Social consequences of recurrent pregnancy loss and maternal myths, past, present, and future in Japan.

In Japan, the myth of motherhood, the idea that every woman harbours maternal love and that a woman only becomes a full-fledged woman after giving birth, has existed for a long time. However, there has been a limited number of studies concerning this motherhood myth in patients with recurrent pregnancy loss (RPL). The present study aimed to examine the experiences of maternal myths in patients with RPL and to determine whether maternal myths affect depression. Participants in the study included 61 patients in 1995, 71 patients in 2002, 503 patients from 2008 to 2012, and 318 patients and 1210 pregnant women from 2017 to 2020. Patients who sought an examination of their RPL visited Nagoya City University Hospital, while pregnant women requiring a prenatal checkup visited Nagoya City West Medical Center. Both groups completed a questionnaire concerning seven maternal myths and how they rated their level of depression (K6). It was found that not only patients with RPL but also pregnant women with no pregnancy loss had encountered maternal myths and many of them felt some discomfort. It has become clear that exposure to such myths has decreased over the 25 years from 1995 to 2020 (p < 0.05). Additionally, opportunities for exposure to maternal myths clearly had an impact on depression (p < 0.05). It is imperative that we recognize the distress caused by these myths. One potential solution to this problem is to improve education on gender issues.

Exploration of the Relationship between Polycystic Ovary Syndrome and Recurrent Pregnancy Loss Based on Bioinformatics.

BACKGROUND: Recurrent Pregnancy Loss (RPL) and Polycystic Ovary Syndrome (PCOS) are both common diseases involving women of childbearing age, and their pathogenesis is still not sufficiently known. OBJECTIVE: This study aimed to explore the relationship between RPL and PCOS in bioinformatics. METHODS: Two expression chips, GSE86241 (obtained from 8 PCOS patients and 9 healthy controls) and GSE73025 (obtained from 5 RPL patients and 5 healthy controls), were downloaded from the Gene Expression Omnibus (GEO) database. We used the GEO database to analyze the gene expression profiles of PCOS and RPL to identify the intersection of abnormal miRNA expression, predicted the target genes of the intersecting miRNAs from miRDB, miRTarBase, and TargetScan databases, and then incorporated the miRNA-mRNA modulation network. By using the string database, the PPI network was built, which could screen the Hub genes and enrich them for analysis. Ultimately, the critical miRNA-mRNA regulatory network was set on the basis of the relationship between hub genes and miRNA. RESULTS: A total of 39 significantly altered miRNAs of PCOS and 137 significantly altered miRNAs of RPL were obtained, three miRNAs (miR-767-5p, miR-3196, and miR-187-3p), five signaling pathways (PI3K-Akt, p53, Toll-like receptor, C-type lectin receptor, and TNF signaling pathways), and six Hub genes (CASP8, PIK3R1, ADAMTS2, ADAMTS3, COL3A1, and MDM2) were found to be related to the development and progression of two diseases. More importantly, all Hub genes were regulated by miR-767-5p. CONCLUSION: This research clarifies the possible relationship between miRNA and mRNA with PCOS and RPL for the first time. It provides a basis for illustrating the pathogenic mechanism and a target of therapies for these two diseases.

Unexplained Recurrent Pregnancy Loss: Clinical Application of Immunophenotyping.

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.

Is lifestyle different in male partners experiencing recurrent pregnancy loss compared to men fathering a live birth?

BACKGROUND: 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. OBJECTIVES: 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. MATERIALS AND METHODS: 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. RESULTS: 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. DISCUSSION: 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. CONCLUSION: 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.

Low-dose aspirin and heparin treatment improves pregnancy outcome in recurrent pregnancy loss women with anti-ß2-glycoprotein I/HLA-DR autoantibodies: a prospective, multicenter, observational study.

Introduction: Anti-ß2-glycoprotein I (ß2GPI)/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-ß2GPI/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 anti-ß2GPI/HLA-DR antibodies. Methods: Between August 2019 and December 2021, 462 women with RPL underwent anti-ß2GPI/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-ß2GPI/HLA-DR antibodies, and their pregnancy outcomes were followed up until December 2023. Finally, 47 pregnancies in 47 women with RPL and anti-ß2GPI/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-ß2GPI/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 aß2GPI/HLA-DR antibody positivity.

High Prevalence of Anti-Prothrombin IgM and IgG Autoantibodies in Women With Unexplained Recurrent Pregnancy Loss.

To investigate the association between anti-prothrombin IgM and IgG antibodies and recurrent pregnancy loss (RPL) in a cohort of Lebanese women, and their impact on pregnancy outcomes. This was a retrospective case-control study involving 207 women with RPL and 179 age-matched multiparous controls. Quantitative sandwich ELISA assayed anti-prothrombin IgM and IgG antibodies. Univariate and multivariate logistic regression were employed to assess the risk imparted by anti-prothrombin antibodies, while ROC analysis was used to determine their sensitivity and specificity. Our study revealed that women with RPL had significantly higher serum levels of anti-prothrombin IgM and IgG than controls. Univariate regression analysis demonstrated that elevated anti-prothrombin IgM (OR = 1.13; 95% CI = 1.07, 1.19; P < 0.001) and IgG (OR = 1.05; 95% CI = 1.03, 1.08; P < 0.001) were associated with increased RPL risk. Multivariate analysis confirmed these findings, indicating that anti-prothrombin IgM (aOR = 1.13; 95% CI = 1.05, 1.20; P < 0.001) and IgG (aOR = 1.08; 95% CI = 1.05, 1.11; P < 0.001) are independent risk factors. ROC analysis yielded an AUC of 0.720 for IgM and 0.649 for IgG, underscoring their predictive value and offering hope for improved risk assessment and management of RPL. Elevated levels of anti-prothrombin IgM and IgG are significantly associated with RPL, suggesting an autoimmune component to pregnancy loss. These findings highlight the importance of screening for these antibodies in women with unexplained RPL to guide management and therapeutic strategies.

The association between methionine synthase reductase c.66A>G variant and the risk of recurrent pregnancy loss: A systematic review and meta-analysis.

OBJECTIVE: We aimed to conduct a comprehensive meta-analysis of the association between methionine synthase reductase (MTRR) c.66A>G variant and recurrent pregnancy loss (RPL) susceptibility. METHODS: We conducted a comprehensive systematic search of literature published before February 25, 2023 using PubMed, Embase, Web of Science, and Cochrane Library. Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the included studies. The odds ratio (OR) was used to estimate the association between MTRR c.66A>G variant and RPL susceptibility. The I squared (I2) statistic and Q statistic were used to assess the heterogeneity among the included studies. And Begg's test and Egger's regression were then used to test the existence of publication bias. RESULTS: In this meta-analysis, we included 10 studies comprising 1842 RPL cases and 2173 healthy pregnant women to investigate the relationship between MTRR c.66A>G variants and the susceptibility of RPL. In the overall population analysis, MTRR c.66A>G variant was not significantly associated with the risk of RPL in different comparison models. Since 9 of the included studies were conducted in Asia, we performed analyses separately for Asian populations, including a total of 1855 cases and 2127 controls. Results showed, in Asian populations, there is no significant correlation between c.66A>G variant and the risk of RPL. Subgroup analyses according to ethnicity and country yielded similar results. CONCLUSION: Our findings suggested that the MTRR c.66A>G variant was not significantly associated with the risk of RPL.

Reproductive outcomes after hysteroscopic adhesiolysis in patients experiencing recurrent pregnancy loss and intrauterine adhesions.

OBJECTIVE: This study aims to evaluate the reproductive outcomes after hysteroscopic adhesiolysis in patients experiencing recurrent pregnancy loss (RPL) combined with intrauterine adhesions (IUA). DESIGN: Single-center retrospective cohort study. SETTING: International referral hospital for women with IUA and RPL. PATIENTS: Between January 2018 and June 2022, a cohort of 64 women diagnosed with RPL and IUA were studied, with a follow-up period of at least one year after hysteroscopic adhesiolysis. INTERVENTIONS: All patients had a diagnosis of IUA from the diagnostic hysteroscopy and were treated with hysteroscopic adhesiolysis, utilizing intraoperative ultrasound monitoring as required. MAIN MEASUREMENTS: Live birth rate and menstrual pattern change (subjective assessment) after hysteroscopic adhesiolysis. RESULTS: In our cohort, 59.38% (38/64) achieved pregnancy following hysteroscopic adhesiolysis, with 92.11% (35/38) conceiving within two years of the procedure. The miscarriage rate was recorded at 17.19% (11/64), and the live birth rate stood at 42.19% (27/64). Throughout the extended follow-up period, 64.06% (41/64) of the patients reported increased menstrual blood volume and improvements in menstrual patterns post-hysteroscopic adhesiolysis. Univariate analysis indicated that being aged ≥35 years (P=.026), having a history of infertility (P=.003), the presence of moderate or severe IUA (P=.023), and experiencing menstrual improvements post-surgery (P=.001) were independent predictors of live birth. Multivariate analysis further identified that women with a history of infertility had a reduced chance of live birth following hysteroscopic adhesiolysis (P=.008), while those who reported menstrual pattern improvements postoperatively had an increased probability of achieving a live birth (P=.031). CONCLUSIONS: Our findings indicate that RPL and IUA patients without prior infertility and showing menstrual pattern improvement after hysteroscopic adhesiolysis, are more likely to achieve live births. Standardized hysteroscopic treatment, postoperative anti-adhesion care, and early pregnancy planning are key to improving fertility outcomes in these patients.

Decoding recurrent pregnancy loss: insights from comparative proteomics studies.

Recurrent pregnancy loss (RPL) represents a common disorder that affects up to 2% of the women aiming at childbirth with long-term consequences on family and society. Factors contributing to it in more than half of the cases are still unknown. Comparative proteomic analysis can provide new insights into the biological pathways underlining the pathogenesis of RPL. Until now, chorionic villi, decidua, placenta, endometrium, and maternal blood from women with RPL have been analyzed by comparative proteomics studies. In this review, we aimed to provide a critical evaluation of the published comparative studies of RPL on human samples, gathered by systematic literature search using PubMed and Google Scholar databases. We provide a detailed overview of the analyzed materials, proteomics platforms, proposed candidate biomarkers and altered pathways and processes linked with RPL. The top, most identified and validated biomarker candidates from all studies are discussed, followed by bioinformatics analysis of the available high-throughput data and presentation of common altered processes and pathways in RPL. Finally, future directions aimed at developing new and efficient therapeutic strategies are discussed as well.

Optimizing evaluation of endometrial receptivity in recurrent pregnancy loss: a preliminary investigation integrating radiomics from multimodal ultrasound via machine learning.

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.

Placental site nodules and reproductive outcomes: a clinicopathologic case series.

BACKGROUND: Placental site nodules (PSNs) are benign tumor-like growths that develop from chorionic-type intermediate trophoblastic cells. Their clinical significance is unknown. This study aims to determine the risk factors associated with PSNs, with focus on possible reproductive impact. METHODS: We performed a retrospective case series of all patients with a pathology diagnosis of PSN in a large urban hospital system from 2018 to 2022. We collected clinical variables such as pathology diagnosis/description, presenting symptoms, method of prior delivery, and prior history of infertility, pregnancy loss, and uterine instrumentation. RESULTS: A total of 32 patients were included in this case series. The most common presenting symptom was abnormal uterine bleeding (40.6%, 13/32). Recurrent pregnancy loss (RPL) (15.6%, 5/32) and infertility (15.6%, 5/32) were common presenting symptoms as well. 62.5% (20/32) patients had a history of prior uterine instrumentation. Coexisting chronic endometritis was identified in 9.4% (3/32) of cases. Of the 5 RPL/infertility patients who underwent hysteroscopic resection of a PSN, 1 achieved a live birth. CONCLUSION: PSNs may be associated with abnormal uterine bleeding, recurrent pregnancy loss, infertility, history of prior uterine instrumentation, and chronic endometritis. Although a rare diagnosis, the presence of a PSN should be considered in patients presenting for infertility or recurrent pregnancy loss workup.

Chronic endometritis and recurrent reproductive failure: a systematic review and meta-analysis.

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. Systematic review registration: https://www.crd.york.ac.uk/prospero/#recordDetails PROSPERO, identifier CRD42024541879.

The relationship between Sjögren's syndrome and recurrent pregnancy loss: a bioinformatics analysis.

RESEARCH QUESTION: As Sjögren's syndrome is an autoimmune disease and an essential factor in recurrent pregnancy loss (RPL), are there gene-related relationships between the pathogenesis of Sjögren's syndrome and RPL? DESIGN: The gene datasets for Sjögren's syndrome and RPL were obtained from the Gene Expression Omnibus database, and the co-expression modules and shared differentially expressed genes were identified through weighted gene co-expression network analysis (WGCNA) and limma analysis based on sample size. Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes analyses were applied to reveal the hidden biological pathways. Additionally, shared hub gene identification, gene set enrichment analysis, association of the hub gene with ferroptosis and immunity, drug sensitivity analysis, single-cell RNA sequencing analysis, and construction of the competing endogenous RNA (ceRNA) network were conducted. RESULTS: By intersecting the genes from WGCNA and limma analysis, one shared hub gene (KCNN3) was derived, exhibiting up-regulation in Sjögren's syndrome and RPL. There was a positive relationship between KCNN3 and the immune-related gene TLR2. The ceRNA network revealed that XIST was the most shared long non-coding RNA, which may bind competitively with eight microRNA to regulate the expression of KCNN3. Forty-eight drugs were found to be strongly associated with KCNN3 expression, including estramustine and cyclosporine. Moreover, KCNN3 exhibited high expression in RPL endothelial cells of villous tissue. CONCLUSIONS: This is one of the first studies to reveal that Sjögren's syndrome shares common biological pathways with RPL. KCNN3 was identified as the hub gene associated with Sjögren's syndrome and RPL, and may be a new target for mechanistic studies on Sjögren's syndrome and RPL.

Identification and validation of oxidative stress-related diagnostic markers for recurrent pregnancy loss: insights from machine learning and molecular analysis.

It has been recognized that oxidative stress (OS) is implicated in the etiology of recurrent pregnancy loss (RPL), yet the biomarkers reflecting oxidative stress in association with RPL remain scarce. The dataset GSE165004 was retrieved from the Gene Expression Omnibus (GEO) database. From the GeneCards database, a compendium of 789 genes related to oxidative stress-related genes (OSRGs) was compiled. By intersecting differentially expressed genes (DEGs) in normal and RPL samples with OSRGs, differentially expressed OSRGs (DE-OSRGs) were identified. In addition, four machine learning algorithms were employed for the selection of diagnostic markers for RPL. The Receiver Operating Characteristic (ROC) curves for these genes were generated and a predictive nomogram for the diagnostic markers was established. The functions and pathways associated with the diagnostic markers were elucidated, and the correlations between immune cells and diagnostic markers were examined. Potential therapeutics targeting the diagnostic markers were proposed based on data from the Comparative Toxicogenomics Database and ClinicalTrials.gov. The candidate biomarker genes from the four models were further validated in RPL tissue samples using RT-PCR and immunohistochemistry. A set of 20 DE-OSRGs was identified, with 4 genes (KRAS, C2orf69, CYP17A1, and UCP3) being recognized by machine learning algorithms as diagnostic markers exhibiting robust diagnostic capabilities. The nomogram constructed demonstrated favorable predictive accuracy. Pathways including ribosome, peroxisome, Parkinson's disease, oxidative phosphorylation, Huntington's disease, and Alzheimer's disease were co-enriched by KRAS, C2orf69, and CYP17A1. Cell chemotaxis terms were commonly enriched by all four diagnostic markers. Significant differences in the abundance of five cell types, namely eosinophils, monocytes, natural killer cells, regulatory T cells, and T follicular helper cells, were observed between normal and RPL samples. A total of 180 drugs were predicted to target the diagnostic markers, including C544151, D014635, and CYP17A1. In the validation cohort of RPL patients, the LASSO model demonstrated superiority over other models. The expression levels of KRAS, C2orf69, and CYP17A1 were significantly reduced in RPL, while UCP3 levels were elevated, indicating their suitability as molecular markers for RPL. Four oxidative stress-related diagnostic markers (KRAS, C2orf69, CYP17A1, and UCP3) have been proposed to diagnose and potentially treat RPL.

The Impact of Human Papillomavirus Infections on Recurrent Pregnancy Loss: A Review of the Literature.

Human papillomavirus (HPV) infections are significantly associated with multiple adverse reproductive outcomes such as miscarriages. Pregnant women are more susceptible to an HPV infection and its prevalence increases as pregnancy progresses. In this present review, we summarize the existing evidence indicating the potential impact of an HPV infection on the occurrence of recurrent pregnancy loss (RPL). Comprehensive research of the literature was performed in the Medline/PubMed and Scopus databases. A total of 185 articles were identified and 40 full-text articles were assessed. Four studies were eligible to be included in this literature review. To our knowledge, this is the first review aiming to summarize the current state of evidence regarding the possible association of HPV infections and RPL. Recurrent pregnancy loss constitutes a distressing reproductive event and scientific research has made significant efforts to determine the causes and mechanisms that could lead to RPL. It is still unclear whether the papillomavirus infection is associated with an increased risk for recurrent miscarriages. Research in the field revealed conflicting results and their deductions are limited by methodological limitations. Given the high prevalence of HPV infections and their potential role in the occurrence of adverse outcomes during pregnancy, further research is required to clarify the possibility of an HPV infection being a potential risk factor for recurrent miscarriages.

Comparison of the predictive value of four insulin resistance surrogates and hyperuricemia in women with recurrent pregnancy loss: A cross-sectional study.

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.

Microbiota and Recurrent Pregnancy Loss (RPL); More than a Simple Connection.

Recurrent Pregnancy Loss (RPL) affects 1-2% of women, and its triggering factors are unclear. Several studies have shown that the vaginal, endometrial, and gut microbiota may play a role in RPL. A decrease in the quantity of Lactobacillus crispatus in local microbiota has been associated with an increase in local (vaginal and endometrial) inflammatory response and immune cell activation that leads to pregnancy loss. The inflammatory response may be triggered by gram-negative bacteria, lipopolysaccharides (LPS), viral infections, mycosis, or atypia (tumor growth). Bacterial structures and metabolites produced by microbiota could be involved in immune cell modulation and may be responsible for immune cell activation and molecular mimicry. Gut microbiota metabolic products may increase the amount of circulating pro-inflammatory lymphocytes, which, in turn, will migrate into vaginal or endometrial tissues. Local pro-inflammatory Th1 and Th17 subpopulations and a decrease in local Treg and tolerogenic NK cells are accountable for the increase in pregnancy loss. Local microbiota may modulate the local inflammatory response, increasing pregnancy success. Analyzing local and gut microbiota may be necessary to characterize some RPL patients. Although oral supplementation of probiotics has not been shown to modify vaginal or endometrial microbiota, the metabolites produced by it may benefit patients. Lactobacillus crispatus transplantation into the vagina may enhance the required immune tolerogenic response to achieve a normal pregnancy. The effect of hormone stimulation and progesterone to maintain early pregnancy on microbiota has not been adequately studied, and more research is needed in this area. Well-designed clinical trials are required to ascertain the benefit of microbiota modulation in RPL.

Intravenous immunoglobulin improves live birth rates in patients with unexplained recurrent pregnancy loss.

This real-world study aimed to assess the clinical efficacy and safety of intravenous immunoglobulin (IVIG) in treating unexplained recurrent pregnancy loss (uRPL) patients. A total of 238 patients with uRPL were enrolled in this retrospective study. According to the treatment, patients were assigned into treatment group (n=184, receiving IVIG+low molecular weight heparin [LMWH]) and control group (n=54, only LMWH). The primary outcome was the live birth rates (LBR) after 24 weeks of gestation. In addition, we performed subgroup analyses to assess the LBR in uRPL patients with age (≥30 years or <30 years), body mass index (BMI, 18-24 kg/m2 or ≥24 kg/m2), number of previous pregnancy losses (2 or ≥3), gestational week of first medication, and IVIG medication regimen during pregnancy. The LBR showed a significant increase after IVIG treatment compared to the control group (77.7 % vs. 53.7 %, P=0.001). Multivariable logistic regression indicated that IVIG was associated with increased LBR (aOR=4.383, 95 %CI 2.024-9.489). Besides, we observed a significantly lower incidence of decreased platelet count (1.6 % vs. 7.4 %, P=0.049) in the treatment group. Subgroup analyses showed that IVIG treatment was associated with improved LBR in uRPL patients with age of <30 years (aOR=4.012, 95 %CI 1.428-11.266), previous pregnancy losses ≥3 times (aOR=17.327, 95 %CI 2.525-118.921), and BMI of 18-24 kg/m2 (aOR=8.914, 95 %CI 2.985-26.618). IVIG treatment significantly improves the LBR in uRPL patients. These findings from real-world data provide evidence for the safety and efficacy of IVIG as a viable treatment for uRPL patients in clinical practice.

Preimplantation genetic testing for aneuploidy in unexplained recurrent pregnancy loss: a systematic review and meta-analysis.

IMPORTANCE: Preimplantation genetic testing for aneuploidy (PGT-A) to deselect aneuploid embryos in assisted reproductive technology (ART) treatment cycles may hold promise by augmenting pregnancy rates per transfer and reducing pregnancy loss rates for patients with unexplained recurrent pregnancy loss (RPL). OBJECTIVE: To explore effectiveness of PGT-A in managing unexplained RPL by evaluating several key aspects: the likelihood of live birth in a subsequent spontaneous pregnancy, whether women with unexplained RPL have a higher rate of aneuploidy, whether euploid blastocysts offer comparable live birth rate (LBR) in patients with unexplained RPL, whether the endometrium is less selective in unexplained RPL loss, and whether PGT-A increases the LBR or reduces pregnancy losses until delivery. DATA SOURCES: PubMed and Cochrane Library databases were searched from inception until June 2024. STUDY SELECTION AND SYNTHESIS: Studies involving patients with ≥2 unexplained RPL who underwent ART with or without PGT-A or expectant management were included. MAIN OUTCOME MEASURES: The primary outcome measure was the LBR. Secondary outcome measures were aneuploidy rate, clinical pregnancy rate, and clinical pregnancy loss rate. RESULTS: Whether couples with unexplained RPL have higher embryo aneuploidy rates remains equivocal. Euploid blastocyst transfers yielded comparable clinical pregnancy loss rate (odds ratio [OR], 1.10; 95% confidence interval [CI], 0.57-2.13) and LBR (OR, 1.04; 95% CI, 0.74-1.44) in patients with and without unexplained RPL. Comprehensive chromosome analysis of products of conception shows similar aneuploidy rates between patients with and without RPL and does not support the less selective endometrium hypothesis. Preimplantation genetic testing for aneuploidy decreased clinical pregnancy loss rate (OR, 0.42; 95% CI, 0.27-0.67) and enhanced LBR per transfer (OR, 2.17; 95% CI, 1.77-2.65) and LBR per patient (OR, 1.85; 95% CI, 1.18-2.91) in patients with unexplained RPL. CONCLUSION AND RELEVANCE: Current low-quality evidence suggests that PGT-A enhances LBR per transfer and per patient in unexplained RPL. Well-designed randomized controlled trials comparing ART with PGT-A vs. expectant management for unexplained RPL are warranted. CLINICAL TRIAL REGISTRATION NUMBER: CRD42021291546.