History Of Repeated Implantation Failure Research Articles

P-468 Personalized embryo transfer guided by transcriptomic endometrial receptivity analysis (ERA) in infertile patients: a systematic review and meta-analysis

Abstract Study question What is the effectiveness of a personalized embryo transfer (pET) guided by an endometrial receptivity test in assisted reproduction? Summary answer We have not found evidence supporting the routine use of a personalized embryo transfer guided by an endometrial receptivity test in any case yet. What is known already Currently, the outcomes of good quality embryo transfers are far from ideal. Clinical focus is shifting towards other actors that could play a key role in the good-quality embryos implantation failure, such as the endometrial preparation and the achievement of an embryo-endometrium synchrony, so that the embryo has a better chance to implant during the window of implantation (WOI). Today, there is a wide range of different endometrial receptivity tests that use different sets of genes to identify patients with displacements of their WOI in order to adjust the individual length of progesterone exposure in a personalized embryo transfer (pET). Study design, size, duration This is systematic review and meta-analysis were conducted following the Cochrane methods and the GRADE approach to rate the certainty of evidence (CoE). The protocol has been sent for registration to PROSPERO (CRD42022299827). We included studies that compared women that were tested with transcriptomic endometrial receptivity tests versus those that were not tested. We only included comparative studies, including randomized controlled trials (RCTs), and retrospective and prospective cohorts. Participants/materials, setting, methods Participants were women undergoing an infertility treatment (both with own or donor gametes), with or without repeated implantation failure (RIF), with or without preimplantation genetic testing for aneuploidies (PGT-A). Each of the above-mentioned populations was analyzed separately as different subgroups. Electronic searches in CENTRAL via the Cochrane Register of Studies Online (CRSO), PubMed, and Embase were performed from inception to October 2022. Screening, study inclusion and data extraction was performed by pairs of independent reviewers. Main results and the role of chance We included 35 studies. Two of them were RCTs and 25 were cohort studies that compared pET guided by an endometrial receptivity tests guided versus sET in women with non-tested endometrium. Besides, we included 16 studies that compared women with sET with a receptive endometrium versus pET in women with non-receptive endometrium. And we included three studies that compared pET guided by an endometrial receptivity test in a specific population of women (RIF or adenomyosis) versus a control population. The two RCTs included women with no history of RIF. In non-RIF women, no important differences (moderate-CoE) were found in live birth rate (LBR) and clinical pregnancy rate (CPR). In that population, cumulative CPR may be higher with pET (RR 1.15, 95%CI 1.00-1.34; low-CoE) but no differences were found in cumulative LBR. Seven cohort studies that adjusted by confounding were meta-analyzed. In RIF, pET may improve the CPR (OR 2.50, 95% CI 1.42-4.40; low-CoE) but, in agreement with the RCTs, no benefits were found in non-RIF. In summary, routine use of pET guided by endometrial receptivity tests is not supported by current published evidence in non-RIF women. However, low-CoE suggests that it may be useful in RIF. Limitations, reasons for caution Most data come from non-RCTs which increases the risk of bias. Besides, the large heterogeneity found in the population, interventions and comparisons led to large imprecision due to the few studies per analyzed strata. It is important to avoid the extrapolation of the results to any different setting. Wider implications of the findings Routine use of pET guided by endometrial receptivity tests is not supported by current published evidence in non-RIF women. However, low-CoE suggests that it may be useful in RIF. Better designed studies are needed to find out if any of these tests work in any specific population. Trial registration number not applicable

Personalized embryo transfer guided by endometrial receptivity analysis: a systematic review with meta-analysis.

Does a personalized embryo transfer (pET) guided by tests for endometrial receptivity (TER) increase the effectiveness of ART procedures? The use of TER-guided pET is not supported by current published evidence in women without repeated implantation failure (RIF), while in women with RIF more research is needed to assess a potential benefit. Implantation rates are still far from ideal, especially in some patients that have RIF with good-quality embryos. As a potential solution, a wide range of diverse TER use different sets of genes to identify displacements of the window of implantation to adjust the individual length of progesterone exposure in a pET. A systematic review with meta-analysis was performed. Search terms included endometrial receptivity analysis, ERA, personalized embryo transfer. CENTRAL, PubMed, Embase, reference lists, clinical trials registers, and conference proceedings (search date October 2022) were searched, with no language restrictions. Randomized controlled trials (RCTs) and cohort studies comparing a pET guided by TER vs standard embryo transfer (sET) in different subgroups that undergo ART were identified. We also investigated pET in non-receptive-TER vs sET in receptive-TER, and pET in a specific population vs sET in a general population. Risk of bias (RoB) was assessed with the Cochrane tool and ROBINS-I. Only those with low/moderate RoB underwent meta-analysis. The GRADE approach was used to evaluate the certainty of evidence (CoE). We screened 2136 studies and included 35 (85% used ERA and 15% used other TER). Two studies were RCTs comparing endometrial receptivity analysis (ERA)-guided pET vs sET in women with no history of RIF. In women without RIF, no important differences (moderate-CoE) were found in live birth rates and clinical pregnancy rates (CPR). We also performed a meta-analysis of four cohort studies that were adjusted for confounding. In agreement with the RCTs, no benefits were found in women without RIF. However, in women with RIF, low CoE suggests that pET might improve the CPR (OR 2.50, 95% CI 1.42-4.40). We found few studies with low RoB. Only two RCTs in women without RIF were published, and none in women with RIF. Furthermore, the heterogeneity observed in populations, interventions, co-interventions, outcomes, comparisons, and procedures limited the pooling of many of the included studies. In the population of women without RIF, in agreement with previously published reviews, pET did not prove to be more effective than sET and, therefore, it precludes the routine use of this strategy in this population until more evidence is available. However, more research is advisable in women with RIF as low-certainty evidence from observational studies adjusted for confounders suggests that the CPR might be higher with pET guided by TER in this population. Although this review presents the best available evidence, it is still insufficient to change current policies. No specific funding was obtained for this study. There are no conflicts of interest to declare. PROSPERO CRD42022299827.

The outcomes of sequential embryo transfer in patients undergoing in vitro fertilization with frozen-thawed embryos: A retrospective study.

To explore whether sequential embryo transfer benefits patients with repeated implantation failure (RIF) undergoing frozen-thawed embryo transfer (FET) cycles. We included 311 patients with a history of RIF in this retrospective study. We did sequential transfers with a cleavage embryo on day 3 and a blastocyst on day 5 in 77 patients; blastocyst transfers with two blastocysts on day 5 in 80 patients; and cleavage embryo transfers with two cleavage embryos on day 3 in 154 patients. We compared clinical outcomes between the three groups. The clinical pregnancy rate was comparable between the blastocyst transfer group (48.8%), the sequential transfer group(48.1%) and the cleavage embryo transfer group (48.1%). There was no statistically significant difference found (p > 0.05). The ongoing pregnancy and multipregnancy rates were also comparable between the three groups (p > 0.05). The early miscarriage rate was significantly higher in the sequential transfer group (32.4%) compared with the blastocyst group (12.8%) and the cleavage embryo group (12.2%) (p < 0.05). However, after adjusting for confounders, there was no significant difference in early miscarriage rates in the sequential transfer group compared with the blastocyst group (odds ratio [OR], 2.97; 95% confidence interval [CI], 0.85-9.24; p=0.07) and the cleavage embryo group (OR, 3.03; 95% CI, 0.94-8.06; p=0.08). Sequential embryo transfer failed to improve clinical outcomes for patients with RIF.

Outcomes of IVF programs with intrauterine administration of autologous mononuclear cells in women with repeated implantation failure

Frequency of the repeated implantation failure (RIF) in assisted reproductive technology programs remains to be high, reaching 50-75%. Intrauterine administration of autologous mononuclear cells before embryo transfer is a technique for the RIF immunocorrection being used in assisted reproductive technology programs. Direct effect of mononuclear cells upon implantation was first studied in 2006 and showed that intrauterine administration of autologous mononuclear cells prior to embryo transfer proved to significantly increase implantation frequency, as well as incidence of clinical pregnancy, and frequency of delivery in the patients with a history of RIF. The aim of this study was to evaluate the effect of intrauterine administration of autologous peripheral blood mononuclear cells prior to embryo transfer upon the results of assisted reproductive technology programs in women with a history of RIF, and to evaluate cytokine profile of the supernates from the injected cultures of peripheral blood mononuclear cells.The study included 129 women with RIF included into the assisted reproductive technology programs. The patients were divided into three groups with intrauterine administration before embryo transfer in a stimulated cycle and in a cryocycle: group 1, treated with mononuclear cells activated by human chorionic gonadotropin; group 2, with mononuclear cells without activation by human chorionic gonadotropin; group 3 who received saline solution (placebo). Clinical and anamnestic data of the women from these groups did not differ. The age of women in all three groups was also similar. The number of RIFs in their anamnesis was comparable for the 3 groups. Analysis of the embryological parameters also showed that there were no significant differences in the number of transferred embryos, including those of good quality.The levels of IL-2 (p = 0.006), IL-4 (p = 0.012), IL-5 (p = 0.012), IL-12p70 (p = 0.011), IFNγ (p = 0.012), GM-CSF (p = 0.026), and TNFα (p = 0.021) were found to be higher in the supernatants of human chorionic gonadotropin-activated mononuclear cells of women with advanced cryocycle implantation, than in supernatants of inactivated chorionic gonadotropin mononuclear cells. Frequencies of implantation and clinical pregnancy were significantly higher in the groups with intrauterine administration of autologous mononuclear cells, both in stimulated cycle and the cryocycle compared to the placebo groups.The cytokine profile of the mononuclear cell culture supernates upon intrauterine administration affects the efficiency of assisted reproductive technology programs in the women with RIF. Hence, the data obtained may allow us to develop a personalized approach to usage of various immunotherapies in assisted reproductive technology programs for the patients with a history of repeated implantation failure.

Analysis of the risk factors and treatment for repeated implantation failure: OPtimization of Thyroid function, IMmunity, and Uterine Milieu (OPTIMUM) treatment strategy.

What are the pregnancy outcomes after the OPtimization of Thyroid function, Immunity, and Uterine Milieu (OPTIMUM) treatment strategy in patients with repeated implantation failure (RIF)? Infertile women with a history of RIF after more than three embryo transfer (ET) cycles underwent implantation testing, including a hysteroscopy, endometrial biopsy for CD138 immunostaining and bacterial culture, and serum 25-hydroxyvitamin D3 , interferon-γ-producing helper T (Th1) cell, IL-4-producing helper T (Th2) cell, thyroid-stimulating hormone, thyroid peroxidase antibody, and thrombophilia screening between April 2017 and August 2018. We treated chronic endometritis with antibiotics, aberrant high Th1/Th2 cell ratios with vitamin D and/or tacrolimus intake, overt/subclinical hypothyroidism with levothyroxine, and thrombophilia with low-dose aspirin. Of the 116 RIF women, 88 women with 133 ET cycles were recruited from a questionnaire-based survey regarding pregnancy outcomes. Fifty-nine consecutive RIF patients without the OPTIMUM treatment strategy were also recruited as a control. The 116 women with RIF after the OPTIMUM treatment strategy were 38.3±3.8years old and had an implantation failure history over 5 (3-19) ET cycles. Implantation testing identified impaired intrauterine circumstances in 75 women (64.7%), an aberrant elevated Th1/Th2 cell ratio in 56 women (48.3%), and thyroid abnormalities in 33 women (28.4%). Cumulative ongoing pregnancy rates including spontaneous pregnancy in the patients aged<40 and≥40years were 72.7% and 45.5% within two ET cycles, respectively. The pregnancy outcomes in the OPTIMUM group were significantly higher than those in the control. The OPTIMUM treatment strategy improved pregnancy outcomes in patients with RIF.

Characterization of Microbiota in Endometrial Fluid and Vaginal Secretions in Infertile Women with Repeated Implantation Failure.

Studies suggest that persisting intrauterine bacterial infectious conditions such as chronic endometritis potentially impair the embryo implantation process. The microbial environment in the female reproductive tract, however, remains largely undetermined in infertile patients with a history of repeated implantation failure (RIF). Using next-generation sequencing, we aimed to characterize the microbiota in the endometrial fluid (EF) and vaginal secretions (VS) in women with RIF. Twenty-eight infertile women with a history of RIF and eighteen infertile women undergoing the first in vitro fertilization-embryo transfer attempt (the control group) were enrolled in the study. On days 6-8 in the luteal phase of the natural, oocyte-pickup, or hormone replacement cycle, the paired EF and VS samples were obtained separately. Extracted genomic DNA was pyrosequenced for the V4 region of 16S ribosomal RNA using a next-generation sequencer. The EF microbiota had higher α-diversity and broader bacterial species than the VS microbiota both in the RIF and control groups. The analysis of the UniFrac distance matrices between EF and VS also revealed significantly different clustering. Additionally, the EF microbiota, but not the VS microbiota, showed significant variation in community composition between the RIF group and the control group. Burkholderia species were not detected in the EF microbiota of any samples in the control group but were detectable in a quarter of the RIF group. To our best knowledge, this is the first study investigating the microbiota in the paired EF and VS samples in infertile women with RIF.

Improved in vitro fertilization success and pregnancy outcome with autologous platelet-rich plasma treatment in unexplained infertility patients that had repeated implantation failure history

Repeated implantation failure (RIF) due to suboptimal endometrial lining is a major challenge in reproductive medicine. The study aims to evaluate effect of intrauterine platelet-rich plasma (PRP) treatment on frozen-thawed embryo transfer (FET) cycles in patients whose endometrium was unable to achieve optimal lining in unexplained infertility patients with history of RIF. We retrospectively analyzed the charts of a total of 302 cycles performed in 273 patients attending Diyar Life ART Centre between January 2014 and January 2017. After excluding 232 cycles, we compared pregnancy outcomes of 34 patients who had suboptimal endometrial lining and underwent PRP + FET and 36 patients who had optimal endometrial lining and underwent only FET. We observed that, endometrial thickness was higher after 48 hours from PRP when compared to endometrial thickness before PRP (10 mm vs. 6.25 mm, p < .001). Clinical pregnancy rate, and importantly live birth rate were also significantly higher in PRP group than the control group. Based on this information, we showed that intrauterine autologous PRP infusion is a safe, inexpensive adjuvant treatment for optimizing endometrium especially in patients with RIF history and intrauterine PRP infusion improved not only endometrial lining but also in vitro fertilization success and pregnancy outcome.

Endometrial lymphocyte concentrations in adverse reproductive outcome populations.

The uterine immunophenotype is relatively poorly understood, with most studies reporting proportions/percentages. A novel technique to calculate local endometrial lymphocyte concentrations is described, and used to compare results between aetiological subgroups such as repeated implantation failure (RIF) and recurrent pregnancy loss (RPL) with male-factor controls. 455 patients had an endometrial biopsy performed. Background history on initial presentation was used to subdivide the population into RIF (n = 149), RPL (n = 121), primary (n = 76) and secondary infertility (n = 80). A control group was identified comprising male factor infertility aetiology with all female investigations normal (n = 29). Endometrial Tissue was assessed using a comprehensive multi-parameter panel. Lymphocyte subpopulations were calculated using flowcount flurospheres and a mathematical correction applied to determine concentrations per milligram of tissue, based on original biopsy weight and volumetric dilutions. The flow cytometry technique was successful in determining population centiles for concentrations of endometrial lymphocyte subsets. Distinct differences were noted across the patient groups. Th2 concentrations were significantly higher in the controls (p = 0.0002). All RPL/infertile populations had increased concentrations of peripheral type NK's (p = 0.016) and B cells (p = 0.045). Relative to male factor controls, CD4+ and CD8+ T lymphocyte populations were increased in RPL patients, and reduced in those with a history of RIF. Th1 concentrations were elevated in the adverse outcome groups (p = 0.032). Concentration centiles alone do not appear to accurately predict outcome with subsequent treatment. Endometrial biopsy analysis by flow cytometry can provide detailed analysis of constituent lymphocyte subsets by concentration as well as proportion. This novel approach provides additional independent data to further assess the significance of endometrial changes in the setting of reproductive failure.

Immunomodulatory effects of hydroxychloroquine on Th1/Th2 balance in women with repeated implantation failure

BackgroundCellular immune abnormalities such as the imbalance between T-helper (Th) 1 and Th2 cytokines have been implicated as potentially modifiable causes of idiopathic repeated implantation failures (RIF). The purpose of this study was to investigate the effects of hydroxychloroquine on IL-10 and TNF-α secretion, expression of T-bet and GATA-3 transcription factors and cellular localization of TNF-α, IFN-γ, IL-10 and IL-4 in endometrial cells in women with RIF. Materials and methodsA total of 17 women with a history of RIF and elevated TNFα/IL-10 ratio (TNFα/IL-10> = 30.6) were included in the study. The serum levels of TNFα and IL-10, the expression of transcription factors related to Th1 and Th2 cells and the immune-reactivity of TNFα, IFN-γ as Th1 related cytokines and IL-10, IL-4 as Th2 related cytokines in endometrial tissues were evaluated by ELISA, real-time PCR, and fluorescent immunohistochemistry respectively. All, evaluations were done both before and after treatment with hydroxychloroquine (400 mg/orally per day). ResultsHydroxychloroquine treatment significantly decreased (p < 0.0001) serum level of TNF-α and significantly increased serum level of IL-10 (p < 0.0001). T-bet, the Th1 transcription factor, expression was down-regulated and GATA-3, the Th2 transcription factor, expression was up-regulated. IL-10 and IL-4 fluorescent immunoreactivities significantly increased (p < 0.05 and p < 0.001 respectively) and TNFα and IFN-γ fluorescent immunoreactivities significantly decreased (p < 0.05) in endometrial tissue in women with RIF after treatment in comparison with before treatment. ConclusionHydroxychloroquine administration in women with RIF With a high TNF-α/IL-10 ratio during the implantation window can decrease this ratio and seems to be an effective therapeutic strategy in RIF caused by cellular immune abnormalities through a shift in Th2 responses.

Serum oxytocin profiles in patients with repeated implantation failure during IVF cycles

Objective: The objective of this study is to investigate the association between oxytocin (OT) levels and repeated implantation failure (RIF) during in vitro fertilization-embryo transfer (IVF-ET) cycles.Methods: Blood samples were collected from 108 women undergoing IVF-ET treatment at the following time points: gonadotrophin (Gn) administration day (Gn Day 0), hCG administration day (hCG Day 0), ET administration day (ET Day 0), and 5 d after ET (ET Day 5). Serum OT and steroid profiles were measured and compared among three groups: Group A included 38 women with a history of RIF, Group B included 41 women who became pregnant following the first fresh ET, and Group C included 29 women who did not become pregnant following the first fresh ET.Results: The OT levels of the three groups at different time points were not significantly different. Serum OT levels were significantly higher on hCG Day 0, ET Day 0, and ET Day 5 than on Gn Day 0, and they were significantly correlated with the estradiol concentration on ET Day 0.Conclusions: RIF patients do not have elevated serum OT levels during IVF-ET cycles.

Hysteroscopy as an investigation tool in recurrent implantation failure in vitro fertilization.

Objectives:To evaluate the use of hysteroscopy in the assessment of uterine pathologies in infertile women with repeated implantation failure (RIF) after in vitro fertilization (IVF) and determine whether removal of such pathologies increased pregnancy rates in women with RIF.Methods:This prospective study was conducted at King Fahd Hospital of the University, Al-Khobar, Kingdom of Saudi Arabia, between January 2010 and December 2015. The inclusion criteria were women who underwent IVF treatment cycles and ended in more than 2 RIF, and women who underwent hysterosalpingography (HSG). Hysteroscopies were performed, findings were recorded, and the clinical pregnancy rates were compared and assessed in patients with and without uterine cavity abnormality. All hysteroscopic procedures were performed by a single consultant.Results:Hysteroscopies were performed on 266 women who had at least 2 RIF. The average duration of infertility was 7.2±3.1 years. In 162 patients (60.9%), a hysteroscopy did not find any abnormality of the uterine cavity. In 104 patients (39.1%) there were one or more abnormal hysteroscopic findings. Hysterosalpingography was able to detect only 54 abnormalities (51.9%). The pregnancy rate was significantly higher in patients who were treated by a hysteroscopy for a detected uterine abnormality (39.4%).Conclusion:A hysteroscopy was able to detect intrauterine pathologies which were missed by other investigative modalities. We believe patients with a history of RIF should undergo hysteroscopic examination before any further cycles are considered.

Effect of Growth Hormone on Uterine Receptivity in Women With Repeated Implantation Failure in an Oocyte Donation Program: A Randomized Controlled Trial

Background and Objective:Administration of growth hormone (GH) during ovarian stimulation has been shown to improve success rates of in vitro fertilization. GH beneficial effect on oocyte quality is shown in several studies, but GH effect on uterine receptivity is not clear. To assess it, we studied whether GH administration can improve the chance of pregnancy and birth in women who experienced repeated implantation failure (RIF) using donated oocyte programs.Design and Study Population:A total of 105 infertile women were enrolled in the randomized controlled trial: 70 women were with a history of RIF with donated oocytes, and 35 infertile women underwent the first oocyte donation attempt. Women receiving donated oocytes were treated with progressively increasing doses of oral estradiol, followed by intravaginal progesterone after previous pituitary desensitization with gonadotropin-releasing hormone agonist. Thirty-five RIF patients were treated with GH (GH patients), whereas the rest of the 35 RIF patients (non-GH patients) and 35 first-attempt patients (positive control group) were not.Results:RIF patients receiving GH showed significantly thicker endometrium and higher pregnancy and live birth rates as compared with RIF patients of non-GH study group, although these rates remained somewhat lower as compared with the non-RIF patients of the positive control group. No abnormality was detected in any of the babies born.Conclusion:Our data of improved implantation, pregnancy, and live birth rates among infertile RIF patients treated with GH indicate that GH improves uterine receptivity.

Effects of autologous platelet-rich plasma on implantation and pregnancy in repeated implantation failure: A pilot study

Repeated implantation failure (RIF) is a major challenge in reproductive medicine and despite several methods that have been described for management, there is little consensus on the most effective one. This study was conducted to evaluate the effectiveness of platelet-rich plasma in improvement of pregnancy rate in RIF patients. Twenty women with a history of RIF who were candidates for frozen-thawed embryo transfer were recruited in this study. Intrauterine infusion of 0.5 ml of platelet-rich plasma that contained platelet 4-5 times more than peripheral blood sample was performed 48 hrs before blastocyst transfer. Eighteen participants were pregnant with one early miscarriage and one molar pregnancy. Sixteen clinical pregnancies were recorded and their pregnancies are ongoing. According to this study, it seems that platelet-rich plasma is effective in improvement of pregnancy outcome in RIF patients.

A pilot survey on obstetric complications in pregnant women with a history of repeated embryo implantation failure and those undergoing single local endometrial injury

To assess if a history of repeated implantation failure (RIF) or local endometrial injury (LEI) for RIF affects the pregnancy course in women who conceived in the subsequent in vitro fertilization (IVF)-embryo/blastocyst transfer (ET/BT) cycle.Of 42 pregnant women with a history of three consecutive failed ET/BT cycles with negative pregnancy tests, 11 patients had a clinical pregnancy in the immediate subsequent ET/BT cycle following (the RIF group), whereas 31 patients had a clinical pregnancy in the subsequent ET/BT cycle following single curettage LEI in the proliferative phase of the preceding spontaneous cycle (the RIF/LEI group). Information on the obstetric complications were retrieved from medical records and compared with that of women who had a live birth in the first ET/BT attempt (the control group). Results: The clinical pregnancy rate, ongoing pregnancy rate, and live birth rate were significantly higher in the RIF/LEI group than in the RIF group (p < 0.010). There were no significant differences in the incidence of pregnancy of unknown location, ectopic pregnancy, miscarriage, stillbirth, preterm birth, premature rupture of the membranes, placenta previa, placental abruption, preeclampsia, pregnancy-induced hypertension, gestational diabetes, fetal growth restriction, caesarean section, and blood transfusion were similar between the three groups (p > 0.31).In this pilot survey, neither a history of RIF nor LEI intervention for RIF increased the incidence of obstetric complications in the women who conceived in the subsequent ET/BT cycle.

Increased Serum IFN-γ in Women with a History of Repeated Implantation Failures after in Vitro Fertilization and Embryo Transfer

Objective: To compare serum cytokines, including interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-4 (IL-4) and IL-10, between non-pregnant women with repeated implantation failures (RIFs) after in vitro fertilization and embryo transfer (IVF-ET) cycles and those with normal fertility during late follicular phase. Methods: Serum levels of IFN-γ, TNF-α, IL-4 and IL-10 in 24 women with RIF and 40 women with normal fertility were measured using Luminex-based cytokine assays. Results: A significantly higher serum level of IFN-γ was observed in women with RIF (median=38.50 pg/mL, interquartile [IQ] range 2.44-86.73 pg/mL) than in controls (median=2.44 pg/mL, IQ range 2.44-47.01 pg/mL, p＜0.05). A significantly higher IFN-γ/IL-4 ratio was observed in women with RIF (median=7.7, IQ range 1.0-21.1) than in controls (median=2.9, IQ range 1.0-8.4, p＜0.05). Conclusion: A significantly higher serum IFN-γ and IFN-γ/IL-4 ratio in women with RIF after IVFET cycles might suggest skewed Th1 immune status was possibly associated with the pathogenesis of implantation failures.