches for RPL. [ABSTRACT FROM AUTHOR]

Reproductive disorders are common events in modern reproductive medicine, occurring both in spontaneous and assisted pregnancies. Studies on the molecular mechanisms of implantation disorders in thin endometria, including the study of gene transcriptional activities, have shed light on the identification of the potential biological markers of endometrial receptivity. Background/Objectives: The goal of this study was to reveal the significantly dysregulated selected gene expressions between RIF and RPL patients with thin endometria. Methods: Endometrial samples were collected from RIF patients (n = 20) and RPL patients (n = 19) during the implantation window days (LH + 7—LH + 10) of their natural menstrual cycles. Ten genes were chosen as the target genes regarding their possible relations with the implantation process. The total RNA was purified and reverse-transcribed, and gene expressions were quantified by RT-PCR. Results: The expressions of the IL-15, INFG, and HPRT1 genes were significantly decreased in the RIF patients with thin endometria compared to the RPL patients (log2 fold change = 0.92, p = 0.023 for IL-15; log2 fold change = 1.24, p = 0.046 for INFG; and log2 fold change = 0.579, p = 0.046 for HPRT1). There were no significant differences in the expressions of the CXCL8, CXCL1, MMP10, C4BPA, TNC, VEGFB, and HAND2 genes between the groups. Conclusions: Decreased expressions of the IL-15, INFG, and HPRT1 genes were found in patients with RIF with thin endometria compared to the endometria of women with RPL. This has practical significance for clinicians for the differentiated prescription of immunomodulatory therapy in patients undergoing ART programs. [ABSTRACT FROM AUTHOR]

Background Objectives Materials and methods Results Discussion Conclusion Recurrent pregnancy loss is characterized by three or more consecutive pregnancy losses. Although the causes of recurrent pregnancy loss are often unknown, chromosomal defects and fetal anomalies account for a significant proportion of cases. Previous research has primarily focused on maternal factors, but recent attention has shifted to the role of male lifestyle factors.This study examined how male lifestyle factors and chronic illnesses affect recurrent pregnancy loss in a Danish cohort. Objectives included analyzing demographic and clinical features, as well as assessing lifestyle factors and pregnancy outcomes.We included 741 males referred to the Danish recurrent pregnancy loss unit between 2009 and 2021, alongside a control group of 1173 males from the PREGCO study. Data on demography, clinical features, lifestyle factors, and pregnancy outcomes were collected and analyzed.The recurrent pregnancy loss group had a higher mean age compared to the controls. Although there was a trend suggesting a higher prevalence of obesity in the recurrent pregnancy loss group, statistical significance was not reached. The prevalence of chronic illnesses was similar in both groups. In the recurrent pregnancy loss group, a higher body mass index and history of previous or current smoking were associated with a lower pregnancy rate, and men who never smoked had an increased likelihood of achieving pregnancy. However, these associations lost significance after adjusting for potential confounders.The study suggests an association between male obesity and smoking, and decreased pregnancy rates after referral for recurrent pregnancy loss. However, further research is needed to understand the underlying mechanisms and establish causality in this association.The study reveals potential associations between male smoking, male obesity, and reduced pregnancy rates in individuals referred for recurrent pregnancy loss. These findings emphasize the importance of considering male lifestyle factors in the evaluation and management of recurrent pregnancy loss. [ABSTRACT FROM AUTHOR]

Recurrent pregnancy loss (RPL), defined as two or more pregnancy losses before the 24th week of gestation, affects 1%–3% of women worldwide. Approximately, 40% of RPL cases are secondary RPL (sRPL), where women have given birth before facing pregnancy losses. The underlying causes of RPL remain unclear, but immune‐related factors may play a role. Previously, a randomised controlled trial using immunoglobulin (IVIG) in sRPL women with a history of four pregnancy losses performed in our RPL unit did not show significant effects of IVIG treatment overall. Yet, some evidence suggests potential benefits for a subset of sRPL patients. In the cohort used for the randomised controlled trial, we examined the role of maternal HLA class II‐presented fetal HLA‐derived epitopes in sRPL using the predicted indirectly recognisable HLA epitopes (PIRCHE‐II) algorithm. In the placebo group, sRPL mothers with an anti‐HLA antibody response had higher PIRCHE‐II scores when having a live birth compared with sRPL women who experienced another pregnancy loss. This difference was not observed in the IVIG‐treated group. Furthermore, as a proxy for T‐cell memory, the number of overlapping peptides between the two paternal haplotypes in couples having live births without treatment displayed a larger number of overlapping peptides. This effect was primarily driven by class II‐derived peptides. These results suggest that specific combinations of sRPL mothers and fathers, particularly those with an anti‐HLA antibody response, may generate higher PIRCHE‐II scores, which could contribute to successful live births. Understanding these immune interactions may provide insights for personalised diagnostic and therapeutic strategies in sRPL. [ABSTRACT FROM AUTHOR]

Problem: Recurrent pregnancy loss (RPL) is defined as the failure of two or more pregnancies and affects approximately 5% of couples, often without a clear cause. The etiologies of RPL include factors such as maternal age, endocrine dysfunction, uterine abnormalities, chromosomal abnormalities, thrombophilias, infections, and autoimmune disorders. However, these conditions account for only 50%–60% of RPL cases. Research has explored whether an altered immune system, compared to the physiological state, may be linked to RPL. This review aims to determine whether specific immunophenotypes are associated with unexplained Recurrent Pregnancy Loss (uRPL) and whether targeted therapies addressing specific immunophenotypic alterations can improve pregnancy outcomes. Methods: A literature review was conducted using Pubmed/Medline, Scopus, and Embase databases, analyzing data from 95 articles published between 2001 and 2023. The roles of various cells of the immune system (B lymphocytes, T lymphocytes, natural killer cells, macrophages) in different tissues (peripheral blood, menstrual blood) were specifically investigated in women with uRPL. Discussion and Conclusion: Specific immunophenotypes have been demonstrated to be associated with this condition. However, there is a need to standardize immunophenotyping assays and conduct more trials to stratify RPL risk and improve potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Insulin resistance (IR), hyperuricemia (HUA), and recurrent pregnancy loss (RPL) elevate the risk of cardiovascular disease and metabolic disorders, while also impacting reproductive health. The relationship between IR, HUA, and RPL has not been thoroughly investigated. This study investigates the relationship between four IR surrogates and the risk of HUA in RPL patients. Methods: Data from a real‐world study on RPL in China were analyzed using multivariable regression to determine the relationship between HUA and triglyceride and glucose (TyG) index, triglyceride glucose‐body mass index (TyG‐BMI), triglyceride to high‐density lipoprotein cholesterol (TG/HDL‐c) ratio, and metabolic score for insulin resistance (METS‐IR). The predictive ability of these surrogates for detecting HUA in RPL patients was evaluated using the area under the curve and receiver operating characteristic analysis. Sensitivity analysis was performed using bootstrapping resampling. Results: The study included 769 patients with a mean age of 30 ± 4 years old, 8.32% of whom had HUA. Four IR surrogates were closely related to HUA in patients of RPL after adjusting for age, menstrual cycle, creatinine, alanine transaminase, aspartate transaminase, total cholesterol, homocysteine, and low‐density lipoprotein, with area under the curve values of TyG index (OR = 0.693, 95% confidence interval [CI]: 0.626, 0.759), TyG‐BMI (OR = 0.731 95% CI: 0.657, 0.805), TG/HDL‐C (OR = 0.703, 95% CI: 0.641, 0.764), and METS‐IR (OR = 0.728, 95% CI: 0.655, 0.799). Bootstrap resampling yielded similar results. Conclusions: The TyG index, TyG‐BMI, TG/HDL‐c, and METS‐IR significantly correlated with HUA in patients with RPL. The TyG‐BMI had the highest predictive value of the four IR surrogates. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Could the risk of subsequent pregnancy loss be predicted based on the risk factors of recurrent pregnancy loss (RPL) patients? SUMMARY ANSWER A nomogram, constructed from independent risk factors identified through multivariate logistic regression, serves as a reliable tool for predicting the likelihood of subsequent pregnancy loss in RPL patients. WHAT IS KNOWN ALREADY Approximately 1–3% of fertile couples experience RPL, with over half lacking a clear etiological factor. Assessing the subsequent pregnancy loss rate in RPL patients and identifying high-risk groups for early intervention is essential for pregnancy counseling. Previous prediction models have mainly focused on unexplained RPL, incorporating baseline characteristics such as age and the number of previous pregnancy losses, with limited inclusion of laboratory and ultrasound indicators. STUDY DESIGN, SIZE, DURATION The retrospective study involved 3387 RPL patients who initially sought treatment at the Reproductive Immunology Clinic of Renji Hospital, Shanghai Jiao Tong University School of Medicine, between 1 January 2020 and 31 December 2022. Of these, 1153 RPL patients met the inclusion criteria and were included in the analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS RPL was defined as two or more pregnancy losses (including biochemical pregnancy loss) with the same partner before 28 weeks of gestation. Data encompassing basic demographics, laboratory indicators (autoantibodies, peripheral immunity coagulation, and endocrine factors), uterine and endometrial ultrasound results, and subsequent pregnancy outcomes were collected from enrolled patients through initial questionnaires, post-pregnancy visits fortnightly, medical data retrieval, and telephone follow-up for lost patients. R software was utilized for data cleaning, dividing the data into a training cohort (n = 808) and a validation cohort (n = 345) in a 7:3 ratio according to pregnancy success and pregnancy loss. Independent predictors were identified through multivariate logistic regression. A nomogram was developed, evaluated by 10-fold cross-validation, and compared with the model incorporating solely age and the number of previous pregnancy losses. The constructed nomogram was evaluated using the AUC, calibration curve, decision curve analysis (DCA), and clinical impact curve analysis (CICA). Patients were then categorized into low- and high-risk subgroups. MAIN RESULTS AND THE ROLE OF CHANCE We included age, number of previous pregnancy losses, lupus anticoagulant, anticardiolipin IgM, anti-phosphatidylserine/prothrombin complex IgM, anti-double-stranded DNA antibody, arachidonic acid-induced platelet aggregation, thrombin time and the sum of bilateral uterine artery systolic/diastolic ratios in the nomogram. The AUCs of the nomogram were 0.808 (95% CI: 0.770–0.846) in the training cohort and 0.731 (95% CI: 0.660–0.802) in the validation cohort, respectively. The 10-fold cross-validated AUC ranged from 0.714 to 0.925, with a mean AUC of 0.795 (95% CI: 0.750–0.839). The AUC of the nomogram was superior compared to the model incorporating solely age and the number of previous pregnancy losses. Calibration curves, DCAs, and CICAs showed good concordance and clinical applicability. Significant differences in pregnancy loss rates were observed between the low- and high-risk groups (P  <   0.001). LIMITATIONS, REASONS FOR CAUTION This study was retrospective and focused on patients from a single reproductive immunology clinic, lacking external validation data. The potential impact of embryonic chromosomal abnormalities on pregnancy loss could not be excluded, and the administration of medication to all cases impacted the investigation of risk factors for pregnancy loss and the model's predictive efficacy. WIDER IMPLICATIONS OF THE FINDINGS This study signifies a pioneering effort in developing and validating a risk prediction nomogram for subsequent pregnancy loss in RPL patients to effectively stratify their risk. We have integrated the nomogram into an online web tool for clinical applications. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the National Natural Science Foundation of China (82071725). All authors have no competing interests to declare. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Cytokines are a type of protein that play an important role in the immune response and can also affect many physiological processes in the body. Cytokine polymorphisms refer to genetic variations or mutations that occur within the genes that code for cytokines, which may affect the level of cytokine production and function. Some cytokine polymorphisms have been associated with an increased risk of developing certain diseases, while others may be protective or have no significant effect on health. In recent years, the role of cytokine polymorphisms in the development of recurrent pregnancy loss (RPL) has been studied. RPL or miscarriage is defined as the occurrence of two or more consecutive pregnancy losses before the 20th week of gestation. There are diverse causes leading to RPL, including genetic, anatomical, hormonal, and immunological factors. With regard to cytokine polymorphisms, a few of them have been found to be associated with an increased risk of RPL, for instance, variations in the genes that code for interleukin‐6, tumor necrosis factor‐alpha, and interleukin‐10. The exact mechanisms by which cytokine polymorphisms affect the risk of recurrent miscarriage are still being studied, and further research is essential to fully understand this complex condition. This brief review aims to summarize the recent literature on the association between cytokine polymorphisms and RPL. Synopsis: Several studies indicate an increased risk of recurrent pregnancy loss in cytokine polymorphisms, specifically for interleukin‐6, tumor necrosis factor‐alpha, and interleukin‐10. [ABSTRACT FROM AUTHOR]

Background: The endometrium holds a crucial role in reproduction by supporting blastocyst adhesion, cytotrophoblast invasion and fetal development. Among the various uterine disorders, endometritis, particularly chronic endometritis (CE), has gained attention due to its association with adverse reproductive outcomes (recurrent pregnancy loss (RPL), recurrent implantation failure (RIF), and infertility). The association between CE and adverse reproductive outcomes stresses the necessity for comprehensive diagnostic and therapeutic strategies to optimize fertility outcomes and support individuals in their journey towards parenthood. Aim: To explore the relationship between CE and reproductive disorders. Methods: Following PRISMA guidelines, a systematic review and meta-analysis using published data from 1990 to 2024 were carried out. Results: A population of 1,038 women was included. Regarding CE-infertility association, a positive correlation was found, with 19.46% CE rate in infertile women compared to 7.7% in controls (OR: 2.96, 95% CI 1.53-5.72, p 0.001). No significant association was observed between RIF and CE (OR: 1.10, 95% CI 0.26-4.61, p 0.90), CE rates in both groups were relatively comparable, with 6.35% in women with RIF and 5.8% in controls. On the opposite, a strong association between CE and RPL was found, reporting a CE rate of 37.6% in RPL cases compared to 16.4% in controls (OR: 3.59, 95% CI 2.46-5.24, p < 0.00001). Conclusions: CE appears to be associated to infertility and RPL, while no significant association was noted in cases of RIF. [ABSTRACT FROM AUTHOR]

Factors contributing to recurrent pregnancy loss (RPL) in more than half of the cases are still unknown. The incidence and societal impact of this condition requires urgent elucidation of the mechanisms behind it, which could aid in significant improvement of clinical management. Using a highly efficient in-solution digestion method and label-free data-independent LC-MS/MS acquisition with ion mobility, we performed comparative proteomics analysis of the decidua tissues from 19 RPL patients and 10 controls. Differentially abundant proteins (DAPs) were compared and correlated with 3 publicly available transcriptomic datasets and the expression of selected biomarkers was tested by qPCR in decidua and chorionic villi from an extended cohort. From 1952 proteins identified based on ≥2 peptides, the statistically significant difference in abundance (Anova p ≤ 0.05) and fold change ≥1.2 showed 85 proteins. Pathway analysis using Reactome, KEGG and Wiki pathways identified enrichment of "Signaling by ROBO receptors", "RNA degradation" and "Cytoplasmic Ribosomal Proteins". The correlation between protein and gene expression in decidua revealed that the down-regulated ribosomal proteins in our dataset (RPS15, RPS17, RPL27A, RPL35A and RPL18) showed the same regulation trend at the mRNA level, which was later confirmed for transcripts of RPS15 and RPL18 in our cohort. Our data suggests that the potential causes of RPL from the maternal side could be associated with impaired RNA processing machinery. Furthermore, the list of DAPs in RPL opens future investigations in terms of screening novel gene variants predisposing to pregnancy failure and developing biomarkers for RPL risk. [Display omitted] • Protein signatures linked to RPL in decidua are identified. • The ribosomal protein's levels are down-regulated in RPL decidua. • Processes associated with RNA degradation are upregulated in RPL decidua. [ABSTRACT FROM AUTHOR]

Background: Recurrent pregnancy loss (RPL) frequently links to a prolonged endometrial receptivity (ER) window, leading to the implantation of non-viable embryos. Existing ER assessment methods face challenges in reliability and invasiveness. Radiomics in medical imaging offers a non-invasive solution for ER analysis, but complex, non-linear radiomic-ER relationships in RPL require advanced analysis. Machine learning (ML) provides precision for interpreting these datasets, although research in integrating radiomics with ML for ER evaluation in RPL is limited. Objective: To develop and validate an ML model that employs radiomic features derived from multimodal transvaginal ultrasound images, focusing on improving ER evaluation in RPL. Methods: This retrospective, controlled study analyzed data from 346 unexplained RPL patients and 369 controls. The participants were divided into training and testing cohorts for model development and accuracy validation, respectively. Radiomic features derived from grayscale (GS) and shear wave elastography (SWE) images, obtained during the window of implantation, underwent a comprehensive five-step selection process. Five ML classifiers, each trained on either radiomic, clinical, or combined datasets, were trained for RPL risk stratification. The model demonstrating the highest performance in identifying RPL patients was selected for further validation using the testing cohort. The interpretability of this optimal model was augmented by applying Shapley additive explanations (SHAP) analysis. Results: Analysis of the training cohort (242 RPL, 258 controls) identified nine key radiomic features associated with RPL risk. The extreme gradient boosting (XGBoost) model, combining radiomic and clinical data, demonstrated superior discriminatory ability. This was evidenced by its area under the curve (AUC) score of 0.871, outperforming other ML classifiers. Validation in the testing cohort of 215 subjects (104 RPL, 111 controls) confirmed its accuracy (AUC: 0.844) and consistency. SHAP analysis identified four endometrial SWE features and two GS features, along with clinical variables like age, SAPI, and VI, as key determinants in RPL risk stratification. Conclusion: Integrating ML with radiomics from multimodal endometrial ultrasound during the WOI effectively identifies RPL patients. The XGBoost model, merging radiomic and clinical data, offers a non-invasive, accurate method for RPL management, significantly enhancing diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Objective To explore the differences of etiology of recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL) . Methods Patients with RIF (n = 315) and patients with RPL (n = 376) admitted to the Reproductive Center of the First Affiliated Hospital of Sun Yat-sen University from June 2018 to June 2021 were included. General and etiological data were collected to compare the differences in baseline data and etiological composition. Relative risk factors of the etiology of these two conditions were identified by multivariate regression analysis. Results Univariate analysis showed a significantly higher proportion of chronic endometritis, endometrial polyps, endometriosis, endometriosis complicated with polyps, diminished ovarian reserve and a significantly lower proportion of unexplained cause in the RIF group than in the RPL group (all P < 0.05) . Multivariate logistic regression analysis showed that the incidence of chronic endometritis (OR=3.044, 95%CI 1.849-5.011, P < 0.001), endometrial polyps (OR=3.769, 95%CI 1.670-8.510, P < 0.001), endometriosis (OR=3.812, 95%CI 2.131-6.819, P < 0.001) and diminished ovarian reserve (OR=2.175, 95%CI 1.285-3.683, P = 0.004) in the RIF group was significantly higher than that in the RPL group. The proportion of patients with lower anti-Mullerian hormone levels (OR=0.917, 95%CI 0.864-0.973, P = 0.004) in the RIF group was higher compared with that in the RPL group. Conclusion Chronic endometritis, endometrial polyps, endometriosis, decreased anti-Mullerian hormone level and diminished ovarian reserve are more common in RIF patients, and the screening and monitoring of the above lesions should be strengthened in the subsequent practice of assisted reproduction. [ABSTRACT FROM AUTHOR]

Recurrent pregnancy loss (RPL) is thought to be related to maternal-fetal immune tolerance disorders. Immune monitoring of RPL patients mainly involves two aspects: inflammatory factors and immune cells. However, most observational studies have reported controversial findings. This study aimed to confirm whether abnormal inflammatory factors and immune cells in peripheral blood may lead to RPL, and guide clinical immune monitoring. We demonstrated causality using two-sample Mendelian randomization. Sensitivity analysis, reverse Mendelian randomization and meta-analysis were used to enhance the effectiveness of the results. There was a causal relationship between the level of IL-12 (OR = 1.78, 95% CI = 1.25–2.55; P = 0.00149) and RPL for 41 inflammatory factors. We screened 5 groups of immune cell subtypes that were causally associated with RPL: switched memory B-cell absolute count (OR = 0.66, 95% CI = 0.49–0.87, P = 0.00406), IgD + CD24 + B-cell absolute count (OR = 0.69, 95% CI = 0.53–0.88, P = 0.00319), CD39 + resting CD4 regulatory T-cell %CD4 regulatory T-cell (OR = 0.86, 95% CI = 0.78–0.95, P = 0.00252), activated & resting CD4 regulatory T-cell %CD4 regulatory T-cell (OR = 0.89, 95% CI = 0.82–0.97, P = 0.00938) and CD45 RA + CD28-CD8 + T-cell %CD8 + T-cell (OR = 0.99, 95% CI = 0.98-1.00, P = 0.01231). In terms of inflammatory factors, a causal relationship between IL-12 and RPL in peripheral blood was confirmed. We also identified five immune cell phenotypes that play a protective role. This suggests that there may be protective B cells and CD8 + T-cell subsets in peripheral blood, and the protective effect of Tregs was proved again. Immune monitoring of peripheral blood in patients with RPL seems to be necessary and the foundation for precision medicine. [ABSTRACT FROM AUTHOR]

STUDY QUESTION What are the outcomes of pregnancies exposed to hydroxychloroquine (HCQ) in women with a history of recurrent pregnancy loss (RPL), and what factors predict the course of these pregnancies beyond the first trimester? SUMMARY ANSWER In our cohort of pregnancies in women with a history of RPL exposed to HCQ early in pregnancy, we found that the only factor determining the success of these pregnancies was the number of previous miscarriages. WHAT IS KNOWN ALREADY Dysregulation of the maternal immune system plays a role in RPL. HCQ, with its dual immunomodulating and vascular protective effects, is a potential treatment for unexplained RPL. STUDY DESIGN, SIZE, DURATION The FALCO (Facteurs de récidive précoce des fausses couches) registry is an ongoing French multicenter infertility registry established in 2017 that includes women (aged from 18 to 49 years) with a history of spontaneous RPL (at least three early miscarriages (≤12 weeks of gestation (WG)) recruited from several university hospitals. PARTICIPANTS/MATERIALS, SETTING, METHODS Spontaneous pregnancies enrolled in the FALCO registry with an exposure to HCQ (before conception or at the start of pregnancy) were included. Pregnancies concomitantly exposed to tumor necrosis factor inhibitors, interleukin-1 and -2 inhibitors, intravenous immunoglobulin, and/or intravenous intralipid infusion, were excluded. Concomitant treatment with low-dose aspirin (LDA), low-molecular weight heparin (LMWH), progesterone, and/or prednisone was allowed. All patients underwent the recommended evaluations for investigating RPL. Those who became pregnant received obstetric care in accordance with French recommendations and were followed prospectively. The main endpoint was the occurrence of a pregnancy continuing beyond 12 WG, and the secondary endpoint was the occurrence of a live birth. MAIN RESULTS AND THE ROLE OF CHANCE One hundred pregnancies with HCQ exposure in 74 women were assessed. The mean age of the women was 34.2 years, and the median number of previous miscarriages was 5. Concomitant exposure was reported in 78 (78%) pregnancies for prednisone, 56 (56%) pregnancies for LDA, and 41 (41%) pregnancies for LMWH. Sixty-two (62%) pregnancies ended within 12 WG, the other 38 (38%) continuing beyond 12 WG. The risk of experiencing an additional early spontaneous miscarriage increased with the number of previous miscarriages, but not with age. The distributions of anomalies identified in RPL investigations and of exposure to other drugs were similar between pregnancies lasting ≤12 WG and those continuing beyond 12WG. The incidence of pregnancies progressing beyond 12 WG was not higher among pregnancies with at least one positive autoantibody (Ab) (i.e. antinuclear Ab titer ≥1:160, ≥1 positive conventional and/or non-conventional antiphospholipid Ab, and/or positive results for ≥1 antithyroid Ab) without diminished ovarian reserve (18/51, 35.3%) than among those without such autoantibody (18/45, 40.0%) (P  =   0.63). Multivariate analysis showed that having ≤4 prior miscarriages was the only factor significantly predictive for achieving a pregnancy > 12 WG, after adjustment for age and duration of HCQ use prior to conception (adjusted odds ratio (OR) = 3.13 [1.31–7.83], P  =   0.01). LIMITATIONS, REASONS FOR CAUTION Our study has limitations, including the absence of a control group, incomplete data for the diagnostic procedure for RPL in some patients, and the unavailability of results from endometrial biopsies, as well as information about paternal age and behavioral factors. Consequently, not all potential confounding factors could be considered. WIDER IMPLICATIONS OF THE FINDINGS Exposure to HCQ in early pregnancy for women with a history of RPL does not seem to prevent further miscarriages, suggesting limited impact on mechanisms related to the maternal immune system. STUDY FUNDING/COMPETING INTEREST(S) The research received no specific funding, and the authors declare no competing interests. TRIAL REGISTRATION NUMBER clinicaltrial.gov NCT05557201. [ABSTRACT FROM AUTHOR]

Purpose: To assess the risk of adverse obstetric and perinatal outcomes in subsequent pregnancies among women with a history of recurrent pregnancy loss (RPL). Methods: Relevant studies were identified by searching the PubMed, Web of Science, and Embase databases. The pooled effect sizes were reported as odds ratios (OR) with their respective 95% confidence intervals (95% CI), and data analysis was performed using the random effects model. Results: A total of 26 studies involving 4,730,728 women were included in this meta-analysis. The results reveal a significant increase in the prevalence of placenta accreta cases after RPL compared to women without RPL (pooled OR 4.04; 95% CI 1.16–14.15; 2 studies; I2 = 94%; P = 0.03). However, no elevated risk of aneuploidies (pooled OR 1.69, 95% CI 0.73–3.90; 5 studies; I2 = 48%; P = 0.22) or congenital anomalies (pooled OR 1.12, 95% CI 0.97–1.30; 7 studies; I2 = 13%; P = 0.12) in subsequent pregnancies of women with RPL was observed. Additionally, a moderate increase in the risk of various other obstetric and perinatal outcomes was found. The magnitude of the elevated risk of these adverse outcomes varied depending on the region. Conclusions: Women with a history of RPL exhibit a significantly elevated risk of placenta accreta in subsequent pregnancies, along with a moderate increase in the risk of various other adverse obstetric and perinatal outcomes. However, RPL does not signify an increased risk of aneuploidies or congenital anomalies in a consecutive pregnancy. [ABSTRACT FROM AUTHOR]

Background Recurrent pregnancy loss (RPL) is a common problem affecting many women. This study aimed to investigate the baseline characteristics of 400 women with RPL and to examine any differences in baseline characteristics of the recruited women with RPL throughout the years. Methods This study used retrospective data, which included the records of patients with RPL who visited King Khalid University Hospital’s obstetric clinic between 2019 and 2022. The records of 400 patients who met the inclusion criteria were reviewed and analyzed. Results The mean age of enrolled women was 36.5 ± 5.4 years, and the mean RPL was 3.8 ± 2.5. The study also revealed that there were significant statistical differences in obesity and vitamin D deficiency among women with RPL based on year (P = 0.013 and P = 0.036, respectively), whereas no significant statistical differences were found between women with RPL in terms of age, parity, diabetes, hypothyroidism, hyperprolactinemia, antiphospholipid antibodies (APLs), uterine malformation, or consanguinity. Conclusion Advanced maternal age, number of previous miscarriages, parity, diabetes, hypothyroidism, APLs, uterine malformations, first-degree consanguinity, and vitamin D deficiency were found to be significant risk factors associated with RPL among women in Saudi Arabia.

Abstract Background and aim Recurrent pregnancy loss (RPL), also known as recurrent implantation failure (RIF), is a distressing condition affecting women characterized by two or more consecutive miscarriages or the inability to carry a pregnancy beyond 20 weeks. Immunological factors and genetic variations, particularly in Vit D Binding Protein (VDBP), have gained attention as potential contributors to RPL. This study aimed to provide insight into the immunological, genetic, and metabolic networks underlying RPL, placing a particular emphasis on the interactions between VDBP, HLA-G1, CTLA-4, ENTPD1, and adenosine-fetal-maternal conflict crosstalk. Methods A retrospective study included 198 women with three or more consecutive spontaneous abortions. Exclusion criteria comprised uterine abnormalities, endocrine disorders, parental chromosomal abnormalities, infectious factors, autoimmune diseases, or connective tissue diseases. Immunological interplay was investigated in 162 female participants, divided into two groups based on their Vit D levels: normal Vit D-RPL and low Vit D-RPL. Various laboratory techniques were employed, including LC/MS/MS for Vit D measurement, ELISA for protein detection, flow cytometry for immune function analysis, and molecular docking for protein–ligand interaction assessment. Results General characteristics between groups were significant regarding Vit D and glucose levels. Low Vit D levels were associated with decreased NK cell activity and downregulation of HLA-G1 and HLA-G5 proteins, while CTLA-4 revealed upregulation. VDBP was significantly downregulated in the low Vit D group. Our findings highlight the intricate relationship between Vit D status and adenosine metabolism by the downregulation of SGLT1, and NT5E, key components of adenosine metabolism, suggests that Vit D deficiency may disrupt the regulation of adenosine levels, leading to an impaired reproductive outcome. HNF1β, a negative regulator of VDBP, was upregulated, while HNF1α, a positive regulator, was downregulated in low Vit D women after RPL. Molecular docking analysis revealed crucial residues involved in the interaction between Vit D and HNF1β. Conclusion Collectively, these findings underscore the importance of Vit D in modulating immune function and molecular pathways relevant to pregnancy maintenance, highlighting the need for further research to elucidate the mechanisms and potential therapeutic interventions for improving pregnancy outcomes in individuals with Vit D deficiency and RPL.

Background: Recurrent pregnancy loss (RPL) is a common complication of pregnancy globally, characterized by multiple miscarriages but with poorly explained etiologies. Insofar as a state of low-grade inflammation (LGI) accompanies RPL, this study explores the link between RPL and markers of LGI among Kazakhstani women. Methods: The retrospective study was conducted on 112 Kazakh women, comprising 64 with a confirmed diagnosis of RPL and 48 women with two or more uncomplicated pregnancies serving as controls. Statistical analysis was performed on SPSS 29 software. Results: All tested blood analytes, including CRP, glucose, cholesterol, LDL-cholesterol, Hemoglobin, and RBC counts, were negatively associated with RPL. The only exception was neutrophil values having a positive association with RPL despite a lack of significant correlation between groups. Conclusion: The study shows a marginal association between the LGI biomarkers considered and the overall risk factors of RPL in Kazakh women, which is in apparent contradiction with earlier studies. The absence of parallel studies in Central Asian countries hampers the analysis of study trends in related communities. Future case-control studies with more sample sizes are needed to explore the RPL biomarkers in depth.

Objective To explore the differences of etiology of recurrent implantation failure （RIF） and recurrent pregnancy loss （RPL）. Methods Patients with RIF （n = 315） and patients with RPL （n = 376） admitted to the Reproductive Center of the First Affiliated Hospital of Sun Yat-sen University from June 2018 to June 2021 were included. General and etiological data were collected to compare the differences in baseline data and etiological composition. Relative risk factors of the etiology of these two conditions were identified by multivariate regression analysis. Results Univariate analysis showed a significantly higher proportion of chronic endometritis， endometrial polyps， endometriosis， endometriosis complicated with polyps， diminished ovarian reserve and a significantly lower proportion of unexplained cause in the RIF group than in the RPL group （all P <0.05）. Multivariate logistic regression analysis showed that the incidence of chronic endometritis （OR=3.044， 95%CI 1.849-5.011， P < 0.001）， endometrial polyps （OR=3.769， 95%CI 1.670-8.510， P < 0.001）， endometriosis （OR=3.812， 95%CI 2.131-6.819， P < 0.001） and diminished ovarian reserve （OR=2.175， 95%CI 1.285-3.683， P = 0.004） in the RIF group was significantly higher than that in the RPL group. The proportion of patients with lower anti-Mullerian hormone levels （OR=0.917， 95%CI 0.864-0.973， P = 0.004） in the RIF group was higher compared with that in the RPL group. Conclusion Chronic endometritis， endometrial polyps， endometriosis， decreased anti-Mullerian hormone level and diminished ovarian reserve are more common in RIF patients， and the screening and monitoring of the above lesions should be strengthened in the subsequent practice of assisted reproduction.

Background: Interleukin (IL) genes are essential for regulating the immune and inflammatory processes. Epidemiological studies suggest that polymorphisms in IL genes are associated with a higher risk of recurrent pregnancy loss (RPL). Objective: This study aimed to examine the association between RPL risk and IL gene polymorphisms. Materials and Methods: A comprehensive search of the literature was conducted using PubMed, Google Scholar and Embase to identify relevant studies published until May 30, 2024. A total of 58 studies involving 13,696 participants (both RPL cases and controls) were included. Pooled odds ratios and 95% confidence intervals were calculated using fixed- or random-effects models, as appropriate, with ReviewManager version 5.4, Cochrane RoB Tool 2 and G*Power 3.1 software. Results: The meta-analysis revealed significant correlations between RPL risk and genetic variations in IL-1β (-511T > C), IL-6 (-174 G > C) and IL-10 (-1082 A > G and-592 C > A), with statistical significance set at P < 0.05. Ethnic subgroup analysis showed that IL-1β (-511T > C) and IL-10 (-592 C > A) variations were strongly associated with RPL risk in Asian populations. Interpretation: Our research suggests that genetic variations in IL-1β (-511T > C), IL-6 (-174 G > C) and IL-10 (-1082 A > G and-592 C > A) are associated with susceptibility to RPL. Limitation: Our meta-analysis concentrated exclusively on single-factor studies and did not consider potential confounding variables such as age, environmental influences and lifestyle, which could affect susceptibility to RPL. In addition, the lack of individual raw data prevented us from investigating gene–environment and gene–gene interactions or the influence of other polymorphisms and cytokines in our analysis. Protocol Registration: http://www.osf.io/qhbva.

Abstract Objective Vitamin D deficiency and variations in the vitamin D binding protein (VDBP) gene may play a role in the development of Polycystic ovary syndrome (PCOS). This study aims to investigate the association of the rs4588 polymorphism with PCOS in Iranian women, as well as its association with infertility and recurrent pregnancy loss (RPL) in these patients. Results The analysis revealed statistically significant differences in the distributions of genotypes and alleles of the rs4588 polymorphism among the three groups (p

Abstract Establishing prediction models of pregnancy outcomes for recurrent pregnancy loss women at specific gestational weeks will provide patients and physicians with more precise information, ultimately leading to time and cost savings associated with unnecessary revisits. Therefore, our aim was to develop a prediction model for first trimester pregnancy loss in RPL patients. We used ultrasound indices during the first trimester of pregnancy in combination with demographic characteristics and commonly used serum markers. The independent risk factors for each week were as follows: age and P in the fifth week; age, mGSD and CRL in the sixth week; age, hCG and CRL in the seventh week; CRL in the eighth week; mGSD and CRL in ninth week. The corresponding AUC was 0.671, 0.796, 0.872, 0.871, 0.813, respectively. There is a linear relationship between age and first trimester pregnancy loss. hCG 48.3 mm in ninth gestational week was associated with a higher risk of pregnancy loss. These models and thresholds may help physicians and patients make more informed decisions together. Further studies are needed to confirm the results.

First-trimester pregnancy losses are commonly attributed to chromosomal abnormalities. The causes of pregnancy loss following transfer of a euploid embryo are not fully elucidated. The aim of this study was to evaluate clinical and embryological parameters for pregnancy failure following the transfer of a single euploid embryo. Pregnancy outcomes of single euploid embryo transfers from a single centre between January 2017 and March 2020 were retrospectively evaluated. Several clinical and embryological parameters were evaluated in consideration to pregnancy outcomes; total pregnancy loss and live birth (LB). Endometrial preparation type, number of previous frozen embryo transfer cycles, history of recurrent pregnancy loss, higher body mass index, presence of endometriosis and/ or adenomyosis and embryo quality were found to be significantly different between two groups. Morphokinetic parameter analysis of 523 euploid embryos using time-lapse imaging did not show any statistical differences between the two groups; however, a significantly higher rate of uneven blastomeres in the cleavage stage was observed in the total pregnancy loss group. Evaluation of clinical and embryological data can reveal possible factors associated with pregnancy loss that can facilitate improved patient consultation. Feasible interventions can potentially increase the chance of achieving an LB.

Abstract Background For women who have experienced recurrent pregnancy loss (RPL), it is crucial not only to treat them but also to evaluate the risk of recurrence. The study aimed to develop a risk predictive model to predict the subsequent early pregnancy loss (EPL) in women with RPL based on preconception data. Methods A prospective, dynamic population cohort study was carried out at the Second Hospital of Lanzhou University. From September 2019 to December 2022, a total of 1050 non-pregnant women with RPL were participated. By December 2023, 605 women had subsequent pregnancy outcomes and were randomly divided into training and validation group by 3:1 ratio. In the training group, univariable screening was performed on RPL patients with subsequent EPL outcome. The least absolute shrinkage and selection operator (LASSO) regression and multivariate logistic regression were utilized to select variables, respectively. Subsequent EPL prediction model was constructed using generalize linear model (GLM), gradient boosting machine (GBM), random forest (RF), and deep learning (DP). The variables selected by LASSO regression and multivariate logistic regression were then established and compared using the best prediction model. The AUC, calibration curve, and decision curve (DCA) were performed to assess the prediction performances of the best model. The best model was validated using the validation group. Finally, a nomogram was established based on the best predictive features. Results In the training group, the GBM model achieved the best performance with the highest AUC (0.805). The AUC between the variables screened by the LASSO regression (16-variables) and logistic regression (9-variables) models showed no significant difference (AUC: 0.805 vs. 0.777, P = 0.1498). Meanwhile, the 9-variable model displayed a well discrimination performance in the validation group, with an AUC value of 0.781 (95%CI 0.702, 0.843). The DCA showed the model performed well and was feasible for making beneficial clinical decisions. Calibration curves revealed the goodness of fit between the predicted values by the model and the actual values, the Hosmer–Lemeshow test was 7.427, and P = 0.505. Conclusions Predicting subsequent EPL in RPL patients using the GBM model has important clinical implications. Future prospective studies are needed to verify the clinical applicability. Trial registration This study was registered in the Chinese Clinical Trial Registry with the registration number of ChiCTR2000039414 (27/10/2020).

Abstract Background Recurrent pregnancy loss (RPL) is a common pregnancy complication that brings great pain to pregnant women and their families. Genetic factors are an important cause reason of RPL. However, clinical research on monogenic diseases with recurrent miscarriage is insufficient. Case presentation Here we reported a Chinese family with RPL and genetic analysis of the abortion and parents. A paternally inherited heterozygous missense variant c.1415T > G (p.V472G) and a maternally inherited heterozygous nonsense variant c.2314del (p.M772*) in TMEM67 gene were identified by trio-exome sequencing. c.2314del (p.M772*) generated a premature stop codon and truncated protein, was classified as “pathogenic”. c.1415T > G (p.V472G) located in extra-cellular region, was classified as “likely pathogenic”. Biallelic variants in TMEM67 gene cause lethal Meckel syndrome 3, consistent with the proband’s prenatal phenotype. Conclusion The current study of the Chinese family expands the pathogenic variant spectrum of TMEM67 and emphasizes the necessity of exome sequencing in RPL condition.

Background: Unexplained recurrent pregnancy loss (URPL) is a clinical dilemma in reproductive fields. Its diagnosis is mainly exclusionary after extensive clinical examination, and some of the patients may still face the risk of miscarriage. Methods: We analyzed follicular fluid (FF) from in vitro fertilization (IVF) in eight patients with URPL without endocrine abnormalities or verifiable causes of abortion and eight secondary infertility controls with no history of pregnancy loss who had experienced at least one normal pregnancy and delivery by direct data-independent acquisition (dDIA) quantitative proteomics to identify differentially expressed proteins (DEPs). In this study, bioinformatics analysis was performed using online software including g:profiler, String, and ToppGene. Cytoscape was used to construct the protein-protein interaction (PPI) network, and ELISA was used for validation. Results: Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the DEPs are involved in the biological processes (BP) of complement and coagulation cascades. Apolipoproteins (APOs) are key proteins in the PPI network. ELISA confirmed that APOB was low-expressed in both the FF and peripheral blood of URPL patients Conclusion: Dysregulation of the immune network intersecting coagulation and inflammatory response is an essential feature of URPL, and this disequilibrium exists as early as the oogenesis stage. Therefore, earlier intervention is necessary to prevent the development of URPL. Moreover, aberrant lipoprotein regulation appears to be a key factor contributing to URPL. The mechanism by which these factors are involved in the complement and coagulation cascade pathways remains to be further investigated, which also provides new candidate targets for URPL treatment. [ABSTRACT FROM AUTHOR]

The high incidence of idiopathic recurrent pregnancy loss (iRPL) may stem from the limited research on male contributory factors. Many studies suggest that sperm DNA fragmentation and oxidative stress contribute to iRPL, but their roles are still debated. MicroRNAs (miRNAs) are short non-coding RNAs that regulate various biological processes by modulating gene expression. While differential expression of specific miRNAs has been observed in women suffering from recurrent miscarriages, paternal miRNAs remain unexplored. We hypothesize that analyzing sperm miRNAs can provide crucial insights into the pathophysiology of iRPL. Therefore, this study aims to identify dysregulated miRNAs in the spermatozoa of male partners of iRPL patients. Total mRNA was extracted from sperm samples of iRPL and control groups, followed by miRNA library preparation and high-output miRNA sequencing. Subsequently, raw sequence reads were processed for differential expression analysis, target prediction, and bioinformatics analysis. Twelve differentially expressed miRNAs were identified in the iRPL group, with eight miRNAs upregulated (hsa-miR-4454, hsa-miR-142-3p, hsa-miR-145-5p, hsa-miR-1290, hsa-miR-1246, hsa-miR-7977, hsa-miR-449c-5p, and hsa-miR-92b-3p) and four downregulated (hsa-miR-29c-3p, hsa-miR-30b-5p, hsa-miR-519a-2-5p, and hsa-miR-520b-5p). Functional enrichment analysis revealed that gene targets of the upregulated miRNAs are involved in various biological processes closely associated with sperm quality and embryonic development. [ABSTRACT FROM AUTHOR]

STUDY QUESTION What is the prevalence of congenital and acquired anomalies of the uterus in women with recurrent pregnancy loss (RPL) of unknown etiology examined using 3D transvaginal ultrasound (US)? SUMMARY ANSWER Depending on the adopted diagnostic criteria, the prevalence of partial septate uterus varies between 7% and 14% and a T-shaped uterus is 3% or 4%, while adenomyosis is 23%, at least one of type 0, type 1 or type 2 myoma is 4%, and at least one endometrial polyp is 4%. WHAT IS KNOWN ALREADY ESHRE and the Royal College of Obstetricians and Gynaecologists guidelines on RPL recommend the adoption of the 3D transvaginal US to evaluate the 'uterine factor'. Nevertheless, there are no published studies reporting the prevalence of both congenital and acquired uterine anomalies as assessed by 3D transvaginal US and diagnosed according to the criteria proposed by the most authoritative panels of experts in a cohort of women with RPL. STUDY DESIGN, SIZE, DURATION This was a retrospective cohort study including 442 women with at least two previous first-trimester spontaneous pregnancy losses (i.e. non-viable intrauterine pregnancies), who referred to the obstetrics and gynecology unit of two university hospitals between July 2020 and July 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS Records of eligible women were reviewed. Women could be included in the study if: they were between 25 and 42 years old; they had no relevant comorbidities; they were not affected by infertility, and they had never undergone ART; they and their partner tested negative to a comprehensive RPL diagnostic work-up; and they had never undergone metroplasty, myomectomy, minimally invasive treatments for uterine fibroids or adenomyomectomy. Expert sonographers independently re-analyzed the stored 2- and 3D transvaginal US images of all included patients. Congenital uterine anomalies (CUAs) were reported according to the American Society for Reproductive Medicine (ASRM) 2021, the ESHRE/European Society for Gynaecological Endoscopy (ESGE) and the Congenital Uterine Malformation by Experts (CUME) criteria. Acquired uterine anomalies were reported according to the International Federation of Gynecology and Obstetrics (FIGO) and the Morphological Uterus Sonographic Assessment (MUSA) criteria. MAIN RESULTS AND THE ROLE OF CHANCE The partial septate uterus was diagnosed in 60 (14%; 95% CI: 11–17%), 29 (7%; 95% CI: 5–9%), and 47 (11%; 95% CI: 8–14%) subjects, according to the ESHRE/ESGE, the ASRM 2021, and the CUME criteria, respectively. The T-shaped uterus was diagnosed in 19 women (4%; 95% CI: 3–7%) according to the ESHRE/ESGE criteria and in 13 women (3%; 95% CI: 2–5%) according to the CUME criteria. The borderline T-shaped uterus (diagnosed when two out of three CUME criteria for T-shaped uterus were met) was observed in 16 women (4%; 95% CI: 2–6%). At least one of FIGO type 0, type 1, or type 2 myoma was detected in 4% of included subjects (95% CI: 3–6%). Adenomyosis was detected in 100 women (23%; 95% CI: 19–27%) and was significantly more prevalent in women with primary RPL and in those with three or more pregnancy losses. At least one endometrial polyp was detected in 4% of enrolled women (95% CI: 3–7%). LIMITATIONS, REASONS FOR CAUTION The absence of a control group prevented us from investigating the presence of an association between both congenital and acquired uterine anomalies and RPL. Second, the presence as well as the absence of both congenital and acquired uterine anomalies detected by 3D US was not confirmed by hysteroscopy. Finally, the results of the present study inevitably suffer from the intrinsic limitations of the adopted classification systems. WIDER IMPLICATIONS OF THE FINDINGS The prevalence of CUAs in women with RPL varies depending on the classification system used. For reasons of clarity, the US reports should always state the name of the uterine anomaly as well as the adopted classification and diagnostic criteria. Adenomyosis seems to be associated with more severe forms of RPL. The prevalence rates estimated by our study as well as the replicability of the adopted diagnostic criteria provide a basis for the design and sample size calculation of prospective studies. STUDY FUNDING/COMPETING INTEREST(S) No specific funding was used. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

The current knowledge on adenomyosis as a risk factor for RPL is very scant. Overall 120 women were included in this retrospective observational study. They were divided in three groups each of which consisted of 40 subjects: Group 1: women with RPL who were diagnosed to have adenomyosis on transvaginal ultrasound (TVS); Group 2: patients with RPL without ultrasonographic findings of adenomyosis; Group 3: patients with ultrasound diagnosis of adenomyosis without RPL and at least one live birth pregnancy. The copresence of endometriosis was also investigated. Among women with RPL, patients with adenomyosis (Group 1) had higher number of pregnancy losses (p = 0.03) and lower age at first pregnancy loss (p = 0.03) than women without adenomyosis (Group 2). Moreover, they had more frequently primary RPL (p = 0.008). Adenomyosis of the inner myometrium was found more frequently (p = 0.04) in patients of Group 1 than in patients of Group 3 in which adenomyosis was mainly in the outer myometrium (p= 0.02). No differences were found in the severity of adenomyosis between these two groups of women. TVS findings for endometriosis were observed more frequently in women with adenomyosis without RPL (Group 3) than in the other two groups of patients. Adenomyosis can be a factor involved in RPL. Differences in adenomyosis localization are associated with different risks for RPL. Patients with RPL should be investigated for the presence of adenomyosis and also for the type and localization of the disease in the different myometrial layers. [ABSTRACT FROM AUTHOR]

Objective: Vitamin D deficiency and variations in the vitamin D binding protein (VDBP) gene may play a role in the development of Polycystic ovary syndrome (PCOS). This study aims to investigate the association of the rs4588 polymorphism with PCOS in Iranian women, as well as its association with infertility and recurrent pregnancy loss (RPL) in these patients. Results: The analysis revealed statistically significant differences in the distributions of genotypes and alleles of the rs4588 polymorphism among the three groups (p < 0.0001). The AC genotype and A allele showed an association with an elevated risk of PCOS and infertility. In this study, no association was found between genotypes and alleles of the rs4588 polymorphism and the risk of RPL in women with PCOS. Subjects with the AA or AC genotype exhibited significantly higher levels of LDL compared to those with the CC genotype. [ABSTRACT FROM AUTHOR]

Establishing prediction models of pregnancy outcomes for recurrent pregnancy loss women at specific gestational weeks will provide patients and physicians with more precise information, ultimately leading to time and cost savings associated with unnecessary revisits. Therefore, our aim was to develop a prediction model for first trimester pregnancy loss in RPL patients. We used ultrasound indices during the first trimester of pregnancy in combination with demographic characteristics and commonly used serum markers. The independent risk factors for each week were as follows: age and P in the fifth week; age, mGSD and CRL in the sixth week; age, hCG and CRL in the seventh week; CRL in the eighth week; mGSD and CRL in ninth week. The corresponding AUC was 0.671, 0.796, 0.872, 0.871, 0.813, respectively. There is a linear relationship between age and first trimester pregnancy loss. hCG < 69,636.6 mIU/ml was associated with a higher risk of pregnancy loss in the seventh gestation week. An mGSD < 18.3 mm, adjusted for age, BMI, and previous pregnancy loss in the sixth week, was linked to an increased risk of first trimester pregnancy loss. A small CRL measurement (less than 2.4 mm, 9.9 mm, 16.9 mm, and 18.6 mm) in the sixth, seventh, eighth and ninth week was closely correlated with higher risk of first trimester pregnancy loss. Furthermore, an mGSD < 33.3 mm and > 48.3 mm in ninth gestational week was associated with a higher risk of pregnancy loss. These models and thresholds may help physicians and patients make more informed decisions together. Further studies are needed to confirm the results. [ABSTRACT FROM AUTHOR]

Background: For women who have experienced recurrent pregnancy loss (RPL), it is crucial not only to treat them but also to evaluate the risk of recurrence. The study aimed to develop a risk predictive model to predict the subsequent early pregnancy loss (EPL) in women with RPL based on preconception data. Methods: A prospective, dynamic population cohort study was carried out at the Second Hospital of Lanzhou University. From September 2019 to December 2022, a total of 1050 non-pregnant women with RPL were participated. By December 2023, 605 women had subsequent pregnancy outcomes and were randomly divided into training and validation group by 3:1 ratio. In the training group, univariable screening was performed on RPL patients with subsequent EPL outcome. The least absolute shrinkage and selection operator (LASSO) regression and multivariate logistic regression were utilized to select variables, respectively. Subsequent EPL prediction model was constructed using generalize linear model (GLM), gradient boosting machine (GBM), random forest (RF), and deep learning (DP). The variables selected by LASSO regression and multivariate logistic regression were then established and compared using the best prediction model. The AUC, calibration curve, and decision curve (DCA) were performed to assess the prediction performances of the best model. The best model was validated using the validation group. Finally, a nomogram was established based on the best predictive features. Results: In the training group, the GBM model achieved the best performance with the highest AUC (0.805). The AUC between the variables screened by the LASSO regression (16-variables) and logistic regression (9-variables) models showed no significant difference (AUC: 0.805 vs. 0.777, P = 0.1498). Meanwhile, the 9-variable model displayed a well discrimination performance in the validation group, with an AUC value of 0.781 (95%CI 0.702, 0.843). The DCA showed the model performed well and was feasible for making beneficial clinical decisions. Calibration curves revealed the goodness of fit between the predicted values by the model and the actual values, the Hosmer–Lemeshow test was 7.427, and P = 0.505. Conclusions: Predicting subsequent EPL in RPL patients using the GBM model has important clinical implications. Future prospective studies are needed to verify the clinical applicability. Trial registration: This study was registered in the Chinese Clinical Trial Registry with the registration number of ChiCTR2000039414 (27/10/2020). [ABSTRACT FROM AUTHOR]

Approximately 60% of recurrent pregnancy loss (RPL) cases lack a clear explanation for their cause. It has a deep emotional impact on the patient and her family. Couples often experience anxiety, frustration, and feelings of despair. While Immunotherapy remains unproven for addressing unexplained RPL, growing evidence suggest high uterine natural killer (uNK) cell activity preventing embryos from implanting and developing properly in the uterus. Intralipids, which are mainly used as a part of total parenteral nutrition, have shown in research to deactivate natural killer cells in a woman's body. Based on these principles, intralipid infusions have been tried in a single or multiple doses to help with conception and to maintain the pregnancy in cases of RPL. We have successfully used a single dose of intralipid infusion in cases of unexplained RPL with excellent outcomes at an affordable cost. [ABSTRACT FROM AUTHOR]

Background: Interleukin (IL) genes are essential for regulating the immune and inflammatory processes. Epidemiological studies suggest that polymorphisms in IL genes are associated with a higher risk of recurrent pregnancy loss (RPL). Objective: This study aimed to examine the association between RPL risk and IL gene polymorphisms. Materials and Methods: A comprehensive search of the literature was conducted using PubMed, Google Scholar and Embase to identify relevant studies published until May 30, 2024. A total of 58 studies involving 13,696 participants (both RPL cases and controls) were included. Pooled odds ratios and 95% confidence intervals were calculated using fixed- or random-effects models, as appropriate, with ReviewManager version 5.4, Cochrane RoB Tool 2 and G*Power 3.1 software. Results: The meta-analysis revealed significant correlations between RPL risk and genetic variations in IL-1ß (-511T > C), IL-6 (-174 G > C) and IL-10 (-1082 A > G and-592 C > A), with statistical significance set at P < 0.05. Ethnic subgroup analysis showed that IL-1ß (-511T > C) and IL-10 (-592 C > A) variations were strongly associated with RPL risk in Asian populations. Interpretation: Our research suggests that genetic variations in IL-1ß (-511T > C), IL-6 (-174 G > C) and IL-10 (-1082 A > G and-592 C > A) are associated with susceptibility to RPL. Limitation: Our meta-analysis concentrated exclusively on single-factor studies and did not consider potential confounding variables such as age, environmental influences and lifestyle, which could affect susceptibility to RPL. In addition, the lack of individual raw data prevented us from investigating gene-environment and gene-gene interactions or the influence of other polymorphisms and cytokines in our analysis. Protocol Registration: http://www.osf.io/qhbva. [ABSTRACT FROM AUTHOR]

Recurrent pregnancy loss (RPL) mainly occurs due to the disorders that cause intrauterine fetal demise or damage, such as fetal, maternal, and paternal chromosomal structural and numerical abnormalities. Approximately, 15-20% of all clinically recognized pregnancies result in the first trimester (before 20 weeks of gestational age) in spontaneous recurrent abortion. Besides all internal factors like Anatomical, immunological, and coagulation factors, genetic factors appear to be most associated with reproductive organ damage and multiple pregnancy loss. Some factors are unexplored as mentioned in the previous research articles, and there is an enormous need to research for establishing the proper etiology and prognosis. This review is all about the various factors responsible for RPL and is mainly focused on the genetic factors involving many unexplored genes associated with recurrent miscarriages. In this review, searched the articles with keywords that were published recently from various journal searches such as Google Scholar, Science Direct, and the National Center for Biotechnology Information (NCBI) platform. [ABSTRACT FROM AUTHOR]

Purpose: This review presents a clinical approach to genetic issues in male infertility. Unlike other related reviews that discuss different types of genetic diseases (such as Klinefelter and Down syndrome), this review focuses on the clinical features that result from these genetic problems (such as azoospermia and oligospermia). Methods: A narrative review of the clinical literature in PubMed was conducted using keywords related to male infertility, recurrent pregnancy loss, recurrent in vitro fertilization failure, and genetics. The search included articles with English reviews published online after 2020. Headlines were defined based on the available literature, and after a critical review of each manuscript, clinical facts were classified under the corresponding headlines, and a primary draft was written. Results: 29 relevant articles were selected from the search. According to the literature, there are clinical genetic approaches for azoospermia, severe oligospermia, severe teratospermia, severe asthenospermia, recurrent miscarriage, and recurrent in vitro fertilization failure. Conclusion: Although many mutations that can affect male fertility and spermogram have been identified, only a few have clinical predictive value. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to identify predictors associated with thyroid function and thromboelastograph (TEG) examination parameters and establish a nomogram for predicting the risk of subsequent pregnancy loss in recurrent pregnancy loss (RPL). Methods: In this retrospective study, we analyzed the medical records of 575 RPL patients treated at Lanzhou University Second Hospital, China, between September 2020 and December 2022, as a training cohort. We also included 272 RPL patients from Ruian People’s Hospital between January 2020 and July 2022 as external validation cohort. Predictors included pre-pregnancy thyroid function and TEG examination parameters. The study outcome was pregnancy loss before 24 weeks of gestation. Variable selection was performed using least absolute shrinkage and selection operator regression and stepwise regression analyses, and the prediction model was developed using multivariable logistic regression. The study evaluated the model’s performance using the area under the curve (AUC), calibration curve, and decision curve analysis. Additionally, dynamic and static nomograms were constructed to provide a visual representation of the models. Results: The predictors used to develop the model were body mass index, previous pregnancy losses, triiodothyronine, free thyroxine, thyroid stimulating hormone, lysis at 30 minutes, and estimated percent lysis which were determined by the multivariable logistic regression with the minimum Akaike information criterion of 605.1. The model demonstrated good discrimination with an AUC of 0.767 (95%CI 0.725-0.808), and the Hosmer-Lemeshow test indicated good fitness of the predicting variables with a P value of 0.491. Identically, external validation confirmed that the model exhibited good performance with an AUC of 0.738. Moreover, the clinical decision curve showed a positive net benefit in the prediction model. Meanwhile, the web version we created was easy to use. The risk stratification indicated that high-risk patients with a risk score >147.9 had a higher chance of pregnancy loss (OR=6.05, 95%CI 4.09-8.97). Conclusions: This nomogram well-predicted the risk of future pregnancy loss in RPL and can be used by clinicians to identify high-risk patients and provide a reference for pregnancy management of RPL. [ABSTRACT FROM AUTHOR]

Background & Objective: Consecutive miscarriages are considered recurrent pregnancy loss (RPL), which affects 1-2% of women and may be unpleasant for couples attempting to conceive. Patients and healthcare professionals confront a difficult situation in this regard. The present study was conducted with aim to investigate the potential role of anti-mullerian hormone (AMH) in predicting the rate of live birth in women with RPL who are trying to conceive naturally. Materials & Methods: This cross-sectional study involved 60 pregnant women from Baghdad and Al-Najaf infertility centers (June 2022 - June 2023), recording age, gestational age, miscarriage frequency, fetal outcomes, parity, and number of live births. AMH levels were measured using Minividas Biomeriux 2020 (France), followed by assessments of FSH and Estradiol. Low AMH prompted further tests for autoimmune and genetic disorders. Inclusion criteria were all pregnant women with spontaneous or induced pregnancies and a history of recurrent miscarriage. Exclusions were those with unexplained pregnancy loss and male factor infertility. Results: The mean age of participants was 32.8 years, with 46.7% aged 21-30 years. AMH levels were higher in females aged 21-30 years, those with two abortions, and those with two parities. A significant correlation was observed between age over 40 years and a history of four abortions. Conclusion: AMH emerges as a crucial biomarker that intertwines with various aspects of female reproductive health, including miscarriage history, age, and parity. Future research is needed to deeply investigate the mechanisms behind these associations and offer more comprehensive insights into female fertility dynamics. [ABSTRACT FROM AUTHOR]

Angiogenesis is one of the most important steps during pregnancy for placental and fetal development. Based on the hypothesis that vascular insufficiency and altered angiogenesis may lead to early pregnancy loss, the present study was aimed to understand the role of Vascular endothelial growth factor (VEGFA) and Placental growth factor (PLGF) gene expression in placental angiogenesis in the pathogenesis of Recurrent pregnancy loss (RPL). Gene expression analysis of VEGFA and PLGF was carried out in the placental tissue collected from 30 women with recurrent pregnancy loss and compared with the placenta obtained from 16 women with medically terminated pregnancy. The mRNA expression of both VEGFA and PLGF genes were significantly downregulated in the placenta of recurrent pregnancy loss in comparison to the placenta of medically terminated pregnancies. In conclusion the results of the present study suggest that altered expression of VEGFA and PLGF genes in placenta disturb the angiogenesis and contribute to the pathogenesis of recurrent pregnancy loss. [ABSTRACT FROM AUTHOR]

Guidelines for the investigation and management of recurrent pregnancy loss (RPL) have been developed in Europe, USA and UK, but there is currently no Australasian guideline. The Australasian Certificate of Reproductive Endocrinology and Infertility Consensus Expert Panel on Trial Evidence group has prepared a two‐part guideline to provide guidance on the management of RPL. In Part I chromosomal, anatomical, and endocrine factors are outlined along with relevant recommendations for clinical management, levels of evidence and grades of consensus. In Part II thrombophilia, autoimmune factors, infective, inflammatory, and endometrial causes, environmental and lifestyle factors, male factor and unexplained causes will be outlined. [ABSTRACT FROM AUTHOR]

Background: Recurrent pregnancy loss refers to the spontaneous demise of two or more pregnancies before the 24 weeks of gestation. In almost half of the cases of recurrent miscarriages, the causes remain unknown since there is no reliable way of prognosis, early diagnosis, or treatment. Recent research has detected differential expression of certain miRNAs in reproductive system pathologies. Methods: The aim of the present review is to focus on microRNAs and their relationship with idiopathic recurrent miscarriages and to correlate miRNA expression with recurrent miscarriage and examine their potential role as biomarkers. Pubmed/Medline and Scopus databases were searched up to 31st January 2024 with terms related to recurrent pregnancy loss and miRNAs. Results: In total, 21 studies were selected for the review. A total of 75 different miRNAs were identified, showing a statistically significant differential expression. Around 40 miRNAs had increased expression, such as miR-520, miR-184 and miR-100-5p, 21 decreased, such as let-7c, and 14 had either increased or decreased expression depending on the study, such as miR-21. Conclusions: The dysregulation of miRNA expression is strongly associated with recurrent miscarriages. The circulating in the peripheral blood miRNAs, miR-100-5p and let-7c, might be utilized as biomarkers and establish a valuable non-invasive prognostic and diagnostic tool in the future. [ABSTRACT FROM AUTHOR]

Background: Recurrent pregnancy loss (RPL) is a common pregnancy complication that brings great pain to pregnant women and their families. Genetic factors are an important cause reason of RPL. However, clinical research on monogenic diseases with recurrent miscarriage is insufficient. Case presentation: Here we reported a Chinese family with RPL and genetic analysis of the abortion and parents. A paternally inherited heterozygous missense variant c.1415T > G (p.V472G) and a maternally inherited heterozygous nonsense variant c.2314del (p.M772*) in TMEM67 gene were identified by trio-exome sequencing. c.2314del (p.M772*) generated a premature stop codon and truncated protein, was classified as "pathogenic". c.1415T > G (p.V472G) located in extra-cellular region, was classified as "likely pathogenic". Biallelic variants in TMEM67 gene cause lethal Meckel syndrome 3, consistent with the proband's prenatal phenotype. Conclusion: The current study of the Chinese family expands the pathogenic variant spectrum of TMEM67 and emphasizes the necessity of exome sequencing in RPL condition. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of our study is to investigate the function of YAP1 in the trophoblast ferroptosis and maternal-fetal interface communication of RPL. Methods: We collected 25 villous tissues and detected the expression of YAP1. Cell counting kit-8 assay, scratch wound-healing assay, and Matrigel invasion assay were performed to observe the proliferation, migration, and invasion of HTR-8/SVneo and JAR cells. Subsequently, measured the levels of reactive oxygen species (ROS), malondialdehyde (MDA), reduced glutathione (GSH), SLC7A11, SOD2, and GPX4. Ultimately, the use of ferroptosis activator (erastin) and inhibitor (Ferrostatin-1, fer-1) further confirmed the regulation by YAP1. In addition, established an in vitro-induced cell model to study the effect of YAP1 on the decidualization process. Finally, animal models were implemented for further confirmation. Results: We found that YAP1 was downregulated in RPL patients. Overexpression of YAP1 could significantly enhance the proliferation, migration, and invasion of trophoblasts, and inhibit ferroptosis. Knocking down YAP1 exhibited the opposite effect. Rescue experiments have shown that YAP1 could upregulate the expression of SLC7A11 and GPX4, which are key molecules in the classic pathway of ferroptosis. In addition, the decidualization was impaired when hESCs were treated with conditioned medium of YAP1 knockdown trophoblasts. Moreover, we found that Yap1, Slc7a11, and Gpx4 were downregulated in the RPL mice, along with increased MDA and decreased GSH. Conclusion: Downregulation of YAP1 induces ferroptosis, thereby damaging the trophoblast invasion processes, which also disturbs the communication at the maternal-fetal interface. Our study identified YAP1 as a potential key molecule in the pathogenesis of RPL. [ABSTRACT FROM AUTHOR]

Decidual natural killer (dNK) cells are the most abundant immune cells at the maternal-fetal interface during early pregnancy in both mice and humans, and emerging single-cell transcriptomic studies have uncovered various human dNK subsets that are disrupted in patients experiencing recurrent early pregnancy loss (RPL) at early gestational stage, suggesting a connection between abnormal proportions or characteristics of dNK subsets and RPL pathogenesis. However, the functional mechanisms underlying this association remain unclear. Here, we established a mouse model by adoptively transferring human dNK cells into pregnant NOG (NOD/Shi- scid /IL-2Rγnull) mice, where human dNK cells predominantly homed into the uteri of recipients. Using this model, we observed a strong correlation between the properties of human dNK cells and pregnancy outcome. The transfer of dNK cells from RPL patients (dNK-RPL) remarkably worsened early pregnancy loss and impaired placental trophoblast cell differentiation in the recipients. These adverse effects were effectively reversed by transferring CD56+CD39+ dNK cells. Mechanistic studies revealed that CD56+CD39+ dNK subset facilitates early differentiation of mouse trophoblast stem cells (mTSCs) towards both invasive and syncytial pathways through secreting macrophage colony-stimulating factor (M-CSF). Administration of recombinant M-CSF to NOG mice transferred with dNK-RPL efficiently rescued the exacerbated pregnancy outcomes and fetal/placental development. Collectively, this study established a novel humanized mouse model featuring functional human dNK cells homing into the uteri of recipients and uncovered the pivotal role of M-CSF in fetal-supporting function of CD56+CD39+ dNK cells during early pregnancy, highlighting that M-CSF may be a previously unappreciated therapeutic target for intervening RPL. [ABSTRACT FROM AUTHOR]

The direct causal relationships between common mental disorders (anxiety disorders, broad depression, major depressive disorder (MDD), bipolar disorder, and insomnia) and miscarriage or recurrent spontaneous abortion (RSA) are unclear. Therefore, this study aimed to explore these, using Mendelian randomization. Genome-wide association studies (GWAS) meta-analyses with the largest sample size possible and selected independent single individuals of European ancestry were selected. Inverse variance weighted (IVW) was the main analysis method. The heterogeneity of the instrumental variables (IVs) was assessed using IVW and MR-Egger, and the horizontal pleiotropy of the IVs was assessed using MR-Egger and MR-PRESSO. Based on IVW results, the four mental disorders were found to be causally associated with spontaneous abortion (anxiety disorder: OR (95%CI), 1.230 (1.063–1.420), P = 0.0050; major depressive disorder: 1.690 (1.239–2.307), P = 0.0009; bipolar disorder: 1.110 (1.052–1.170), P = 0.0001; insomnia: 1.292 (1.076–1.552), P = 0.0060). Furthermore, no causal relationship was observed between broad depression and spontaneous abortion. Five common mental disorders were not causally associated with the RSA. (1) Our analysis was limited to the European population; (2) the duration of mental disorders was not analyzed, as no information was available; and (3) it was difficult to completely detect genetic pleiotropy. Anxiety disorders, MDD, bipolar disorder, and insomnia may contribute to spontaneous abortion. Therefore, we should focus on the mental and sleep health of pregnant women. Future studies may be required on whether mental disorders directly lead to RSA, especially unexplained RSA. • Previous studies mainly explored the prevalence of these mental disorders in abortion women. • Few studies discovered the direct causal relationship between mental disorders and miscarriage. • Anxiety disorders, major depressive disorder, bipolar disorder, and insomnia may contribute to spontaneous abortion. • No evidence supports the causal relationship between mental disorders and recurrent spontaneous abortion. • The relationships between unexplained recurrent spontaneous abortion and mental disorders are unclear. [ABSTRACT FROM AUTHOR]

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