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 2017 to June 2018 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.

Inclusion Criteria:

• The patients selected for this study will be with elevated Th17/Treg ratio
• Enrolled patients will experience at least 3 times we have consecutive defeats implantation.
• Patients in the study will record their medical history do not have any type of immunotherapy.

Exclusion Criteria:

• Our criteria for exclusion of patients from the study include the following:
• Patients aged 20 years and above 41 years
• Patients or their spouse has abnormal karyotype or chromosomal and genetically disorders.
• Patients who have bleeding problems.
• Patients who have chronic disorders those are forced to use the specific drug.
• Patients who test HIV, hepatitis C virus (HCV) or hepatitis C virus (HBV) are positive.
• Patients who have a history of asthma and allergies to certain drugs.
• Patients who have abnormalities of the uterus