Systemic lupus erythematosus (SLE) is associated with adverse pregnancy outcomes, but its causal relationship with recurrent pregnancy loss (RPL) and their shared molecular characteristics remain unclear. This study integrated bidirectional two-sample Mendelian randomization (MR) and transcriptomic bioinformatics analyses to investigate this relationship and identify candidate shared biomarkers. FinnGen and UK Biobank were selected because they provide large, non-overlapping, European-ancestry genome-wide association study (GWAS) summary statistics. Differentially expressed genes (DEGs) were identified from GSE61635 (blood; |log2 fold change| > 1) and GSE165004 (endometrium; |log2 fold change| > 0.5) using an adjusted P < 0.05, followed by functional enrichment, protein-protein interaction (PPI) analysis, hub-gene screening, least absolute shrinkage and selection operator (LASSO) regression, external validation using GSE50772 and GSE198700, receiver operating characteristic (ROC) analysis, and single-sample gene set enrichment analysis (ssGSEA). Genetically predicted SLE was associated with a statistically significant but quantitatively modest increase in spontaneous miscarriages (inverse-variance weighted [IVW] odds ratio [OR] = 1.01, 95% confidence interval [CI] = 1.00-1.02; P < 0.001). Instrument strength was adequate, and sensitivity analyses detected no material heterogeneity, directional pleiotropy, or influential single variant. Fifty-nine shared DEGs were enriched in antiviral immune responses, cell adhesion, and apoptosis-related processes. IFI27 was consistently overexpressed in SLE blood but underexpressed in RPL endometrium and chorionic villi, whereas CXCL11 lacked consistent external validation. Retrospective ROC analyses yielded areas under the curve (AUCs) of 0.822 for SLE and 0.872 for RPL. Computationally inferred ssGSEA scores showed correlations between IFI27 expression and several immune-cell signatures, including T helper 2 (Th2) cells. These findings identify IFI27 as a candidate biomarker shared by SLE and RPL; however, prospective clinical and experimental studies are required to validate its biological and clinical significance.

Pregnancy is a unique physiological stage characterized by the coordinated remodeling of maternal metabolism, immunity, and endocrine systems. Previous studies have primarily focused on the local uterine microenvironment, neglecting the role of the maternal gut microbiota in mediating distal, cross-organ regulation via the gut-placental axis. The concept of the gut-placental axis was formally proposed in 2018 and has attracted widespread research attention in recent years. Studies using germ-free animals, fecal microbiota transplantation (FMT), and in vitro experiments with human multi-omics cohorts suggest that live gut bacteria generally cannot colonize the placenta, and that soluble microbial metabolites mediate bidirectional signaling between the gut and the placenta. Pregnancy-related factors such as a high-sugar, high-fat diet, antibiotic use, and obesity can induce gut microbiota dysbiosis and intestinal barrier dysfunction, leading to decreased levels of potentially protective metabolites such as short-chain fatty acids (SCFAs) and tryptophan derivatives, while pro-inflammatory molecules such as lipopolysaccharide (LPS), and trimethylamine N-oxide (TMAO) to accumulate in the bloodstream. These substances cross the placental barrier, disrupting maternal-fetal immune homeostasis, inhibiting trophoblast function and spiral artery remodeling, and are statistically associated with adverse pregnancy outcomes such as recurrent spontaneous abortion (RSA), preeclampsia (PE), gestational diabetes mellitus (GDM), fetal growth restriction (FGR), and spontaneous preterm birth. This article is a narrative review that systematically elucidates the - placental axis for substance transport and the potential molecular mechanisms by which metabolites regulate maternal-fetal immune balance; it maps out the pathological pathways through which microbiota dysbiosis mediates various adverse pregnancy outcomes; it objectively analyzes controversies and gaps in areas such as placental microbial colonization, bidirectional feedback loops, and evidence for clinical interventions; and it proposes a future research framework centered on multi-omics candidate biomarkers and stratified microbiome interventions. Microbial metabolites are promising candidates for non-invasive biomarkers; stratified microbiome interventions are merely potential prevention and control strategies suggested by laboratory and small-scale clinical studies. There is still a lack of unified, standardized clinical protocols, and large-scale, long-term, randomized controlled trials (RCTs) are needed to validate their safety and efficacy, thereby providing a theoretical foundation for subsequent mechanistic and translational research on maternal-fetal microbiome interactions.

Recurrent pregnancy loss (RPL) is a clinically heterogeneous reproductive disorder, and in many women the underlying mechanism remains unexplained by standard thrombophilia evaluation. Pregnancy is characterized by a tightly regulated hemostatic balance at the maternal-placental interface. Heparanase, tissue factor pathway inhibitor 2 (TFPI-2), and heparan sulfate (HS) are expressed in placental and hemostatic pathways and may contribute to coagulation-related pregnancy complications. We investigated whether the heparanase/TFPI-2/HS axis is altered in women with RPL. Blood samples were obtained from 69 women with RPL and 47 control women with at least two normal deliveries and no history of pregnancy-related vascular complications. Samples were collected at least three months after pregnancy and in the absence of hormonal therapy. Plasma and white blood cell samples were analyzed using an enzyme-linked immunosorbent assay, Western blotting, real-time polymerase chain reaction, co-immunoprecipitation, and Sanger sequencing. Mechanistic experiments using heparanase-derived peptide 16 and TFPI-2-derived peptide 6 were performed in MCF-7 and JAR cells. We found that women with RPL had increased plasma heparanase levels, heparanase procoagulant activity, HS levels, and heparanase mRNA expression compared with controls. TFPI-2 protein and mRNA expression were also elevated. The heparanase rs4693608 AA genotype was more frequent in women with RPL and, together with rs4364254 TT, was associated with increased heparanase expression and procoagulant activity. Although TFPI-2 levels were higher in RPL, co-immunoprecipitation showed reduced heparanase/TFPI-2 complex formation, suggesting impaired inhibitory regulation. HS modulated heparanase binding to TF and TFPI-2 in a concentration-dependent, bell-shaped manner. Heparanase-derived peptide 16 increased TFPI-2 expression, supporting a regulatory feedback loop. In conclusion, RPL is associated with dysregulation of the heparanase/TFPI-2/HS axis, including increased heparanase expression and activity, altered heparanase/TFPI-2 interaction, and heparanase-related genetic variation. These findings suggest a coagulation-related reproductive mechanism that may contribute to pregnancy loss and warrants validation in larger prospective studies.

Objective: To evaluate the efficacy and safety of cyclosporine A (CsA)-containing treatment for recurrent spontaneous abortion/recurrent pregnancy loss (RSA/RPL) through a systematic review and meta-analysis. Methods: PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang Database, and VIP were searched from inception to 31 December 2025. Randomized controlled trials and non-randomized controlled studies evaluating CsA-containing treatment in women with RSA/RPL were included. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using a random-effects model. The main outcomes were live birth/successful delivery, pregnancy success/fetal protection success, miscarriage using the total enrolled population as the denominator, and maternal adverse events. The certainty of evidence was evaluated using the GRADE approach. Results: 13 studies involving 1181 participants were included. CsA-containing treatment was associated with a higher live birth/successful delivery rate than control treatment (RR = 1.32, 95% CI: 1.21-1.45). It was also associated with a higher pregnancy success/fetal protection success rate (RR = 1.34, 95% CI: 1.22-1.48) and a lower miscarriage rate (RR = 0.42, 95% CI: 0.33-0.54). No statistically significant difference in maternal adverse events was observed between the CsA-containing treatment and control groups (RR = 0.80, 95% CI: 0.43-1.49). The certainty of evidence was rated as low for efficacy outcomes and very low for maternal adverse events. Conclusions: CsA-containing treatment may be associated with improved pregnancy-related outcomes in women with RSA/RPL, including higher live birth/successful delivery and pregnancy success rates and a lower miscarriage rate. However, the certainty of evidence remains limited because of risk of bias, heterogeneous co-interventions, potential publication bias, and insufficient safety reporting. Further high-quality multicenter randomized controlled trials are needed.

Recurrent pregnancy loss (RPL), a multifactorial condition in reproductive medicine, affects approximately 1-3% of couples. Increasing evidence implicates endometrial dysfunction, immune dysregulation, impaired angiogenesis, and oxidative stress (OS) in its pathophysiology, highlighting the need for biologically targeted therapeutic strategies. In this context, platelet-rich plasma (PRP) has emerged as a regenerative approach with the potential to modulate these underlying mechanisms. This narrative review critically evaluates the biological rationale and current clinical evidence supporting PRP as an adjunctive treatment for RPL while proposing a precision medicine framework for biologically guided patient selection. A comprehensive narrative synthesis of the literature was performed, focusing on studies investigating PRP in RPL and related reproductive conditions, including thin endometrium and recurrent implantation failure (RIF). Mechanistically, PRP promotes angiogenesis through vascular endothelial growth factor (VEGF)-mediated pathways, enhances endometrial regeneration by stimulating stromal and epithelial cell proliferation, and modulates immune responses by promoting regulatory T-cell activity while attenuating pro-inflammatory signaling. In addition, PRP-derived extracellular vesicles (EVs) and microRNAs may contribute to the post-transcriptional and epigenetic regulation of implantation-related genes, including leukemia inhibitory factor (LIF) and HOXA10. Clinical studies in RIF and thin endometrium populations suggest that PRP may improve endometrial thickness, implantation, and clinical pregnancy outcomes; however, these findings constitute indirect evidence for RPL. Direct RPL-specific evidence remains very limited and is insufficient to establish a reduction in miscarriage or an improvement in live birth. These biological features instead provide a rationale for investigating PRP in defined patient subgroups characterized by impaired endometrial receptivity, defective angiogenesis, immune dysregulation, or unexplained RPL with suspected endometrial dysfunction. Accordingly, we propose that future clinical investigation of PRP should move beyond empirical use toward biomarker-informed, precision reproductive medicine strategies. Although PRP represents a biologically plausible and promising adjunctive therapy, robust randomized controlled trials incorporating standardized PRP protocols and biologically stratified patient populations are required before its routine clinical use can be recommended.

Progesterone is essential for establishing uterine receptivity and sustaining early pregnancy. However, how the uterus acquires the competence to respond to progesterone at the appropriate time remains poorly understood. Here we show that ERBB2 governs the timing of progesterone responsiveness required for uterine receptivity. In endometrial samples from women with recurrent spontaneous abortion (RSA), ERBB2 is downregulated specifically in the stromal compartment, accompanied by a parallel reduction in stromal progesterone receptor (PGR). Uterine deletion of Erbb2 in mice blunts the rise of stromal PGR at the onset of the receptive window, deferring implantation and impairing decidualization despite normal circulating progesterone and estrogen. Epithelial deletion has no such effect, placing the requirement in the stroma. High-dose progesterone fails to rescue the phenotype; advancing progesterone priming by 24 hours restores stromal PGR, HAND2, Bmp2, and on-time implantation. Collectively, the present study provides evidence that ERBB2 directs the temporal window of stromal progesterone priming by setting the threshold for PGR induction, thereby synchronizing the maternal-fetal interface and safeguarding pregnancy.

Recurrent spontaneous abortion (RSA) is a troublesome pregnancy disorder, and metabolic reprogramming of decidual macrophages is implicated in disrupted maternal-fetal interface homeostasis and RSA pathogenesis, yet the specific mechanism remains poorly defined. This study aimed to explore the regulatory role of GTP-binding protein 10 (GTPBP10) in RSA by targeting macrophage metabolic reprogramming. We detected GTPBP10 expression in decidual macrophages from RSA patients and healthy controls, and investigated its effects on macrophage phenotypes, glycolysis and fatty acid oxidation (FAO) via gene overexpression/knockdown, metabolic detection, and multiple molecular experiments. The direct interaction between GTPBP10 and AMPK was verified, and in vivo mouse models and cell co-culture systems were constructed for functional validation. Results showed that GTPBP10 was markedly upregulated in RSA-derived decidual macrophages and induced a pro-inflammatory macrophage phenotype. Mechanistically, GTPBP10 bound and inhibited AMPK phosphorylation, promoting glycolysis while suppressing FAO and causing mitochondrial damage; these aberrations were rescued by the AMPK activator AICAR. In vivo, GTPBP10-overexpressing macrophages increased embryo resorption, impaired placental vasculature and triggered pro-inflammatory immune imbalance. Moreover, macrophage GTPBP10 overexpression inhibited trophoblast motility, impaired endometrial decidualization and biased CD4[+] T cells toward Th1/Th17 phenotypes. In conclusion, GTPBP10-mediated AMPK inhibition triggers immunometabolic reprogramming of decidual macrophages, disrupts maternal-fetal immune homeostasis, and ultimately drives the occurrence of RSA, providing a promising therapeutic target for RSA.

Recurrent pregnancy loss affects 1%-2% of reproductive-aged couples, with chromosomal abnormalities accounting for 40%-60% of cases. There is a close link between adverse pregnancy history (APH) and recurrent pregnancy loss (RPL). However, cryptic balanced translocations with translocated fragments smaller than the resolution of karyotyping or with similar banding patterns are often missed. This study, based on the testing results of 586 families who underwent preimplantation genetic testing for aneuploidy (PGT-A) due to RPL or APH, identified cryptic balanced translocations that were not detectable by conventional karyotyping, and validated them using Optical Genome Mapping (OGM). The prevalence of cryptic balanced translocations in the overall RPL/APH cohort was 1.19% (7/586, 95% CI: 0.58%-2.45%, Wilson score). It determined the incidence of cryptic balanced translocations in RPL or APH and changed the clinical management of these patients. Additionally, OGM resolved a 4-chromosome complex chromosomal rearrangement (CCR) involving 6 breakpoints and elucidated the genetic basis of two whole-exome sequencing-negative monogenic disorders by demonstrating pathogenic disruptions of EXT1 and PITX2 genes. OGM can be used as a second-line diagnostic tool, in addition to karyotype analysis and CNV-seq, for etiological screening of couples with recurrent pregnancy loss and adverse pregnancy history. The main conclusion of this study is that OGM can identify cryptic structural rearrangements, thereby enabling timely conversion of clinical management from PGT-A to preimplantation genetic testing for chromosomal structural rearrangements (PGT-SR), and facilitating the transfer of euploid, non-carrier embryos for couples with RPL or APH.

This report describes the case of a 37-year-old woman (G5P1041) with Asherman syndrome who failed both medication and procedural abortions. Her medical history included recurrent pregnancy loss, postpartum hemorrhage, and multiple suction and sharp dilation and curettages. She was found to have intrauterine adhesions and while awaiting lysis of adhesions, she became pregnant and desired termination of pregnancy. The patient's clinical course was as follows: unsuccessful vacuum aspiration at 6 weeks 0 days due to inability to reach the gestational sac, failed medication abortion, unsuccessful hysteroscopic abortion with morcellation at 6 weeks 5 days, and successful hysteroscopic removal of retained products of conception one month later. Clinical guidance is lacking for patients with intrauterine adhesions that fail procedural and medication abortions. This single case suggests that management modalities to consider include comprehensive preoperative planning, ultrasound guidance, hysteroscopic removal of the products of conception, use of second-look hysteroscopy, and close postoperative follow-up.