Lactate is a key metabolite of glycolysis. Since the proposal of the lactate shuttle hypothesis, accumulating evidence indicates that lactate is not only an essential energy substrate but also a key signalling molecule that regulates cellular functions under both physiological and pathological conditions. Uterine spiral artery (SpA) remodelling is a critical event in successful pregnancy. It involves complex interactions among trophoblasts, vascular smooth muscle cells (VSMCs), decidual immune cells, and endothelial cells (ECs). Similar to the tumour microenvironment, physiological hypoxia at the maternal-foetal interface during early pregnancy drives decidual cells, blastocysts, trophoblasts, and immune cells to undergo aerobic glycolysis, leading to local lactate accumulation and the formation of an acidic microenvironment. This review systematically elucidates the role and molecular mechanisms of lactate metabolism in SpA remodelling. It explores the association between dysregulated lactate metabolism and recurrent pregnancy loss (RPL), preeclampsia (PE), and foetal growth restriction (FGR). The findings of this review indicate that targeting lactate metabolism may represent a promising strategy for the management of pregnancy complications. Further in-depth mechanistic research and clinical obstetric research are warranted.
Premature ovarian insufficiency (POI) is a heterogeneous disorder characterized by loss of ovarian function before age 40, causing infertility, hypoestrogenism-related complications, and significantly impaired quality of life. Although hormone replacement therapy (HRT) remains the standard treatment for symptom relief and long-term health protection, it cannot restore ovarian reserve or natural fertility.This review summarizes the etiology and pathogenesis of POI, emphasizing mitochondrial dysfunction, oxidative stress, chronic inflammation, and progressive deterioration of the ovarian microenvironment. We critically evaluate the strengths and limitations of conventional HRT based on the latest 2024 international evidence-based guidelines, and comprehensively overview emerging regenerative therapies, focusing on mesenchymal stem cells (MSCs) and MSC-derived small extracellular vesicles (sEVs).MSCs exert therapeutic effects mainly through paracrine actions, including anti-apoptotic, anti-inflammatory, and pro-angiogenic activities. MSC-sEVs, particularly hypoxia-preconditioned ones, offer a safer cell-free alternative. They protect mitochondrial function via the SIRT3/PGC-1α pathway and other related mechanisms such as Nrf2/Keap1 and AMPK signaling.Current clinical evidence for both approaches remains preliminary, consisting mainly of small-scale trials with heterogeneous protocols and short follow-up. We propose an innovative ovarian microenvironment remodeling framework that integrates symptomatic HRT with etiology-targeted regenerative interventions using MSCs or engineered sEVs.In summary, while HRT forms the foundation of POI management, MSC-sEVs represent a highly promising cell-free platform that may shift the paradigm from hormone replacement to functional regeneration, restoring both endocrine function and fertility in POI patients.
Threatened miscarriage is common, and individualized risk stratification remains difficult when progesterone, beta-human chorionic gonadotropin, and ultrasound findings are discordant. This two-center retrospective prediction-model study evaluated whether progesterone-induced blocking factor (PIBF) adds prognostic information for early pregnancy loss before 16 gestational weeks. A total of 396 women were assigned to development (n = 182), internal validation (n = 78), and external validation (n = 136) cohorts. Development-only repeated cross-validation and a one-standard-error parsimony rule selected serum progesterone, fetal-heartbeat visibility, previous miscarriages, and log PIBF. Early pregnancy loss occurred in 45 (24.7%), 19 (24.4%), and 32 (23.5%) women, respectively. Compared with the three-variable conventional model, the PIBF-enhanced model increased the area under the receiver operating characteristic curve (AUC) in development (0.956 vs 0.901; P = 0.004), internal validation (0.942 vs 0.855; P = 0.009), and external validation (0.942 vs 0.813; P < 0.001). External bootstrap AUC was 0.942 (95% CI, 0.903-0.973), and the calibration slope was 0.971 (95% CI, 0.759-1.399). PIBF provided incremental prognostic information. The calculator is not a clinical decision tool without local recalibration. Larger independent external validation, treatment-confounding assessment, and assay standardization are also required before clinical use.
Sepsis is a multiple organ dysfunction syndrome caused by the dysregulated host response to infection, and this condition could lead to testicular injury and cause male infertility. Testicular macrophages play a key role in testicular injury caused by sepsis. This study focused on the communication mechanism between macrophages and spermatocytes and the role of ginsenoside Rb1 in testicular injury caused by sepsis. We established animal models of sepsis and cell experiments, and applied transcriptome sequencing, flow cytometry, Western blotting and other techniques to explore the related mechanisms in depth. The study found that macrophages were significantly enriched in the testes during sepsis. These macrophages secreted a large amount of IL-6, promoted spermatogenic apoptosis, and exacerbated testicular injury. Rb1 could significantly inhibit LPS-induced spermatocyte apoptosis and reduce the pathological injury of mice testes. Further mechanistic studies revealed that Rb1 directly bound to TNF-α and changed its protein conformation, which blocked the activation of the TNF and NF-κB signaling pathways in macrophages, reduced the secretion of IL-6, thereby inhibiting spermatocyte apoptosis. This study clarified for the first time the new mechanism of IL-6-mediated crosstalk between macrophages and spermatocytes and the unique role of Rb1 therein, providing new ideas and a theoretical basis for the treatment of testicular injury caused by sepsis, and it is expected to improve the reproductive health prognosis of sepsis patients.
Whether tumour necrosis factor inhibitors (TNFi) provide a safe and effective adjunctive therapy for enhancing pregnancy outcomes in women with unexplained recurrent spontaneous abortion (URSA) remains unclear. To resolve this ambiguity, we performed a meta-analysis. We systematically searched Web of Science, PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang Database (last search was performed on January 8, 2026). Eligible studies included randomized controlled trials (RCTs) and retrospective cohort studies (RCS) assessing TNFi in URSA patients. A random-effects model was applied. Odds ratios (ORs) or mean differences (MDs) with 95% confidence intervals (CIs) were calculated. A total of 529 patients from four studies were included. The results showed that adjunctive TNFi therapy significantly improved the live birth rate (OR = 2.50, 95% CI: 1.66-3.78; P < 0.0001) and reduced the miscarriage rate (OR = 0.37, 95% CI: 0.24-0.59; P < 0.0001). TNFi was associated with a slightly higher neonatal Apgar score without increasing the risk of adverse maternal or other neonatal outcomes. Exploratory subgroup analysis suggested that the benefit of TNFi on live birth rates appeared consistent regardless of concomitant intravenous immunoglobulin (IVIG) use; however, this finding requires further validation. Adding TNFi to conventional treatment may represent a promising strategy to improve live birth rates in women with URSA, with no major safety concerns identified. Nevertheless, the small number of included studies provides insufficient evidence for definitive conclusions and precludes a robust assessment of publication bias, thereby compromising the reliability of our findings. (PROSPERO: CRD420261305573).
Recurrent pregnancy loss (RPL) is a multifactorial condition, and reliable predictors of miscarriage remain limited. This observational cohort study investigated whether hysteroscopy, chronic endometritis (CE), and endometrial microbiome analysis can predict pregnancy outcomes in women with unexplained RPL. Ninety-nine patients with at least two previous miscarriages were enrolled, excluding those with antiphospholipid syndrome, chromosomal abnormalities in either partner, uterine anomalies, or a history of aneuploid miscarriage. CE was diagnosed by CD138-positive endometrial stromal cells, and affected patients received doxycycline 200 mg/day for 14 days. The primary outcome was cumulative live birth assessed in pregnancies resulting in either live birth or euploid miscarriage in relation to hysteroscopic findings, CE, and microbiome composition. The presence of Fusobacterium and Campylobacter was negatively associated with cumulative live birth. Focusing on Lactobacillus species, L. jensenii was positively associated with live birth. Additionally, the incidence of euploid miscarriage was significantly higher among cases with Lactobacillus abundance < 98% and the presence of Fusobacterium and Campylobacter. In contrast, CD138-positive cell counts and hysteroscopic findings were not predictive of pregnancy outcomes, and no associations were observed between the microbiome and hysteroscopic findings. However, the relative abundance of Lactobacillus tended to be lower when CD138-positive cell counts were higher. These findings suggest that Lactobacillus composition, as well as the presence of Fusobacterium and Campylobacter in the endometrial microbiome, may be associated with pregnancy outcomes, indicating that microbiome profiling could provide useful prognostic information for patients with unexplained RPL.
INTRODUCTION:Preeclampsia (PE) is a serious complication of pregnancy for which reliable early predictive biomarkers are currently lacking. Cell-free RNA (cfRNA) has emerged as a promising non-invasive approach that may enhance clinical management and facilitate earlier diagnosis. METHODS:To investigate PE, we applied single‑cell RNA sequencing (scRNA‑seq) to placental tissues, enabling the identification of differentially expressed genes. Integration of weighted gene co‑expression network analysis (WGCNA) with cfRNA profiles from PE patients revealed two gene modules that showed significant relevance to the pathogenesis of PE. By intersecting the genes within these modules and applying advanced machine learning algorithms, we successfully pinpointed optimal cfRNA biomarkers for PE prediction. Furthermore, we constructed a nomogram and predictive model to enhance clinical utility, complemented by immune infiltration analysis and multi-database expression validation to elucidate the functional relevance of these biomarkers in PE. RESULTS:A diagnostic nomogram was established based on five candidate cfRNAs: KRT19, CCND1, ZBTB16, TUBB6, and HMGB2. In the training cohort, the model yielded strong performance with an AUC of 0.927 (95% CI: 0.872-0.981). Subsequent validation across two independent datasets confirmed its robustness, producing AUCs of 0.910 (95% CI: 0.806-1.000) and 0.772 (95% CI: 0.714-0.830), respectively. CONCLUSIONS:A candidate PE predictive model was constructed from placental single-cell transcriptomic data with a five-cfRNA panel, warranting further large multi-centre prospective validation.
Bovine viral diarrhea virus (BVDV) infects bovine trophoblast cells (BTCs) to induce abortion, stillbirth and other reproductive disorders, and severely threatens the global cattle industry. Exosomes serve as vital viral transmission carriers mediating immune evasion. Tumor susceptibility gene 101 (TSG101), a core ESCRT component, regulates exosome biogenesis and cargo sorting. Nevertheless, the mechanism of TSG101 in exosome-mediated BVDV transmission across BTCs remains unknown. In this study, BTCs were used as cell models to explore the role and mechanism of TSG101 in BVDV transmission. BVDV infection caused obvious cytopathic effects (CPE) in BTCs, with viral particles packaged in exosomes to facilitate immune evasion and transmission. BVDV also upregulated TSG101 and exosomal CD63, and TSG101 colocalized with BVDV E2. TSG101 knockdown suppressed BVDV proliferation and exosome-mediated transmission, and impaired CD63 trafficking into exosomes. Co-IP and immunofluorescence assays further confirmed the interaction between BVDV E2 and TSG101. Molecular docking and 100-ns MD simulation showed that E2 and TSG101 formed a stable binding complex, with key interacting residues identified at the contact surface. TSG101 mutations at Y110K, K118A, and E284A exerted distinct effects. TSG101 Y110K and K118A restricted BVDV replication by impairing TSG101 function, while the E284A mutation preserved TSG101 responsiveness, promoted viral proliferation. These findings expand understanding of BVDV E2-mediated ESCRT homeostasis regulation and provide a molecular basis for targeting the TSG101 to limit BVDV vertical transmission in BTCs.
Chronic chorioamnionitis (CCA) is a placental inflammatory lesion characterized by maternal T cell infiltration and trophoblast apoptosis, resembling allograft rejection. MicroRNA-155 (miR-155) is a central regulator of immune and inflammatory pathways, but its role in CCA remains unclear. This study investigated whether miR-155 contributes to the pathogenesis of CCA by targeting karyopherin α1 (KPNA1) and modulating STAT3 signaling in human trophoblasts. Placental tissues from 28 CCA cases and 16 gestational age-matched controls were analyzed for miR-155 expression using quantitative RT-PCR and in situ hybridization. Functional assays were conducted in Swan 71 trophoblast cells following miR-155 overexpression and siRNA-mediated KPNA1 knockdown. Microarray and qRT-PCR analyses identified gene expression changes, while western blotting and dual-luciferase reporter assays were conducted to evaluate STAT3 activity and direct target binding. miR-155 expression was significantly elevated in CCA fetal membranes. KPNA1 was identified as a direct target of miR-155, and its suppression reduced STAT3 phosphorylation and nuclear translocation. Dual-luciferase assays confirmed that miR-155 binds to the 3' untranslated region of KPNA1 mRNA, thereby inhibiting its translation. These findings suggest that miR-155 downregulates KPNA1, leading to inhibition of STAT3 signaling in trophoblasts, which may contribute to maternal-fetal immune dysregulation and trophoblast apoptosis in CCA. The miR-155-KPNA1-STAT3 axis may represent a potential therapeutic target in pregnancy-related inflammatory disorders.
Unexplained recurrent pregnancy loss affects many fertile couples who want to conceive. Possibly, the maternal immune system is involved in the underlying mechanism of such unexplained cases and immune-suppressing corticosteroids can be used to modulate this system and improve pregnancy outcome. As a high quality, sufficiently powered randomized controlled trials in the unselected unexplained RPL population is currently lacking, the PREMI (Prednisolone administration in patients with unexplained REcurrent Miscarriages) trial was designed. Here, we discuss the rationale for the administration of prednisolone, including its potential mechanisms, safety, administration protocol and study population.
The maternal-fetal interface (MFI) serves as a crucial bidirectional crosstalk site between the mother and the developing fetus, wherein precisely orchestrated immune regulatory networks are indispensable for sustaining tolerance toward the semi-allogeneic fetus while concurrently defending effectively against pathogenic challenges. Excessive inflammatory activation can perturb immune homeostasis at the MFI, particularly during the first trimester, and can compromise placental development and function, thereby contributing to adverse pregnancy outcomes, including recurrent spontaneous abortion, preeclampsia of placental origin, and even aberrant embryonic development. Therefore, a detailed understanding of the cellular composition of the MFI and its dynamic relationship with placental development is fundamental to elucidating disease etiology and informing interventional research on placenta-related pregnancy complications. This review summarizes the major immune cell populations present at the MFI (namely T cells, decidual Natural Killer cells and decidual macrophages) and their functional characteristics, examines their roles in physiological placental formation and remodeling, and evaluates their associations with several common adverse pregnancy outcomes. Collectively, the findings highlight the central role of major maternal immune cells in establishing immune tolerance during early gestation and underscore the potential clinical value of immune profiling in predicting and managing adverse pregnancy outcomes.
The goal of the study was to establish an efficient first-trimester prediction model for gestational hypertension (GH) and preeclampsia (PE). GH is defined as new-onset hypertension without proteinuria or end-organ dysfunction, whereas PE involves hypertension accompanied by proteinuria and/or systemic maternal complications. Current first-trimester screening strategies are primarily based on the Fetal Medicine Foundation (FMF) algorithm, which combines maternal characteristics with biophysical and biochemical markers (e.g., mean arterial pressure, uterine artery Doppler, and PlGF) to estimate the risk of early-onset PE. The retrospective nested case-control study was performed on whole peripheral blood leukocyte lysates collected between November 2012 and March 2020 during the first trimester of gestation. The cohort included pregnancies that later developed GH (n = 83) or PE (n = 66), and 80 randomly selected controls matched by sample storage time. Multiparametric models were constructed using the levels of circulating microRNAs aberrantly expressed during early gestation together with maternal clinical characteristics identified as significant risk factors. A first-trimester prediction model for PE combining the levels of six selected microRNAs with six maternal clinical characteristics-age, body mass index, infertility treatment, nulliparity, prior PE, and any autoimmune disease-identified 78.79% of PE pregnancies at 10.0% false positive rate (FPR). Adding first-trimester FMF screening results for PE and/or fetal growth restriction (FGR) and spontaneous preterm birth further increased predictive performance to 84.85% at 10.0% FPR. The GH prediction model, integrating the levels of miR-181a-5p with five maternal clinical characteristics (age, BMI, infertility treatment, nulliparity, and any autoimmune disease), identified 62.65% of GH cases at 10% FPR, increasing to 69.88% when FMF screening results were included. Importantly, the dysregulated microRNAs identified in early gestation were linked to immune-regulatory and angiogenic pathways at the maternal-fetal interface, supporting the biological plausibility of their involvement in the early pathogenesis of GH and PE. These findings suggest that combining peripheral blood microRNA profiles with maternal clinical characteristics offers a promising new approach for early prediction of GH and PE. Larger prospective studies are needed to validate these pilot results and assess clinical utility.
Recurrent reproductive failure impairs women's health, and the efficacy of immunosuppressants for this condition remains uncertain. This study aimed to explore the clinical application of common immunosuppressive agents including cyclosporine A, tacrolimus, etanercept and adalimumab for recurrent reproductive failure, which covers recurrent spontaneous abortion and recurrent implantation failure after IVF/ICSI, and to assess their efficacy and safety so as to provide evidence-based references for clinical practice. We retrieved eligible randomized controlled trials and cohort studies published from January 1, 2005 to February 28, 2025 from PubMed, Web of Science, CNKI and Wanfang databases, and conducted a systematic review and meta-analysis. This study was registered on PROSPERO (ID: CRD420251057130). A total of 13 randomized controlled trials and 7 cohort studies involving 2266 patients were finally included. Meta-analysis revealed that compared with the control group, immunosuppressive therapy significantly elevated live birth rate (RR=1.33, 95%CI:1.20-1.47, P < 0.00001) and clinical pregnancy rate (RR=1.24, 95%CI:1.11-1.39, P = 0.0001), while lowering miscarriage rate (RR=0.45, 95%CI:0.37-0.54, P < 0.00001). No significant differences were found in the incidence of adverse events (RR=0.96, 95%CI:0.69-1.34, P = 0.83) and birth defect rate (RR=0.63, 95%CI:0.19-2.07, P = 0.45) between the two groups. In conclusion, the above immunosuppressive drugs can improve pregnancy outcomes in patients with recurrent reproductive failure and do not obviously increase adverse reactions and birth defects. Considering the limited quality of existing evidence and potential publication bias, the results should be interpreted cautiously, and the use of these drugs is recommended to be limited to clinical trials until verified by more large-scale and high-quality randomized studies.
Deep infiltrating endometriosis (DIE) and focal adenomyosis of the outer myometrium (FAOM) are closely related chronic inflammatory conditions that often coexist. The systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and pan-immune-inflammation value (PIV) are novel inflammatory indices derived from peripheral blood cell counts. This study investigates the association between these indices and FAOM in patients with DIE. A retrospective analysis was conducted on 300 patients with pathologically confirmed DIE, comprising 158 patients with FAOM and 142 without. Preoperative peripheral blood counts were collected to calculate SII, SIRI, and PIV levels. After adjusting for all potential confounding factors, multivariate logistic regression analysis showed that SII, SIRI, and PIV were significantly positively associated with FAOM (P < 0.05). Restricted cubic spline (RCS) analysis indicated a significant nonlinear relationship between PIV and FAOM (P for nonlinear < 0.01). Receiver operating characteristic (ROC) curve analysis revealed that the combination of SII, SIRI, and PIV demonstrated the highest diagnostic efficacy for FAOM, with an area under the curve (AUC) of 0.757, a sensitivity of 62.0%, and a specificity of 81.0%. This study demonstrates that elevated levels of SII, SIRI, and PIV in patients with DIE are significantly associated with FAOM. These findings suggest that the aforementioned inflammatory indices can provide valuable supplementary information for the clinical assessment of whether patients with DIE have concomitant FAOM, particularly when MRI or other imaging results are inconclusive. Large-scale, multicenter prospective studies are needed to validate these results and further investigate the underlying biological mechanisms.
Premature ovarian insufficiency (POI) poses significant challenges to reproductive health due to follicular depletion and hormonal dysregulation. Despite advances in stem cell therapy, clinical translation remains hindered by donor variability and ethical constraints. This study evaluates the therapeutic potential of exosomes derived from induced pluripotent stem cell-derived mesenchymal stem cells (iPSCMSC-exo) versus umbilical cord-derived MSC exosomes (hUCMSC-exo) for POI intervention. In vitro, both exosome types enhanced migration and tube formation of human umbilical vein endothelial cells (HUVECs), while iPSCMSC-exo additionally promoted proliferation. iPSCMSC-exo attenuated cisplatin-induced granulosa cell apoptosis, while both types suppressed p21-mediated cell cycle arrest. In the cisplatin-induced POI mouse model, exosome treatment effectively restored Follicle-stimulating hormone (FSH) levels. However, the therapeutic efficacy of exosomes in restoring anti-Müllerian hormone (AMH) levels and follicle counts was limited, as confirmed by synchrotron radiation microtomography revealing persistent structural depletion. Notably, iPSCMSC-exo demonstrated functional outcomes similar to hUCMSC-exo. The autologous origin and scalable production of iPSCMSCs address donor heterogeneity and supply limitations inherent to traditional MSC sources. Further optimization of targeted delivery systems is warranted to overcome biodistribution challenges and enhance structural regeneration.
This systematic review and meta-analysis examines the association between inflammatory factors in the follicular fluid and assisted reproductive technology (ART) outcomes among women with polycystic ovary syndrome (PCOS). Multiple databases were comprehensively searched, which identified 37 studies, including 24 case-control, 7 cohort, and 6 cross-sectional studies, with a total of 1421 patients with PCOS and 1458 controls. Methodological quality was rated as high in 86.49% (32/37) of included studies. The meta-analysis revealed significantly higher levels of proinflammatory cytokines, including TNF-α (MD = 6.51 [95% CI 4.95-8.07]; P < 0.0001), IL-6 (MD = 7.16 [95% CI 4.19-10.13]; P < 0.0001), IL-18 (MD = 61.27 [95% CI 17.47-105.07]; P = 0.0061), IL-1β (MD = 4.32 [95% CI 0.08-8.55]; P = 0.0456), and IL-8 (MD = 187.77 [95% CI 14.81-360.73]; P = 0.0334), in the follicular fluid of patients with PCOS compared with controls. However, no significant difference was observed in IL-10 levels. Inflammation in the follicular fluid was associated with reductions in oocyte maturation rate, high-quality embryo rate, implantation rate, and clinical pregnancy rate, whereas fertilization rate remained unaffected. These findings suggest that elevated proinflammatory cytokine levels in the follicular fluid of patients with PCOS adversely affect ART outcomes, underscoring the need for further validation in large-scale randomized controlled trials.
Antiphospholipid syndrome (APS) is an autoimmune prothrombotic state defined by vascular thrombosis and adverse pregnancy outcomes, most notably recurrent miscarriage. While APS epidemiology is well characterized in Western populations, comprehensive data from Asia remain fragmented. This systematic review (PRISMA-compliant) synthesized evidence from 22 studies across eight Asian countries, encompassing over 40,000 individuals, including nationwide registries, APS cohorts, and high-risk groups such as systemic lupus erythematosus (SLE), recurrent pregnancy loss (RPL), and malignancy. Population-based studies from South Korea and Taiwan reported an APS incidence of 0.50-0.82 per 100,000 person-years and prevalence of 5-7 per 100,000, with female predominance. Among women with RPL, APS prevalence ranged from 5% to 22.9%; Japanese studies identified an aPL-positive rate of 8.7% in 5708 women and a novel anti-β2GPI-HLA-DR autoantibody in 22.9% of RPL patients, while a Chinese cohort reported APS in 10.3% of women with fetal death. In obstetric APS cohorts, antithrombotic therapy was consistently associated with improved live birth rates. Beyond pregnancy morbidity, more than half of APS patients experienced thrombotic events, with comparable frequencies of venous and arterial thrombosis; ischemic stroke was particularly prominent in SLE-associated APS. Catastrophic APS occurred in 1-5% of patients, with annual thrombosis recurrence of 4-10%. These findings demonstrate that although APS is rare at the population level in Asia, it carries a disproportionately high burden of both recurrent miscarriage and thrombotic events. From a reproductive immunology perspective, systematic aPL screening in women with unexplained RPL represents a high-yield strategy to improve pregnancy outcomes in Asian populations.
