Etiology and management of recurrent implantation failure: A focus on intra-uterine PBMC-therapy for RIF

Highlights

• Implantation failure is one of the factors contributing to pregnancy rate reduction after IVF.

• Local immunological cells and factors at implantation site play an important role in pregnancy process.

• PBMC-therapy has positive effect, by developing required initial inflammation for implantation.

Abstract

Infertility is one of the most common problems among couples worldwide. Recurrent pregnancy loss, premature ovarian failure, recurrent implantation failure and etc. are common high prevalence disorders in societies. We will review the definition, causes and treatment of recurrent implantation failure disorder in recent studies. Implantation refers to the attachment of the embryo to the endometrial luminal surface and recurrent implantation failure (RIF) is defined as the failure to achieve a pregnancy after transferring high-grade embryos through at least three in vitro fertilization (IVF) cycles to the endometrium. The embryo factors, maternal age, uterine factors, and multifactorial effectors have been considered as the causes of implantation failure. In this review, we aim to focus on immunological factors and cells such as pro-inflammatory cytokines and dendritic cells, macrophages, decidual and uterine NK cells, as well as Th-1 cells. There are different types of treatment according to the cause of RIF including aspirin and low-molecular-weight heparin therapy, immunosuppressive drugs, intravenous immunoglobulins, and hydroxychloroquine. Among immunological recurrent implantation failure therapy, we will discuss the intrauterine PBMC-therapy in detail.

Introduction

Implantation refers to embryo attachment to the endometrium luminal surface (Benkhalifa et al., 2012). Successful implantation usually occurs when the intrauterine gestational sac is detectable by ultrasonography (Zegers-Hochschild et al., 2009). It has been reported that the implantation failure may occur during the early stages of migration or attachment, resulting in the negative hCG pregnancy test and no detectable gestational sac (Coughlan et al., 2014). Implantation failure may also be happened later, following successful embryo migration through the luminal surface of the endometrium, when embryo produces hCG (it may be detectable in urine or blood), however, prior to gestational sac formation, this process will be impaired (Coughlan et al., 2014). Implantation rate is also defined as the ratio of gestational sac producing embryos to the total number of embryos which are transferred into the uterine cavity (Zegers-Hochschild et al., 2009). It has been reported that the implantation rate is higher after day-5 or -6 of embryo transfer (40 %) than that of day-2 or 3 (25 %) in the IVF process (Coughlan et al., 2014). Recurrent implantation failure is also defined as the failure to achieve a pregnancy after transfer of high-grade embryos into the endometrium through at least three IVF cycles (Das and Holzer, 2012). The embryo factors, maternal age, uterine factors and multifactorial effectors have been considered as causes of implantation failure (Box 1) (Bildirici et al., 2001; Demirol and Gurgan, 2004; Devroey et al., 1996; Margalioth et al., 2006; Simur et al., 2009).