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The aim of this study is to evaluate the effect of granulocyte colony-stimulating factor on clinical pregnancy rate in patients with endometriosis undergoing in-vitro fertilization after recurrent implantation failure.
Azathioprine increase pregnancy rate in patients with recurrent implantation failure
The aim of the study is to investigate whether Low Dose Aspirin and Low Molecular Weight Heparin could increase the uterine perfusion, and finally improve the implantation and pregnancy rates in patients with unexplained recurrent implantation failure.
In order to increase the likelihood of achieving IVF-treated pregnancy, good quality embryo transfer is important. To get good quality embryos, good quality gametes are needed. The selection of sperm is regulated according to the changing and mobility characteristics of today's conditions. The choice of multi-fluid sperm is thought to provide better sperm to obtain the environment in physiological conditions. Better embryo transfer to achieve better sperm elongation will increase the likelihood of pregnancy.
Infertility and miscarriage ordinary events in reproductive failure in humans, as are affected one couple in every six couples of reproductive age and abortion is including in approximately 15-20% of all pregnancies. Over the decades since the beginning of Assisted Reproductive Technology (ART) and in vitro fertilization (IVF) pregnancy rate still remains below 30% and Recurrent Implantation Failure in one of the most important limiting factor is the assisted reproductive techniques. According to studies conducted in recent years one of the most important mechanisms of implantation failure is maternal immune system because the fetus as an allograft toxic (Semi allograft) to the mother. Studies have demonstrated that ratio of Th1 to Th2 cells increase in maternal peripheral blood cells can be directly associated with implantation failure. Lymphocytes during implantation, in association with endometrium and blastocyst, participate in the production of cytokines, in particular Th1 pre-inflammatory cytokines. TNFα, IFNγ ،LIF ،IL12 ،IL15 Among these are pre-inflammatory cytokines that appear to be necessary in the early stages of implantation. The initial inflammatory response should therefore be selectively reduced to preserve pregnancy. Inflammatory response impairment at the beginning of pregnancy causes fetal implantation failure, while high inflammation leads to acute rejection (spontaneous abortion) or chronic (pre-eclampsia) ). Preserving pregnancy requires a specific cytokine pattern, in particular Th2 cytokines (IL3, IL4, IL5, IL10, IL13, GMCSF), which causes the anti-inflammatory state of pregnancy required. Therefore, maternal immunity seems to be involved in creating and sustaining pregnancy through the Th1 / Th2 Thalassic Balance. An imbalance between the two systems can be an explanation for the implantation failure in some patients. The effect of intra-uterine lymphocyte therapy on the fertility rate of women with RIF in the mouse model has been shown to be controlled by the Th1 system. While the Th2 system has a protective role, two thirds of patients have had an incomplete endometrial admission. Since the immune cells of the uterus are balanced through a broad cytokine pattern, it is important to evaluate the implantation success of RIF patients after intrauterine insemination (IUI) of their own lymphocytes in the uterus in the pre-implantation phase. Laboratory tests on mice show an increase in the number of embryonic implantations with human PMBCs. Considering the importance of TH1 and TH2 cells in the success or failure of pregnancy and the relationship between the function and balance of these cells with pregnancy problems, such as implantation failure (RIF), and the role of factors and inflammatory cytokines in creating proper nesting conditions, by introducing the lymphocytes of a participants infected with RIF into the uterus in order to induce primary inflammation, the investigators will examine its effect on fertility and the success of implantation in women with RIF.
Infertility and miscarriage ordinary events in reproductive failure in humans, as are affected one couple in every six couples of reproductive age and abortion is including in approximately 15-20% of all pregnancies. Over the decades since the beginning of Assisted Reproductive Technology (ART) and in vitro fertilization (IVF) pregnancy rate still remains below 30% and Recurrent Implantation Failure in one of the most important limiting factor is the assisted reproductive techniques. According to studies conducted in recent years one of the most important mechanisms of implantation failure is maternal immune system because the fetus as an allograft toxic (Semi allograft) to the mother. Studies have demonstrated that ratio of Th1 to Th2 cells increase in maternal peripheral blood cells can be directly associated with implantation failure. It also increases the number of natural killer (NK) cells and Th17 cells and their cytokines in peripheral blood of mother and is also associated with an increased risk of infertility. Several studies have also shown that the fertile persons in compare to infertile have increased amount of Treg cells and inhibitory cytokines associated with it. The studies have shown that if patients are properly selected RIF and placed under appropriate immunotherapy approaches it will be seen a significant increase in fertility. In previous years, followed by the production of intravenous immunoglobulin (IVIg) and determine its effect on immune suppression, IVIg uses for the treatment of various diseases such as thrombocytopenic purpura, Guillain-Barre syndrome, Kawasaki disease and Myasthenia gravis. It is also valuable drug for the treatment of patients with infertility problems have also been used but still remains how well the drug and its mechanism of action are unknown. Probably one of the mechanisms of IVIg is its effect in suppressing the activity of NK cells. Likely IVIg cause to increase Cluster of Differentiation 94 (CD94) molecule as an inhibitor molecule on the NK cells and reduced the cytotoxic activity of NK cells. So because of reduce the cytotoxic activity of NK cells by IVIg in patients with RIF injection increases the likelihood of successful implantation. Previous studies have shown that the incidence of genetic abnormalities in children who have received immunosuppressive drugs such as IVIg like normal people and normal society. In this study we used IVIg before IVF to suppress the immune system in patients with immunological causes of RIF and the results will be compared with a control group that did not receive any type of drug.
Repeated implantation failure (RIF) is determined as failure to achieve pregnancy following at least 3 embryo transfers of high quality embryos in IVF cycles. Successful implantation and pregnancy depend on the activity of a variety of factors such as adhesion molecules, cytokines and immune cells.The process by which the foreign conceptus is accepted requires the appropriate function of regulatory T cells (Treg), which are known as the mediators of immune regulation. Tregs are capable of inducing maternal tolerance toward the fetus and their systemic expansion has been observed in early pregnancy. Furthermore, Th17 cells that play important roles in mounting inflammation are involved in the maintenance of pregnancy as a subset of effector T cells.The mammalian target of rapamycin (mTOR) inhibitors are immunosuppressive agents used after solid organ transplantation. Sirolimus as the most common mTOR inhibitor is able to effectively prevent allograft rejection and possesses significant antitumor properties. Pregnancy is a state of immunosuppression and the dysregulated immune responses has been observed in women with RIF. Accordingly, modulation of the immune system by an immunosuppressant drug may present an approach to overcome implantation failure. In this context, the use of Sirolimus might offer promise to achieve a better pregnancy outcome among women with implantation failure who undergo IVF. Based on previous findings, we hypothesized that Sirolimus may be beneficial for the improvement of pregnancy rate in women with IVF failure. In the current study, we performe randomized phase II clinical trial to determine whether Sirolimus could be used as a bona fide treatment to increase the success rate of IVF in women with RIF of immune etiologies.A total 121 patients with a history of at least 3 RIF after IVF/ET cycles that will refer to Eastern Azerbaijan ACECR ART center, Alzahra Hospital of Tabriz University of Medical Sciences and Infertility Treatment center ACER Qom from July 2016 to June 2017 were select and enroll in this multicenter, randomized, double-blind, phase II study. Normal ranges for Th17/Treg cell ratios establish using 50 normal fertile women who had a history of normal delivery by natural conception. In patients with elevated Th17/Treg ratios, half of them treat with Sirolimus (Rapamune®; Pfizer, UK) and rest of patients not treat (control group). The patients in the treatment group will began Sirolimus 2 days prior to embryo transfer (ET) and will continue until the day of pregnancy test (15 day after ET), for a total of 17 days Sirolimus administe in a daily dose of 2mg.
300 recurrent implantation failure patients will be alternatively assigned to assisted hatching , endometrial scratch , and no treatment ,100 patients in each group
Endometrial biopsy has been shown to improve IVF pregnancy and live birth rates. The optimal time of performing the biopsy is yet to be established. In this study, the investigators will compare different temporal timing of the biopsies with regards to the menstrual cycle and their affect on the success rates of the treatment.
Recurrent implantation failure is the failure to achieve a pregnancy after multiple attempts with in vitro fertilization treatment. The reason is usually obscure. Many empirical treatments have been offered without substantial evaluation. Heparin is thought to play a role in the embryo implantation process beyond its anticoagulation effects. The proposed study aims to assess the effectiveness and safety of empirical administration of low molecular weight heparin in patients undergoing a new IVF treatment cycle after multiple failed attempts.