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Objective: Despite the great advance of assisted reproductive technology (ART) in recent decades, many IVF patients failed to achieve a pregnancy even after multiple IVF-ET attempts. These patients are considered to have repeated implantation failure (RIF). While exhausting efforts have been devoted to the improvement of pregnancy rate in RIF patients, it is not clear whether RIF patients have aberrant obstetric or perinatal outcomes after they eventually achieved a pregnancy., Materials and Methods: Taking advantage of a relatively large database of IVF-ET cycles at the Chang Gung Memorial Hospital, we compared obstetric and perinatal outcomes of RIF patients who have a successful pregnancy after IVF-ET treatment(s) to those of control IVF-ET patients., Results: Because multiple pregnancies are associated with a high risk of obstetric complications, we restricted the analysis to patients who had singleton pregnancies. Analysis of a total of 596 control and 46 RIF cases showed the rates of almost all obstetric and perinatal outcomes investigated are not different between the two groups. However, the rate of placental abruption in the RIF group (4.35%) appeared to be significantly higher than that of controls (0.50%; OR = 8.99). This difference is still statistically significant after adjustment with the age (adjusted OR = 8.2)., Conclusion: While the rates of a spectrum of obstetric and perinatal outcomes are normal in RIF patients, these patients could have an enhanced risk of placental abruption. However, investigations with a large sample size are needed to substantiate this inference., (Copyright © 2019. Published by Elsevier B.V.)

Natural killer (NK) cells are thought to play a key role in the successful establishment of a pregnancy by facilitating immunological adaptation of the semi-allogeneic developing embryo. The aim of this study was to explore the cell number, immunophenotypic characteristics, and activities of peripheral blood NK cells in women with repeated implantation failure (RIF). Peripheral blood was obtained from 27 women with RIF and 11 healthy, fertile controls during the middle luteal phase of the menstrual cycle. CD3 - CD56 + NK cells were quantified and analyzed by flow cytometry for the expression of cytolytic molecules (granzyme B, granulysin, and perforin) as well as cell surface receptors responsible for NK cell activation or inhibition (NKG2D, NKp30, NKp46, CD158a, CD158b). NK cytotoxicity was measured at three effector-to-target cell ratios. Women with RIF and fertile controls did not differ significantly in the percentage of circulating CD3 - CD56 + NK cells, or in the proportions of these cells that expressed granzyme B, granulysin, or perforin. The two groups also did not differ significantly in the proportions of NK cells expressing the receptors NKG2D, NKp30, NKp46, CD158a or CD158b. General linear model analysis showed that NK cytotoxicity increased with effector-to-target cell ratio. However, NK cytotoxicity did not differ significantly between patients with RIF and fertile controls. These results suggest that RIF is not associated with significant alterations in the number or function of peripheral blood NK cells., (© 2019 Chongqing Medical University. Production and hosting by Elsevier B.V.)

Objective: To study if hysteroscopy and short-term copper intrauterine device placement (Cu-IUD) improves the pregnancy rates of women with repeated implantation failure (RIF) undergoing frozen-thawed embryo transfer (FET).Design: Retrospective study.Setting: Medical university hospital.Patient(s): Infertile women with at least two implantation failures with the use of at least one good-quality embryo.Intervention(s): All patients received operative hysteroscopy in the follicular cycle, and if endometrial polyps, polypoid endometrium, or intrauterine adhesions were found they were removed. In some patients, a Cu-IUD was inserted immediately after hysteroscopy and removed after two menstrual periods before embryo implantation. All patients underwent in vitro fertilization or intracytoplasmic sperm injection and FET.Main Outcome Measure(s): Clinical pregnancy and implantation rates.Result(s): A total of 440 women with a mean age of 33.42 ± 4.45 years (range 23-47 y) were included. There were 382 patients (554 cycles) in the IUD group and 58 patients (87 cycles) in the non-IUD group. The two groups were similar regarding age, body mass index, and infertility factors. The IUD group had a significantly higher implantation rate (29.29% vs. 16.56%), chemical pregnancy rate (53.25 vs. 41.38%), and clinical pregnancy rate (45.13% vs. 26.44%) than the non-IUD group. Multivariable regression analysis indicated that the odds of a chemical pregnancy was significantly increased with IUD usage.Conclusion(s): Cu-IUD placement for two menstrual cycles at the time of hysteroscopy can improve the implantation and pregnancy rates in women with RIF. [ABSTRACT FROM AUTHOR]

Objective: To study the current evidence on the role of immunotherapy in IVF and in the management of recurrent pregnancy loss (RPL)., Design: Systematic review and meta-analysis., Setting: A literature search was performed using MEDLINE, PUBMED, CINAHL, and EMBASE until May 2017. Only randomized controlled trials were included, and a meta-analysis was carried out where appropriate., Patient(s): Women undergoing IVF treatment with or without a history of recurrent implantation failure and women with idiopathic RPL., Intervention(s): Assessment of the efficacy of commonly used immunomodulators such as IV use of [1] immunoglobulin, [2] lymphocyte immunotherapy and [3] intralipid; intrauterine infusion of [4] granulocyte colony-stimulating factor and [5] peripheral blood mononuclear cells; subcutaneous administration of [6] TNF-alpha inhibitors, [7] leukaemia inhibitory factor; and oral administration of [8] glucocorticoids., Main Outcome Measure(s): The primary outcomes were live birth rate and miscarriage rate; secondary outcome was clinical pregnancy rate., Result(s): Of the 7,226 publications identified, 53 were selected during the initial screening; 30 satisfied the selection criteria and were included in this review., Conclusion(s): The available medical literature shows controversial results about the role of immunotherapy when used for improving reproductive outcomes. This study did not show a role for immunotherapy in improving the live birth rate in women undergoing IVF treatment or in the prevention of idiopathic RPL. Currently, immunotherapy should be used in the context of research and should not be used in routine clinical practice to improve reproductive outcomes., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

In vitro fertilization-embryo transfer (IVF-ET) can be used by infertile couples to assist with reproduction; however, failure of the embryo to implant into the endometrial lining results in failure of the IVF treatment. The present study investigated the expression of chemokine receptor 7 (CCR7)(lo) programmed death-1(PD-1)(hi) chemokine receptor type 5 (CXCR5) + cluster of differentiation 4 (CD4) + T cells and associated factors in patients with repeated implantation failure (RIF). A total of 30 females with RIF and 30 healthy females were enrolled in the current study. Flow cytometry was used to detect the proportion of CCR7(lo)PD-1(hi) CXCR5 + CD4 + T cells in the peripheral blood. Cytokine bead arrays were performed to detect the levels of interleukin (IL)-6, -4 and -2 in the serum. ELISAs were used to detect the level of IL-21 in the serum. Quantitative real time polymerase chain reaction analysis and immunohistochemistry were used to investigate the expression of B-cell lymphoma 6 (Bcl-6), chemokine receptor type 5 (CXCR5) and IL-21 in the endometrium. The results revealed that the percentage of CCR7(lo)PD-1(hi) CXCR5 + CD4 + T cells was increased in the RIF group compared with the control group during the mid luteal phase. The mRNA and protein levels of Bcl-6, IL-21 and CXCR5 in the endometrium and the concentrations of IL-21 and IL-6 in the serum were significantly increased in the RIF group; however, no significant difference was observed between the two groups in regards to the expression of IL-4 and IL-2. Furthermore, a significant positive correlation was identified between the percentage of CCR7(lo)PD-1(hi) CXCR5 + CD4 + T cells and IL-21 and IL-6 levels. The expression of IL-21 also had a positive correlation with Bcl-6 and CXCR5 expression in the RIF group. These results suggest that increased levels of CCR7(lo)PD-1(hi) CXCR5 + CD4 + T cells and associated factors contribute to RIF and could therefore be a potential therapeutic target.

Objective: To assess the effects of fertiloscopy procedure on the outcomes of subsequent in vitro fertilization cycles in patients with repeated implantation failure (RIF)., Methods: A retrospective study was performed on 50 patients underwent fertiloscopy and 41 controls with RIF. Pelvic and intrauterine pathologies related to infertility, clinical pregnancy rate (CPR) and ongoing pregnancy rate (OPR) of subsequent IVF cycles were assessed., Results: Twenty-six out of 50 patients (52%) had abnormal fertiloscopic findings. The women who underwent fertiloscopy exhibited significantly increased CPRs (46.8% vs. 24.4%) and OPRs (36.2% vs. 12.2%) compared with the control subjects who did not undergo fertiloscopy., Conclusion: The incidence of pathologic findings on fertiloscopy is high among patients with RIF. Fertiloscopy is valuable in subsequent cycles among patients with RIF., (Copyright © 2017. Published by Elsevier Masson SAS.)

The purpose of this study was to investigate the clinical application of uterine artery blood flow parameters by vaginal color Doppler ultrasonography in patients with repeated embryo implantation failure and to examine the correlation between uterine artery blood flow parameters and microvessel density (MVD). We monitored the outcomes of in vitro fertilization and embryo transfer in eighty patients. We divided the patients into two groups: Pregnancy (successful pregnancy, n=50) and repeated implantation failure (more than two failures of in vitro fertilization-embryo transfer, n=30). The patients were subjected to vaginal color Doppler ultrasonography to measure endometrial thickness, peak systolic velocity/end diastolic velocity (S/D), pulsatility index (PI), resistance index (RI), and other uterine artery blood flow parameters. We found no significant differences in endometrial thickness (human chorionic gonadotropin endometrial thickness) and uterine artery blood flow parameters (S/D, PI) between the two groups. The RI value of endometrial blood flow was significantly higher in the repeated implantation failure group than that in pregnancy group. The endometrium MVD in the repeated implantation failure group was significantly lower than that of the pregnancy group. Spearman correlation analysis showed that S/D value of uterine artery blood flow in repeated implantation failure group was not correlated with MVD or uterine artery blood flow PI, but was positively correlated with RI. Endometrium MVD in patients with repeated implantation failure was significantly lower than that in patients with successful pregnancy during the implantation window. We also found a significant difference in uterine artery blood flow RI between the two groups. The uterine artery blood flow RI in patients with repeated implantation failure was positively correlated with MVD, which has clinical significance in predicting the outcome of embryo transfer.

Chronic endometritis (CE) is a condition involving the breakdown of the peaceful co-existence between microorganisms and the host immune system in the endometrium. A majority of CE cases produce no noticeable signs or mild symptoms, and the prevalence rate of CE has been found to be approximately 10%. Gynecologists and pathologists often do not focus much clinical attention on CE due to the time-consuming microscopic examinations necessary to diagnose CE, its mild clinical manifestations, and the benign nature of the disease. However, the relationship between CE and infertility-related conditions such as repeated implantation failure and recurrent miscarriage has recently emerged as an area of inquiry. In this study, we reviewed the literature on the pathophysiology of CE and how it may be associated with infertility, as well as the literature regarding the diagnosis and treatment of CE. In addition, we discuss the value of hysteroscopic procedures in the diagnosis and treatment of CE., Competing Interests: No potential conflict of interest relevant to this article was reported.

Introduction: Repeated implantation failure (RIF) is due to poor quality of embryo, endometrium, uterine and fallopian tube. Also perinatal and immunologic factors can be noted. RIF means failure of 2 IVF cycle in patients with more than 10 high quality embryos. Granulocyte colony stimulating factor (GCSF) is a glycoprotein that stimulates cytokine growth factor and induced immune system. The aim of this study was to evaluate GCSF ability to improve pregnancy rate in women with repeated implantation failure. Materials and Methods: This was a randomized control trial which conducted in Yazd Research and Clinical Center for Infertility, 2014-2015. Women with history of RIF and under 40 years old were included. Participants with GCSF contraindication, endometriosis and sever male factor were excluded. Totally 90 eligible women were randomly allocated in two groups. All of participants received antagonist protocol. Then 30 ml (300 mg/ml) GCSF was administered in intervention group by intrauterine infusion. Pregnancy outcomes were assessed based on chemical and clinical pregnancy. Results: Totally 90 patients were included. The mean age of participants was 31.95+4.71 years old. There were no differences in ART and demographic characteristics of two groups (p>0.05). The pregnancy outcome in GCSF group was improved significantly (p=0.043). Conclusion: In this RCT we could detect a significant treatment effect of GCSF on pregnancy rates. GCSF can improve pregnancy outcome in patients with RIF. [ABSTRACT FROM AUTHOR]

Thyroid autoimmunity (TAI), which is defined as the presence of autoantibodies against thyroid peroxidase (TPO) and/or thyroglobulin (TG), is related to repeated implantation failure (RIF). It is reported that TAI was involved in reproductive failure not only through leading thyroid function abnormality, but it can also be accompanied with immune imbalance. Therefore, this study was designed to investigate the association of thyroid function, immune status and TAI in women with RIF. Blood samples were drawn from 72 women with RIF to evaluate the prevalence of TAI, the thyroid function, the absolute numbers and percentages of lymphocytes. The prevalence of thyroid function abnormality in RIF women with TAI was not significantly different from that in RIF women without TAI (c(2) = 0.484, p > 0.05). The absolute number and percentage of T cells, T helper (Th) cells, B cells and natural killer (NK) cells were not significantly different in RIF women with TAI compared to those without TAI (all p > 0.05). The percentage of T cytotoxicity (Tc) cells was significantly decreased in RIF women with TAI compared to those without TAI (p < 0.05). Meanwhile, Th/Tc ratio was significantly increased (p < 0.05). These results indicated that the decreased Tc percentage and increased Th/Tc ratio may be another influential factor of adverse pregnancy outcomes in RIF women with TAI.