Unexplained Recurrent Spontaneous Abortion Research Articles

Exosomal miR-494 Regulates the Biological Behavior of Trophoblasts by Targeting mTOR in Unexplained Recurrent Spontaneous Abortion.

Recurrent spontaneous abortion (RSA) is a pregnancy disorder, and trophoblasts are involved in its complex pathogenesis. This study aimed to identify the functional role of exosomal miR-494 in promoting the development of unexplained RSA (uRSA). 15 uRSA tissues and 15 healthy controls were collected to compare the exosomal miR-494 expression. The ultracentrifugation method was used for serum exosome isolation, and exosome characteristics were examined using transmission electron microscopy (TEM). The affection of exosomal miR-494 on HTR-8/SVneo cells were determined by CCK-8, EdU, Wound healing, and Transwell assays. Our findings demonstrated that miR-494 levels were markedly lower in placental tissue and plasma exosomes from patients with uRSA than in normal pregnant women. Furthermore, treatment with miR-494-overexpressing exosomes reduced the viability, invasion, and migration of HTR-8/SVneo cells. In terms of regulation, exosomal miR-494 downregulated mTOR levels in HTR-8/SVneo cells. Mechanism research suggested that exosomal miR-494 reduces the viability, invasion, and migration of trophoblasts by targeting mTOR. Exosomal miR-494 and mTOR are potential predicative biomarkers and therapeutic targets for uRSA patients.

KLF4 regulates trophoblast function and associates with unexplained recurrent spontaneous abortion

BackgroundRecurrent spontaneous abortion (RSA) is defined as two or more consecutive spontaneous abortions before 20 weeks with the same spouse [1]. However, approximately 50% of RSA cases of unknown cause are classified as unexplained recurrent spontaneous abortion (URSA). Potential factors include decreased trophoblast cell migration and invasion, leading to impaired placental implantation and maintenance of the normal maternal-fetal interface. However, the mechanism of this pathogenesis remains unknown. In this study, we investigated the potential role and mechanism of KLF4 in regulating URSA by influencing the invasion and migration ability of trophoblast cells.MethodsWe firstly identified 817 differentially expressed genes by performing a difference analysis of the dataset GSE121950 [2] related to recurrent abortion, and intersected the top 10 genes obtained respectively by the three algorithms: DMNC, MNC, and EPC using Venn Diagram.To detect the expression levels of core genes, villi samples were obtained from normal pregnant women and patients with URSA. RT-qPCR analysis revealed a significant difference in KLF4 mRNA expression and KLF4 was then analyzed. Trophoblast cell lines HTR8 and JEG3 were used to investigate the effect of KLF4 on trophoblastic function. Wound healing and transwell assays was performed to detect the invasion and migration of trophoblast cells. The expression of epithelial-mesenchymal transition(EMT) molecules were detected by RT-qPCR and western blot. Promoter detection and epigenetic modification were detected by chromatin immunoprecipitation (ChIP) assay. Molecular nuclear localization was detected by immunofluorescence and subcellular fractionation. Miscarried mice model was used to study the effects of KLF4 on URSA induced by reduced trophoblast invasion and migration.ResultsKLF4 is highly expressed in the villi of patients with URSA. KLF4 inhibits the expression level of H3R2ME2a in trophoblast cells by regulating the transcriptional level and nuclear translocation of PRMT6, thereby inhibiting the possible regulatory mechanism of trophoblastic invasion and providing a potential treatment strategy for URSA in vivo.ConclusionsThe KLF4/PRMT6/H3R2ME2a axis regulates mechanisms associated with unexplained recurrent spontaneous abortion by regulating trophoblast function.

Study of plasma metabolic markers in unexplained recurrent spontaneous abortion based on non-target metabolomics approach

Objective: To screen plasma metabolic markers in patients with unexplained recurrent spontaneous abortion (URSA) by non-target metabolomics approach. Methods: From September 2022 to May 2023, the plasma of 23 URSA pregnant women with threatened abortion who visited the outpatient clinic of Gansu Provincial Maternity and Child-care Hospital in the first trimester (URSA group) was collected, and the plasma of 22 healthy pregnant women in the first trimester who underwent prenatal examination during the same period (normal control group) was collected. Plasma metabolomics was analyzed by ultra performance liquid chromatography (UPLC) coupled with mass spectrometry (MS), fold change analysis, principal component analysis and partial least square discriminant analysis were applied to screen for differential metabolites, and the metabolites and their pathways associated with URSA were screened using receiver operating characteristic (ROC) curve and pathway enrichment analysis. Results: There were no significant differences in age, body mass index and gestational weeks between URSA and normal control group(all P<0.05). Metabolomics analysis using UPLC-MS showed that a total of 526 metabolites were detected from plasma, of which 33 were found to be differential metabolites associated with URSA based on the screening standards. Six potential metabolites with large area under the curve (AUC) were identified by ROC curve analysis, including phosphatidylethanolamine (AUC=0.972, 95%CI: 0.920-1.000), santene hydrate (AUC=0.902, 95%CI: 0.786-0.982), L-leucine (AUC=0.884, 95%CI: 0.772-0.960), cembrene (AUC=0.881, 95%CI: 0.758-0.956), caffeine (AUC=0.875, 95%CI: 0.756-0.962), and 4-hydroxybenzoic acid propyl ester (AUC=0.864, 95%CI: 0.732-0.946). The AUC for the combined diagnosis of URSA by the six metabolites was 0.983 (95%CI: 0.929-1.000). Pathway enrichment analysis of the differential metabolites showed that the pathogenesis of URSA was associated with a variety of metabolic pathways including caffeine metabolism, glycerophospholipid metabolism, and unsaturated fatty acid biosynthesis. Conclusion: The plasma metabolic profiles of pregnant women with normal pregnancies versus URSA differ in early pregnancy, and six potential metabolites such as phosphatidylethanolamine, santene hydrate, L-leucine, cembrene, caffeine, 4-hydroxybenzoic acid propyl ester, and their metabolic pathways may be involved in the pathogenesis of URSA.

Impact of Organochlorine Pesticides Exposure on Histone Modification H3K9ac: Implications for Unexplained Recurrent Miscarriage.

Epigenetic alterations, changes in gene expression without DNA sequence modifications, are associated with various health disorders, including reproductive health issues. These alterations can be influenced by environmental factors such as pesticides. This study aimed to explore the relationship between exposure to Organochlorine Pesticides (OClPs) and the histone modification mark H3K9ac in the placenta and fetal tissue, in the context of unexplained recurrent miscarriage (URM). In the case-control study, serum samples from 73 women with URM and 30 healthy women were examined for the presence of OClPs, which include 2,4-DDT, 2,4-DDE, 4,4-DDT, 4,4-DDE, α-HCH, β-HCH, and γ-HCH, using gas chromatography. Western blot analysis was used to assess H3K9ac expression in placental and fetal tissues. In the URM group, significant increases were observed in the values of α-HCH, β-HCH, 2,4-DDE, and 4,4-DDE, as well as in the concentration of total OClPs (Ʃ3HCH, Ʃ2DDE, Ʃ2DDT, and Ʃ7OClP), compared to controls. While H3K9ac levels in fetal tissue showed no significant difference, a notable decrease was found in the placental tissue of the URM. In the placenta tissue of URM, logistic regression analysis also revealed a significant inverse correlation between the toxins α-HCH, 2,4-DDE, 4,4-DDE, 4,4-DDT, total OClPs, and reduced H3K9ac expression. Our findings suggest that OClPs exposure may contribute to URM by reducing H3K9ac expression in the placenta, potentially affecting placental growth and immune tolerance. This underscores the need for further investigation into the involved mechanisms and potential therapeutic interventions, and the importance of OClPs regulation for reproductive health protection.

Role of Luteal Phase Steroids in Unexplained Recurrent Miscarriages

Role of Luteal Phase Steroids in Unexplained Recurrent Miscarriages

Clinical predictive value of pre-pregnancy tests for unexplained recurrent spontaneous abortion: a retrospective study.

Early prediction and intervention are crucial for the prognosis of unexplained recurrent spontaneous abortion (uRSA). The main purpose of this study is to establish a risk prediction model for uRSA based on routine pre-pregnancy tests, in order to provide clinical physicians with indications of whether the patients are at high risk. This was a retrospective study conducted at the Prenatal Diagnosis Center of Henan Provincial People's Hospital between January 2019 and December 2022. Twelve routine pre-pregnancy tests and four basic personal information characteristics were collected. Pre-pregnancy tests include thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine thyroid (FT4), thyroxine (TT4), total triiodothyronine (TT3), peroxidase antibody (TPO-Ab), thyroid globulin antibody (TG-Ab), 25-hydroxyvitamin D [25-(OH) D], ferritin (Ferr), Homocysteine (Hcy), vitamin B12 (VitB12), folic acid (FA). Basic personal information characteristics include age, body mass index (BMI), smoking history and drinking history. Logistic regression analysis was used to establish a risk prediction model, and receiver operating characteristic (ROC) curve and decision curve analysis (DCA) were employed to evaluate the performance of prediction model. A total of 140 patients in uRSA group and 152 women in the control group were randomly split into a training set (n = 186) and a testing set (n = 106). Chi-square test results for each single characteristic indicated that, FT3 (p = 0.018), FT4 (p = 0.048), 25-(OH) D (p = 0.013) and FA (p = 0.044) were closely related to RSA. TG-Ab and TPO-Ab were also important characteristics according to clinical experience, so we established a risk prediction model for RSA based on the above six characteristics using logistic regression analysis. The prediction accuracy of the model on the testing set was 74.53%, and the area under ROC curve was 0.710. DCA curve indicated that the model had good clinical value. Pre-pregnancy tests such as FT3, FT4, TG-Ab, 25-(OH)D and FA were closely related to uRSA. This study successfully established a risk prediction model for RSA based on routine pre-pregnancy tests.

Optical coherence tomography angiography evaluation of retinal and choroidal microvascular changes in pregnant women with a history of unexplained recurrent spontaneous abortions.

To study retinal and choroidal microcirculation by optical coherence tomography angiography (OCTA) in pregnant women with unexplained recurrent spontaneous abortion (RSA) and to compare them with healthy pregnant and nonpregnant subjects. Pregnant women with an unexplained history of RSA (group 1), healthy pregnant (group 2), and healthy non-pregnant women (group 3) were included in the study. After a thorough ophthalmologic examination:best-corrected visual acuity, intraocular pressure,slit-lamp biomicroscopy, fundus examination,autorefractometer, biometry, and axial length measurement; OCT and OCTA measurements were performed with Swept Source OCT-Angiography (Topcon Co, Japan). The nonpregnant group had higher values for central foveal superficial capillary plexus (SCP) and deep capillary plexus (DCP) vessel density (VD) and lower values for superior, inferior, and mean VD compared with pregnant groups (p < 0.001). Choriocapillaris values (CC) VD were higher in groups 1 and 2 than in group 3 (p < 0.001). The group with unexplained RSA had a relatively smaller FAZ (foveal avascular zone) area than the group of healthy pregnant women (p:0.047). There were no statistically significant differences between groups in the retina, retinal nerve fiber layer, ganglion cell layer, and choroidal thickness (p > 0.05). Although our study did not identify any etiology in pregnant women with RSA, we observed detectable differences in FAZ area and vessel density values using OCTA, when comparing them with healthy pregnant women and healthy nonpregnant controls. We believe that OCTA, as used in many pathologies such as diabetic and hypertensive retinopathy and retinal vascular occlusion, can also be extended to unexplained RSA both to detect etiology and to monitor treatment in studies with a larger number of patients.

P-436 Uterine NK cells underexpress KIR2DL1/S1 and LILRB1 receptors recognizing HLA-C2 and HLA-G on extravillous trophoblasts in reproductive failure

Abstract Study question Is there a difference in frequency, receptor expression and cytokine production of uterine NK cells (uNK) subpopulations in women with reproductive failure compared to controls? Summary answer Reproductive failure is associated with global underexpression of uNK receptors interacting with extravillous trophoblasts (EVT) that may result in defective implantation and placentation. What is known already A significant proportion of infertility, recurrent miscarriage and recurrent implantation failure are unexplained. This may be caused by immunological dysfunction at the maternal-fetal interface resulting in defective implantation and placentation. uNK is thought to play an important role in early pregnancy by cross-talking with EVT via KIR/HLA-C, LILRB1/HLA-G and CD94/HLA-E interactions to regulate EVT invasion and spiral arteriole remodeling in the decidua. Dysregulation of uNK function may cause reproductive failure; however it is unclear whether NK cell over- or under-activation is the pathology. Previous studies have been conducted on uNK obtained after miscarriage, which may be confounded by inflammatory processes. Study design, size, duration Here, we conducted a cross-sectional study to assess frequency, phenotype and function of matched pNK and uNK during the window of implantation in 16 women with reproductive failure compared to 11 controls. Women with reproductive failure cohort included unexplained subfertility (9), recurrent miscarriage (4) and recurrent implantation failure (3). The women were subsequently followed up after IVF and comparison made between women who did and did not fall pregnant. Participants/materials, setting, methods Matched peripheral blood and endometrial tissue were obtained from participants during the mid-secretory phase. Samples were accurately timed for 7-9 days after ovulation by urine LH test or histological dating. Flow cytometry was used to assess the frequency, phenotype and function. Phenotype was measured by KIR, LILRB1 and CD94 and receptor expression. Function was measured by degranulation (anti-CD107a internalization) and cytokine production (TNF-α, GM-CSF, IFN-γ and IL-8), with and without stimulation by PMA and ionomycin. Main results and the role of chance The expression of KIR2DL1/S1 and LILRB1 were significantly lower in reproductive failure group for both uNK (total uNK, uNK2 and 3) and pNK. The common finding in both uNK and pNK suggests that this is not tissue specific and may have an immunogenetic aetiology. We have previously found that degranulation peaks during secretory phase and in first trimester pregnancy. TNF-α production was also found to peak in secretory phase. Here, we found that degranulation activity of total uNK, as well as TNF-α production all uNK subsets was significantly lower in reproductive failure compared to control group. However, no significant difference was found in women in the reproductive failure cohort who fell pregnant compared to women who did not fall pregnant or miscarried after IVF. Contrary to findings from previous studies, we have not found any difference in uNK or pNK frequencies in any of the groups that were examined. Taken together, our findings suggest that reproductive failure is associated with global underexpression of receptors important for interaction with HLA-C and HLA-G on EVT, resulting in reduced uNK activation. This in turn may lead to dysregulation of implantation and placenta formation in early stage of pregnancy. Limitations, reasons for caution KIR2DL1/S1 antibody used does not distinguish between KIR2DL1 and KIR2DS1 which exerts inhibitory and activating effects respectively. Larger cohort studies on both pNK and uNK that consider KIR2DL1 and KIR2DS1 separately is needed to confirm which of these receptors are specifically reduced in reproductive failure. Wider implications of the findings Overall, our findings suggest that reproductive failure is associated with global underexpression of NK cell receptors leading to impaired implantation and placentation. This is the first study to examine uNK subsets during window of implantation and will serve as a platform to focus on particular uNK subsets in future studies. Trial registration number Not applicable

Low-molecular-weight heparin in the prevention of unexplained recurrent miscarriage: a systematic review and meta-analysis

The etiology of recurrent pregnancy loss (RPL) is complex and multifactorial and in half of patients it remains unexplained (U-RPL). Recently, low-molecular-weight heparin (LMWH) has gained increasing relevance for its therapeutic potential. On this regard, the aim of this systematic review and meta-analysis is to analyze the efficacy of low molecular weight heparin (LMWH) from the beginning of pregnancy in terms of live birth rates (LBR) in U-RPL. Registered randomized controlled trials (RCTs) were included. We stratified findings based on relevant clinical factors including number of previous miscarriages, treatment type and control type. Intervention or exposure was defined as the administration of LMWH alone or in combination with low-dose aspirin (LDA). A total of 6 studies involving 1016 patients were included. The meta-analysis results showed that LMWH used in the treatment of U-RPL was not associated with an increase in LBR with a pooled OR of 1.01, a medium heterogeneity (26.42%) and no publication bias. Results of other sub-analyses according to country, treatment type, and control type showed no significant effect of LMWH on LBR in all subgroups, with a high heterogeneity. The results highlight a non-significant effect of LMWH in U-RPL on LBR based on moderate quality evidence.Registration number: PROSPERO: (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022326433).

Hypermethylation and low expression of FOXM1 predisposes women to unexplained recurrent miscarriage by impairing trophoblast stem cell proliferation

Recurrent miscarriage (RM) is a distressing pregnancy complication with an unknown etiology. Increasing evidence indicates the relevance of dysregulation of human trophoblast stem cells (hTSCs), which may play a role in the development of RM. However, the potential molecular regulatory mechanism underlying the initiation and maintenance of hTSCs is yet to be fully elucidated. In this study, we performed data analysis and identified Forkhead box M1 (FOXM1) as a potential factor associated with RM. FOXM1 is a typical transcription factor known for its involvement in various pathophysiological processes, while the precise function of FOXM1 functions in hTSCs and RM remains incompletely understood. Utilizing RNA-seq, CUT&Tag, ChIP-qPCR, and sodium bisulfite conversion methods for methylation analysis, we elucidate the underlying regulatory mechanisms of FOXM1 in hTSCs and its implications in RM. Our findings demonstrate the relative high expression of FOXM1 in proliferating cytotrophoblasts (CTBs) compared to differentiated extravillous cytotrophoblasts (EVTs) and syncytiotrophoblasts (STBs). Besides, we provide evidence supporting a significant correlation between FOXM1 downregulation and the incidence of RM. Furthermore, we demonstrate the significant role of FOXM1 in regulating hTSCs proliferation and cell cycle through the transcriptional regulation of CDKN3, CCNB2, CCNA2, MAD2L1 and CDC25C. Notably, we observed a correlation between the downregulation of FOXM1 in RM and hypermethylation in its promoter region. Collectively, these results provide insights into the impact of FOXM1 on trophoblast regulation and offer a novel perspective on RM.

Decreased thrombospondin-1 impairs endometrial stromal decidualization in unexplained recurrent spontaneous abortion†.

Inappropriate endometrial stromal decidualization has been implied as an important reason of many pregnancy-related complications, such as unexplained recurrent spontaneous abortion, preeclampsia, and intrauterine growth restriction. Here, we observed that thrombospondin-1, an adhesive glycoprotein, was significantly downregulated in endometrial decidual cells from patients with unexplained recurrent spontaneous abortion. The immortalized human endometrial stromal cell line was used to investigate the possible THBS1-mediated regulation of decidualization. In vitro experiments found that the expression level of THBS1 increased with the normal decidualization process. Knockdown of THBS1 could decrease the expression levels of prolactin and insulin-like growth factor binding protein-1, two acknowledged human decidualization markers, whereas THBS1 overexpression could reverse these effects. The RNA sequencing results demonstrated that the extracellular regulated protein kinases signaling pathway was potentially affected by the knockdown of THBS1. We further confirmed that the regulation of THBS1 on decidualization was achieved through the ERK signaling pathway by the treatment of inhibitors. Moreover, knockdown of THBS1 in pregnant mice could impair decidualization and result in an increased fetus resorption rate. Altogether, our study demonstrated a crucial role of THBS1 in the pathophysiological process of unexplained recurrent spontaneous abortion and provided some new insights into the research of pregnancy-related complications.

Decidual stromal cell–derived exosomes deliver miR-22-5p_R-1 to suppress trophoblast metabolic switching from mitochondrial respiration to glycolysis by targeting PDK4 in unexplained recurrent spontaneous abortion

IntroductionStudies have shown that EMT (epithelial-mesenchymal transition) and energy metabolism influence each other, and it is unclear whether the trophoblast energy metabolism phenotype is dominated by glycolysis or mitochondrial respiration, and the relationship between trophoblast energy metabolism and EMT is still unclear. MethodsExosomes were isolated from the DSC of URSA patients and their miRNA profile was characterized by miRNA sequencing. Wound healing assays and transwell assays were used to assess the invasion and migration ability of trophoblasts. Mitochondrial stress and glycolysis stress test were used to evaluate energy metabolism phenotype of trophoblast. Luciferase reporter assays, qRT-PCR and WB were conducted to uncover the underlying mechanism. Finally, animal experiments were employed to explore the effect of DSC-exos on embryo absorption in mice. ResultsOur results showed that URSA-DSC-exos suppressed trophoblast EMT to reduce their migration and invasion, miR-22-5p_R-1 was the most upregulated miRNAs. URSA-DSC-exos can suppress trophoblast MGS (metabolic switch from mitochondrial respiration to glycolysis) and inhibit trophoblast migration and invasion by transferring miR-22-5p_R-1. Mechanistically, miR-22-5p_R-1 suppress trophoblast MGS and inhibit trophoblast EMT by directly suppressing PDK4 expression at the post-transcriptional level. Furthermore, in vivo experiment suggested that URSA-DSC-exos aggravated embryo absorption in mice. Clinically, PDK4 and EMT molecule were aberrant in villous of URSA patients, and negative correlations were found between miR-22-5p_R-1 and PDK4. DiscussionOur findings indicated that URSA-DSC-exos induced MGS obstacle playing an important role in intercellular communication between trophoblast and DSC, illuminating a novel mechanism in DSC regulation of trophoblasts and their role in URSA.

Association between eNOS gene polymorphisms and the risk of unexplained recurrent spontaneous abortion in Yunnan province, China.

Recurrent spontaneous abortion affects approximately 1-2% of reproductive-age women, with roughly half of RSA cases classified as unexplained recurrent spontaneous abortion (URSA). Genetic polymorphisms in eNOS gene have been shown to have significant implications across various disease processes. Nevertheless, the potential impact of eNOS gene polymorphisms on the susceptibility to URSA in Yunnan population has yet to be explored or documented. This study aims to investigate the potential association between specific variations in the eNOS gene (VNTR 4b/a, -786T > C, and +894G > T) and the risk of URSA in Yunnan population. A total of 243 URSA patients and 241 healthy females are involved in this study. We conducted amplification of the eNOS gene fragment and performed sanger sequencing to detect the specific eNOS gene polymorphisms, including VNTR 4b/a, -786T > C, and +894G > T. Using a multivariate logistic regression model, we evaluate the potential association between eNOS gene polymorphisms (VNTR 4b/a, -786T > C, and +894G > T) and the risk of URSA. Furthermore, serum NO levels were measured in URSA patients. The presence of VNTR 4a, -786C, and +894T alleles was found to be associated with an increased risk of URSA. Additionally, our study revealed a significant association between the G-C-4b haplotype of the investigated eNOS gene polymorphisms and a predisposition to URSA. Notably, these eNOS polymorphisms were shown to reduce serum NO levels in URSA patients. This study provides evidence supporting the association between eNOS gene polymorphisms, VNTR 4b/a, -786T > C, and +894G > T, and the occurrence of URSA in Yunnan Province, China.

Beyond Immune Balance: The Pivotal Role of Decidual Regulatory T Cells in Unexplained Recurrent Spontaneous Abortion.

Recurrent spontaneous abortion (RSA) is defined as two or more consecutive pregnancy failures, which brings tremendous stress to women of childbearing age and seriously affects family well-being. However, the reason in about 50% of cases remains unknown and is defined as unexplained recurrent spontaneous abortion (URSA). The immunological perspective in URSA has attracted widespread attention in recent years. The embryo is regarded as a semi-allogeneic graft to the mother. A successful pregnancy requires transition to an immune environment conducive to embryo survival at the maternal-fetal interface. As an important member of regulatory immunity, regulatory T (Treg) cells play a key role in regulating immune tolerance at the maternal-fetal interface. This review will focus on the phenotypic plasticity and lineage stability of Treg cells to illustrate its relationship with URSA.

The safety and efficacy of tumor necrosis factor-alpha inhibitor on pregnancy outcomes in patients with unexplained recurrent miscarriage

ObjectivesAlthough tumor necrosis factor-alpha inhibitor (TNFi) treatment may improve pregnancy outcomes in unexplained recurrent miscarriage (URM) patients, evidence for its efficacy and safety is still insufficient. The goal of this study was to evaluate the efficacy and safety of TNFi on pregnancy outcomes in patients with URM. MethodsThis retrospective study was conducted at a single institution in China, involving 121 patients treated with TNFi for URM from 2019 to 2022. Patients enrolled were divided into treatment group (receiving TNFi and heparin therapy) and control group (receiving heparin therapy). The outcome variables were the 24-week live birth rate, miscarriage rate, ectopic pregnancy rate, neonatal outcomes, and adverse events. ResultsIn our study, patients receiving TNFi treatment exhibited a significant increase in live birth rates, achieving 71.2 % compared to the 50.9 % observed in the control group (OR 2.507, 95 % CI: 1.127–5.579). Concurrently, there was a discernible reduction in the miscarriage rate within the TNFi-treated group, marking 24.2 %, in contrast to 43.6 % in the control group (OR 0.387, 95 % CI: 0.170–0.884). Subgroup analyses further illuminated that those under the age of 35 benefitted remarkably from TNFi treatment, with live birth rates soaring to 62.5 % (OR 2.525, 95 % CI: 1.041–6.125). For patients with a history of two miscarriages, the TNFi regimen significantly augmented the live birth rate to 58.9 % (OR 3.044, 95 % CI: 1.039–8.921). Patients with a normal weight range registered a 58.4 % live birth rate post-TNFi treatment (OR 4.261, 95 % CI: 1.539–11.397). Notably, an evident interaction between BMI and TNFi treatment was identified, suggesting a potential modulatory role of BMI on the therapeutic efficacy of TNFi. About safety assessments, neither the TNFi-treated group nor the control manifested any significant disparities in liver function abnormalities, platelet count anomalies, or other pregnancy-related complications. ConclusionsTNFi, alongside basic therapy, notably enhances the live birth rate in URM patients under 35, with two prior miscarriages or a normal BMI, without increasing adverse event risk. Further prospective studies are essential to validate these observations.

Maternal-fetal immunity and recurrent spontaneous abortion.

Recurrent Spontaneous Abortion (RSA) is a common pregnancy complication, that has multifactorial causes, and currently, 40%-50% of cases remain unexplained, referred to as Unexplained RSA (URSA). Due to the elusive etiology and mechanisms, clinical management is exceedingly challenging. In recent years, with the progress in reproductive immunology, a growing body of evidence suggests a relationship between URSA and maternal-fetal immunology, offering hope for the development of tailored treatment strategies. This article provides an immunological perspective on the pathogenesis, diagnosis, and treatment of RSA. On one hand, it comprehensively reviews the immunological mechanisms underlying RSA, including abnormalities in maternal-fetal interface immune tolerance, maternal-fetal interface immune cell function, gut microbiota-mediated immune dysregulation, and vaginal microbiota-mediated immune anomalies. On the other hand, it presents the diagnosis and existing treatment modalities for RSA. This article offers a clear knowledge framework for understanding RSA from an immunological standpoint. In conclusion, while the "layers of the veil" regarding immunological factors in RSA are gradually being unveiled, our current research may only scratch the surface. In terms of immunological etiology, effective diagnostic tools for RSA are currently lacking, and the efficacy and safety of immunotherapies, primarily based on lymphocyte immunotherapy and intravenous immunoglobulin, remain contentious.

Therapeutic Potential of Hydrogen Sulfide in Reproductive System Disorders.

Hydrogen sulfide (H2S), previously regarded as a toxic exhaust and atmospheric pollutant, has emerged as the third gaseous signaling molecule following nitric oxide (NO) and carbon monoxide (CO). Recent research has revealed significant biological effects of H2S in a variety of systems, such as the nervous, cardiovascular, and digestive systems. Additionally, H2S has been found to impact reproductive system function and may have therapeutic implications for reproductive disorders. This paper explores the relationship between H2S and male reproductive disorders, specifically erectile dysfunction, prostate cancer, male infertility, and testicular damage. Additionally, it examines the impact of H2S regulation on the pathophysiology of the female reproductive system, including improvements in preterm birth, endometriosis, pre-eclampsia, fetal growth restriction, unexplained recurrent spontaneous abortion, placental oxidative damage, embryo implantation, recovery of myometrium post-delivery, and ovulation. The study delves into the regulatory functions of H2S within the reproductive systems of both genders, including its impact on the NO/cGMP pathway, the activation of K+ channels, and the relaxation mechanism of the spongy smooth muscle through the ROCK pathway, aiming to broaden the scope of potential therapeutic strategies for treating reproductive system disorders in clinical settings.

Maternal Serum Amyloid a Level as a Novel Marker of Primary Unexplained Recurrent Early Pregnancy Loss

Background: Recurrent abortion affects 1-2% of women. Serum Amyloid A belongs to a family of apolipoproteins produced in response to cytokines released by activated monocytes and macrophages, isolated in the last 50 years. Our current study emphasizes human SAA protein as a sensitive biochemical marker for primary unexplained recurrent miscarriage. The aim of the current study is to examine the hypothesis that primary unexplained REPL might be associated with high maternal serum levels of SAA, which in turn could lead to defective trophoblastic invasion into the decidua, and subsequent pregnancy failure and miscarriage. Patients and Method: A prospective study (case control study) in Al-Zahraa Maternity Hospital, Najaf, Iraq, from first of January to the first of December of 2019. The study was conducted among 91 who were divided into two groups Group 1: women with missed miscarriage in the first trimester with at least two consecutive primary unexplained REPLs and no previous live births were enrolled. Group 2: A control group was formed of women with miscarriage no history of REPL who had at least one previous uneventful pregnancy with no adverse outcomes. Serum samples were collected to measure SAA levels. Result: The main outcome was the association between SAA and primary unexplained REPL. A total number of 91 participants. Mean SAA level was significantly higher among women with REPL than among women in the control group (P&lt;0.001). The SAA level was dependent indicator of primary unexplained REPL, P&lt;0.001 Elevated SAA levels found among women with primary unexplained REPL could represent biomarker for this complication of pregnancy. Conclusions: The present findings suggest that SAA is potentially a novel marker for primary unexplained REPL that warrants further investigation. For example, studies could be conducted to compare SAA levels among women with a history of primary unexplained REPL during the pregnant and non-pregnant states, as well as before and after miscarriage. In future, such studies might guide the timing for initiation of new treatments, such as gene therapy or the use of immune-receptor antagonists.

Correlation between hysteroscopic features and specific microbial species in women with chronic endometritis

Objective and rationaleChronic endometritis (CE) has recently been associated with unexplained infertility and recurrent miscarriages. The current gold standard for CE detection is histopathological examination. However, office hysteroscopy and endometrial cultures are also significant, due to the possible link between CE and various microorganisms. Bacterial colonization of the endometrium has been associated with reduced success rates of in vitro fertilisation embryo transfer. Few studies have tried to correlate CE hysteroscopy findings with pathogenic microorganisms. This prospective cohort study sought to establish whether hysteroscopic diagnostic lesions correlate with specific microbial species. MethodsThe study encompassed women undergoing diagnostic tests for a range of subfertility health issues. 189 women completed the standard office diagnostic hysteroscopy (DH). 181 had also endometrial samples taken for microbial culture investigation. Correlation analysis (χ2 and Fisher's exact test) between hysteroscopic findings suggestive of CE and endometrial cultures was carried out. Logistic regression models were also fitted to measure whether a positive endometrial culture could affect CE conditions. ResultsA significant association of E. coli was observed between the hysteroscopically characterized CE + group with focal hyperplasia, when compared to the non–CE group. Logistic regression analysis revealed that women positive for E. coli were 4.423 times more likely to have focal endometrial hyperplasia. No other significant correlations were identified between DH and positive endometrial cultures. ConclusionsThe presence of E. coli in the endometrium was significantly correlated with focal hyperplasia findings from hysteroscopy, emphasizing the importance of microbial cultures in the diagnosis and targeted treatment of CE in women with subfertility.

Strong association between angiotensin I-converting enzyme insertion/deletion polymorphism and unexplained recurrent spontaneous abortion of Sudanese women: a case-control study

This study investigated the link between angiotensin I-converting enzyme insertion/deletion (ACE I/D) polymorphism and unexplained spontaneous abortion. This retrospective analytical case-control was conducted at the Omdurman Maternity Hospital in Sudan. The current study contained 230 individuals, including 119 cases (women who had at least three abortions) of unknown cause and 119 controls (healthy women who had at least two full-term deliveries without spontaneous abortion). Patients and controls were provided five ml of ethylenediaminetetraacetic acid blood and answered questionnaires about their demographics, personal lives, and family histories. ACE I/D polymorphisms were assessed using a conventional polymerase chain reaction approach after total genomic DNA was isolated from blood leukocytes using the GF-1 blood DNA extraction kit. Data was analyzed using the Statistical Package for the Social Sciences version 24. ACE I/D polymorphism is strongly linked to unexplained spontaneous abortion, and women with the I/D and D/D genotypes are more likely to have it than those with the I/I genotype. The current study reveals that ACEI/D polymorphism increases pregnancy problems. Sudanese women may have spontaneous abortions due to the ACE I/D polymorphism.