Article Type: Original Article

Introduction: In the past three decades considerable improvement has been achieved in stimulation protocols. However, the efficacy of assisted reproductive technology (ART) in term of live birth rate has remained relatively constant and has showed minimal progress in embryo implantation and pregnancy rates over the years. Approximately 30% of women undergoing in vitro fertilization and embryo transfer (IVF-ET) will achieve an ongoing pregnancy and the birth rate is still 29.9-43.7% per cycle. Thus, failure to obtain pregnancy occurs at the time of implantation or a short time thereafter. It has been estimated that 30% of embryos are wasted in the preimplantation period and 30% are wasted after implantation. So implantation failure following embryo transfer is a principle problem in ART cycles. Definition of RIF: Implantation is determined as a procedure depending on several step and a continuous embryo-uterus interaction is observed at every step. The maternal immune system plays a major role in the establishment and maintenance of a normal pregnancy. Local and systemic immunological factors have been recognized that decrease the immunogenicity of the allogenic embryo and/or change the maternal immune response to facilitate implantation and the maintenance of early pregnancy. The maternal-fetal relationship is bidirectional process that immunestimulation might be more important than immunosupression. A high rate of human leukocyte antigen (HLA) loci sharing is an expression of genetic similarity and may act to prevent the appearance of anti-paternal antibodies and most couples will share no more the one loci (of 10 alleles inherited from both parents). Furthermore, implantation require coordination of multiple parameters including growing trophoblast and proper expression of numerous molecules that play essential roles in invasion of the embryo into the endometrium. Implantation failure in patients undergoing IVF is comparatively common in spite of good quality embryos transfer. Implantation failure may be a repeated event in some couples even in successful units with high pregnancy and live birth rates and it is leading to disappointment in these couples and their supervisors. Recurrent implantation failure (RIF) is defined as failure to achieve a pregnancy following 2-6 IVF cycles with more than 10 good quality embryos transfer and endometrial receptivity. Recently, the definition of RIF is not obvious and it is due to a trend for transferring only one or two embryos. Etiologies of RIF: Implantation is a complex process dependent upon many variable, most of which have not been adequately defined. Some agents have been recognized that affect success or failure of IVF-ET procedure and include decreased endometrial receptivity (due to uterine cavity abnormalities, endometrial thickness, immunological factors, thrombophilias, altered expression of adhesive molecules such as cytokines, NK cells, ILs, and integrins), embryo quality defect (due to parental age, ovarian reserve, infertility etiology, stimulation protocols) and problems in embryo transfer technique. Assessment of RIF: It depends on assumed etiologies and proper diagnosis may help select those patients who benefit from appropriate treatment. Some of these methods include repeated hysteroscopy, change in stimulation protocols, PGS, HLA typing, and identification of specific antibodies and NK cells. Treatment of RIF: whereas therapeutic options are limited and RIF is a clinical definition that include several subgroup, each patient may be have exclusive treatment. Multiple experimental treatments have been presented such as low dose aspirin, low-molecular weight heparin, intravenous immunoglobulin (IVIG), pentoxyfylline, ET under ultrasonographic guidance, blastocyst transfer and ZIFT. There is evidence to suggest that immunological factors may be involved in RIF, immunotherapy with IVIG has been introduced empirically into IVF programs. Preliminary studies found variable success with IVIG. The use of IVIG is very controversial but may be justified after many failures in specific cases and need large randomized prospective studies. IVIG therapy may not be a relevant routine treatment for failed IVF and large randomized studies are needed but these studies are extremely difficult to conduct. Conclusion: We proposed that specialized investigation should be initiated after four or more implantation failure with good quality embryos transfer and also based on our experiences, we believed that the use of surrogacy is the best choice in couples with RIF who other exclusive treatments have failed.