Objectives: This prospective study evaluated whether endometriosis is associated with chronic endometritis (CE) and affects the uterine endometrium microbiome (UEM) in women with repeated implantation failure (RIF). Methods: Forty-three women with RIF were divided into 12 with endometriosis (EM) and 31 without endometriosis (non-EM). The UEM was examined by 16S ribosomal RNA (rRNA) sequencing, and CE was determined by CD 138 staining (plasma cells > 5.15/10 mm2) simultaneously. Results: The EM group had a higher bacterial number (EM vs. non-EM; median [range], 6.5 vs. 3 [3-11, 1-16], p = 0.009), while the frequency of Lactobacillus species did not change. The rates of presence of Dialister (41.7% [5/12] vs. 3.3% [1/31], p = 0.004) and Streptococcus species (58.3% [7/12] vs. 16.1% [5/31], p = 0.017) were higher in the EM group. The prevalence of CE did not differ between the two groups. Multivariable logistic regression analysis revealed that the presence of Dialister species (odds ratio, 10.97, 95% confidence interval, 1.17-249.37, p = 0.036) was associated with endometriosis. In the EM group, five women with Dialister species had a higher number of bacterial species (10 vs. 5 [6-11, 3-7], p = 0.021) and higher Shannon diversity index (0.50 vs. 0.20 [0.19-1.39, 0.03-0.46], p = 0.026) than seven without Dialister species. Conclusions: Dialister and Streptococcus species, and the increased number of bacterial species in UEM may be related to the pathogenesis of RIF complicated by endometriosis.

OBJECTIVE: To investigate the impact of antibiotic treatment for chronic endometritis (CE) on the pregnancy outcome of frozen-thawed embryo transfer (FET) cycles and the relevant clinical risk factors associated with CE.
METHODS: A retrospective cohort analysis was conducted on 1352 patients who underwent hysteroscopy and diagnostic curettage at Nanjing Maternal and Child Health Hospital from July 2020 to December 2021. All patients underwent CD138 immunohistochemical (IHC) testing to diagnose CE, and a subset of them underwent FET after hysteroscopy. Patient histories were collected, and reproductive prognosis was followed up.
RESULTS: Out of 1088 patients, 443 (40.7%) were diagnosed with CE. Univariate and multivariate binary logistic regression analyses revealed that parity ≥ 2, a history of ectopic pregnancy, moderate-to-severe dysmenorrhea, hydrosalpinx, endometrial polyps, a history of ≥ 2 uterine operations, and RIF were significantly associated with an elevated risk of CE (P < 0.05). Analysis of the effect of CE on pregnancy outcomes in FET cycles after antibiotic treatment indicated that treated CE patients exhibited a significantly lower miscarriage rate (8.7%) and early miscarriage rate (2.9%) than untreated non-CE patients (20.2%, 16.8%). Moreover, the singleton live birth rate (45.5%) was significantly higher in treated CE patients than in untreated non-CE patients (32.7%). Survival analysis revealed a statistically significant difference in the first clinical pregnancy time between treated CE and untreated non-CE patients after hysteroscopy (P = 0.0019). Stratified analysis based on the presence of recurrent implantation failure (RIF) demonstrated that in the RIF group, treated CE patients were more likely to achieve clinical pregnancy than untreated non-CE patients (P = 0.0021). Among hysteroscopy-positive patients, no significant difference was noted in pregnancy outcomes between the treatment and control groups (P > 0.05).
CONCLUSIONS: Infertile patients with a history of parity ≥ 2, hydrosalpinx, a history of ectopic pregnancy, moderate-to-severe dysmenorrhea, endometrial polyps, a history of ≥ 2 uterine operations, and RIF are at an increased risk of CE; these patients should be recommended to undergo hysteroscopy combined with CD138 examination before embryo transfer. Antibiotic treatment can improve the reproductive outcomes of FET in patients with CE, especially those with RIF.

OBJECTIVE: To explore the therapeutic efficacy of acupuncture treatment on repeated implantation failure (RIF) patients with cryo-thawed embryo transfer (CET).
METHODS: In a retrospective cohort study, all eligible women undergoing RIF were recruited in our center from January 1, 2018 to December 31, 2021. The patients were grouped by whether an acceptance of acupuncture treatment before CET, including the acupuncture group (Acu-group, 55 cycles) and control group (Con-group, 244 cycles). Data were analyzed by using binary logistic regression to explore the relationship of acupuncture treatment with pregnancy outcomes.
RESULTS: The Acu-group had higher live-birth rate (LBR) [54.5% vs41.0%, respectively; odds ratio (OR) = 1.105, 95% confidence interval (CI) (1.029, 1.187), P =0.006] and ongoing pregnancy rate (OPR) [56.4% vs43.0%, respectively; OR= 1.100, 95% CI(1.025, 1.181), P =0.008] than the Con-group. There were no significant between-group differences in the rates of implantation [OR= 1.070, 95% CI(0.996, 1.149), P =0.064], clinical pregnancy [OR= 1.065, 95% CI(0.997, 1.138), P =0.061], biochemical pregnancy [OR= 1.002, 95% CI(0.903, 1.112), P =0.967], or miscarriage [OR= 0.778, 95% CI(0.551, 1.099), P =0.155]. Perinatal outcomes did not differ significantly between the two groups.
CONCLUSIONS: Acupuncture treatment could improve the LBR and OPR in RIF patients with CET cycles, suggesting a potential adjuvant therapy of acupuncture to improve the pregnancy outcomes in RIF patients.

UNASSIGNED: The primary objective was to investigate whether the utilization of next-generation sequencing (NGS) for preimplantation genetic testing for aneuploidy (PGT-A) could enhance the reproductive outcomes in patients with unexplained recurrent pregnancy loss (uRPL) or unexplained repeated implantation failure (uRIF) undergoing intracytoplasmic sperm injection (ICSI) cycles.
UNASSIGNED: We studied the reproductive outcomes of uRPL or uRIF sufferers in Chengdu women and children\'s central hospital from July 2020 to Jan 2024 retrospectively. These patients were categorized into two groups based on whether they underwent PGT-A or not. As the patients in the PGT-A group all had ICSI and frozen-thawed embryo transfer (FET), only patients who underwent ICSI and FET were included in the non-PGT-A group for comparison. Demographic characteristics and reproductive outcomes were compared in uRPL or uRIF sufferers.
UNASSIGNED: For uRPL group, a significant increased ongoing pregnancy rate (63.6 % vs 26.1 %, p = 0.002) and reduced pregnancy loss rate (18.4 % vs 73.3 %, p < 0.001) were found in the PGT-A group in comparison with those in the non-PGT-A group. For uRIF group, no significant difference was noted in the HCG-positive rate, ongoing pregnancy rate, or pregnancy loss rate between the two groups. It is noteworthy that the maternal age in the PGT-A group was significantly higher than that in the non-PGT-A group (p = 0.048).
UNASSIGNED: NGS-based PGT-A effectively optimized the reproductive outcomes in uRPL sufferers. Although its benefits in uRIF appeared to be limited, there is a potential advantage for those with advanced maternal age. Considering the small sample size, further randomized controlled trials are warranted to validate these findings.

UNASSIGNED: Embryo implantation requires synchronous communication between the embryo and maternal endometrium. Inadequate maternal endometrial receptivity is one of the principal causes for embryo implantation failure [especially repeated implantation failure (RIF)] when biopsied good-quality euploid embryos are transferred. An RNA-seq-based endometrial receptivity test (rsERT) was previously established to precisely guide successful embryo implantation. In this study, we aimed to evaluate the effect of personalized embryo transfer (pET) via rsERT on the clinical outcomes in patients with RIF.
UNASSIGNED: A total of 155 patients with RIF were included in the present retrospective study and were divided into two groups: 60 patients who underwent rsERT and pET (Group rsERT) and 95 patients who underwent standard frozen embryo transfer (FET) without rsERT (Group FET). Reproductive outcomes were compared for patients who underwent rsERT-guided pET and standard FET.
UNASSIGNED: Forty percent (24/60) of the patients who underwent rsERT were receptive, and the remaining 60% (36/60) were non-receptive. The positive human chorionic gonadotropin (β-hCG) rate (56.3% vs. 30.5%, P = 0.003) and clinical pregnancy rate (43.8% vs. 24.2%, P = 0.017) were significantly higher in Group rsERT patients than in FET group patients. Additionally, Group rsERT patients also showed a higher implantation rate (32.1% vs. 22.1%, P = 0.104) and live birth rate (35.4% vs. 21.1%, P = 0.064) when compared with FET patients, although without significance. For subpopulation analysis, the positive β-hCG rate, clinical pregnancy rate, implantation rate, and live birth rate of receptive patients were not statistically significant different from those of non-receptive patients.
UNASSIGNED: The rsERT can significantly improve the pregnancy outcomes of RIF patients, indicating the clinical potential of rsERT-guided pET.

Although both subcutaneous injection and intrauterine infusion of granulocyte colony-stimulating factor (G-CSF) have been reported to improve pregnancy outcomes in patients with recurrent implantation failure (RIF), how to administer it is still no consensus. The study aimed to investigate which administration route is optimal. We searched PubMed, Embase, the Cochrane Library (CENTRAL), Web of Science, and China National Knowledge Internet (CNKI) from inception to April 10, 2023, with language in both English and Chinese. The randomized controlled trials (RCTs) compared the effectiveness of G-CSF to treat patients with RIF were included in this network meta-analysis (NMA). The odds ratio (OR) and 95% confidence interval (CI) in pregnancy outcomes (implantation rate, IR; clinical pregnancy rate, CPR; live birth rate, LBR; miscarriage rate, MR; ectopic pregnancy rate, EPR) were summarized by NMA with a random-effects model. A total of 1360 RIF patients from 14 RCTs were included in this NMA, with no publication bias and small sample effects. No direct evidence compared the effectiveness of different administration routes of G-CSF on IR, LBR and MR. Both subcutaneous injection and intrauterine infusion of G-CSF increased the IR (OR = 2.81, 95% CI: 1.10-7.24; OR = 2.15, 95% CI: 1.50-3.07, respectively) and CPR (OR = 2.79, 95% CI: 1.86-4.17; OR = 1.74, 95% CI: 1.30-2.33, respectively) in patients with RIF. According to SUCRA, subcutaneous injection is more likely to be the optimal medication administration route. However, more high-quality studies were also needed to support these, especially IR and LBR.

OBJECTIVE: Does repeated implantation failure (RIF) sometimes have a cause, or is it simply treatment failure by chance?
METHODS: A hypothetical model of a cohort of 1000 women undergoing four repeated IVF attempts was constructed. A proportion of women with RIF carried an underlying risk factor negatively affecting implantation, compared with women without the factor. In strategy A, women had standard IVF without additional treatment; in strategy B, the women received standard IVF plus an additional treatment. The sensitivity analysis varied the prevalence of the underlying risk factor from 5% to 50%. The model was compared with literature studies where a treatment strategy had been applied.
RESULTS: With strategy A, the clinical pregnancy rate decreased with subsequent IVF attempts (31% in the first transfer with a risk factor prevalence of 5%, to 8% in the fourth transfer with a risk factor prevalence of 50%). As the prevalence increased, the clinical pregnancy rate was higher with strategy A. For strategy B, the clinical pregnancy rates for the modelled cohort decreased with each subsequent IVF attempt. Regardless of the prevalence of the risk factor, the decline in clinical pregnancy rate was less strong (from 32% in the first transfer with a prevalence of 5%, to 25% in the fourth transfer with a prevalence of 50%). When applying the model to the literature studies, the trends expected for strategy B (decreasing clinical pregnancy rates) were not expressed.
CONCLUSIONS: RIF might therefore be of iatrogenic origin due to the low success rate of IVF and might be triggered by the increasing female age associated with higher numbers of RIF.

OBJECTIVE: This study investigated the metabolic status of the spent culture media from embryos of patients with repeated implantation failure (RIF) undergoing in vitro fertilization-intracytoplasmic sperm injection cycles in comparison with the embryos from healthy fertile women.
METHODS: Metabolite levels in spent culture media were assessed and compared between embryos from RIF patients (n=35) and oocyte donors as controls (n=15). Protein levels of insulin-like growth factor 1 (IGF-1) were determined using Western blotting. Concentrations of glucose, pyruvate, and lactate were measured using spectrophotometry. Ionic colorimetric assay kits were utilized to analyze the concentrations of sodium, chloride, calcium, and magnesium ions. High-performance liquid chromatography was employed to measure the concentrations of glutamic acid, aspartic acid, methionine, phenylalanine, and histidine.
RESULTS: Glucose consumption and lactate secretion were higher in the control group than in the RIF group. The magnesium concentration was significantly higher in the control group than in the RIF group, but glutamic acid and aspartic acid concentrations were lower in the control group than in the RIF patients (p<0.05). The levels of IGF-1, sodium, calcium, chloride, methionine, histidine, and phenylalanine did not show statistically significant differences between the two groups.
CONCLUSIONS: The metabolic profile of the culture medium of the embryos in the RIF group differed from that of the control group. These findings suggest potential factors that may affect implantation capacity in RIF patients and provide a new perspective on embryo selection.

OBJECTIVE: Gene expression analysis of the endometrium has been shown to be a useful approach for identifying the molecular signatures and pathways involved in recurrent implantation failure (RIF). Nevertheless, individual studies have limitations in terms of study design, methodology and analysis to detect minor changes in expression levels or identify novel gene signatures associated with RIF.
METHODS: To overcome this, we conducted an in silico meta-analysis of nine studies, the systematic collection and integration of gene expression data, utilizing rigorous selection criteria and statistical techniques to ensure the robustness of our findings.
RESULTS: Our meta-analysis successfully unveiled a meta-signature of 49 genes closely associated with RIF. Of these genes, 38 were upregulated and 11 downregulated in RIF patients\' endometrium and believed to participate in key processes like cell differentiation, communication, and adhesion. GADD45A, IGF2, and LIF, known for their roles in implantation, were identified, along with lesser-studied genes like OPRK1, PSIP1, SMCHD1, and SOD2 related to female infertility. Many of these genes are involved in MAPK and PI3K-Akt pathways, indicating their role in inflammation. We also investigated to look for key miRNAs regulating these 49 dysregulated mRNAs as potential diagnostic biomarkers. Along with this, we went to associate protein-protein interactions of 49 genes, and we could recognize one cluster consisting of 11 genes (consisted of 22 nodes and 11 edges) with the highest score (p = 0.001). Finally, we validated some of the genes by qRT-PCR in our samples.
CONCLUSIONS: In summary, the meta-signature genes hold promise for improving RIF patient identification and facilitating the development of personalized treatment strategies, illuminating the multifaceted nature of this complex condition.

OBJECTIVE: Reduced Lactobacillus occupancy in the uterine microflora has been associated with implantation failure. This study aimed to evaluate a treatment for improving the uterine microflora.
METHODS: This study included patients diagnosed with repeated implantation failure-defined as failure to achieve pregnancy after two or more transfers of viable embryos-who were classified as non-Lactobacillus dominant. Treatment A comprised oral administration of antibiotics for 1 week, followed by oral probiotic butyrate tablets (3 g/day) for approximately 30 days. Treatment B comprised a 1-week course of oral (750 mg/day) and vaginal (250 mg/day) metronidazole, followed by a 1-week intravaginal administration of probiotic capsules (1 capsule/day) and continued oral administration of probiotics (1 capsule/day). Both treatments were compared in terms of efficacy in improving vaginal flora. Improvement was defined as Lactobacillus occupancy >90% or an increase in Lactobacillus occupancy >20%.
RESULTS: Seven (41.2%) of 17 patients in the Treatment A group improved in response to the treatment. Contrastingly, 9 (90.0%) of 10 patients improved in the Treatment B group (p = 0.0127). Following treatment, Lactobacillus occupancy in the Treatment B group (62.9% ± 12.7%) was significantly higher than that in the Treatment A group (5.7% ± 9.8%) (p = 0.0242).
CONCLUSIONS: This study demonstrates the effectiveness of combining antibiotics and probiotics in vaginal formulations for treating abnormal uterine microflora. However, its potential impact on in vitro fertilization outcomes remains unclear and warrants further investigation through larger, more comprehensive studies.