Reasons and Mechanisms of Recurrent Failed Implantation in IVF

*Violeta Fodina, Alesja Dudorova and Juris Erenpreiss*

### **Abstract**

Recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF) are serious problems in IVF and ICSI cycles. Different factors are showed to be responsible for these clinical challenges – such as paternal, maternal, embryonic, immunological, infectious, hormonal, and others. In this chapter we have tried to review the available data on reasons for the RIF, and systematize them into: 1) uterine factors; 2) embryo factors; 3) immunological factors; 4) other factors. Interplay between all these factors play a role in RIF, and further investigations are needed to elucidate their significance and interactions – in order to elaborate more definite suggestions or guidelines for the clinicians dealing with artificial reproductive techniques and facing RPL and RIF.

**Keywords:** IVF, failed implantation, embryo loss, pregnancy loss

#### **1. Introduction**

1978 was the year when the first IVF baby Louise Brown was born. From that time reproductive technology progress grew exponentially as well as the experience in current field. In the next years after Louise Brown birth initial implantation rates were < 5% per embryo [1]. As ART technology progressed, many clinics replaced cleavage-stage embryos to blastocyst-stage embryos, and switched from multiple embryo transfers to double- or single-embryo transfers. Each of those achievements led to the point where modern reproductology stands.

Despite the accumulated experience and knowledge, there are many medical questions that need to be answered, because recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF) still exist.

RPL is a disorder defined by the American Society for Reproductive Medicine (ASRM) as the loss of two or more consecutive clinical pregnancies until 20 weeks of gestation [2]. It is known that around 5% of all women are experiencing two consecutive pregnancy losses, 75% of which are implantation failures [3]. In the case of RIF, because of rapidly changing field of ART there has been always a lack of consensus on the definition of RIF, and up till today the definition of RIF is still not unanimous.

One of the first attempts to define RIF was done by Coulam twenty years ago. He defined RIF as a failure to achieve pregnancy with more than 12 embryos transferred in several procedures [4]. During the consecutive 20 years, more and criteria have been added. A parameter of the blastocyst in the definition of RIF was introduced in 2007: it has been stated that for RIF to be diagnosed, in the patients history there should be the transfer of ≥8 of the 8-cell embryos, the transfer or ≥ 5 blastocysts without achieving the pregnancy [5]. After that the researchers started to specify that good-quality embryos is also a significant factor that should be taken into account [6]. Good-quality embryo was defined as having the correct number of cells corresponding to the day of its development and day-5 embryos (blastocysts) were graded according to expansion and quality of the inner cell mass and trophectoderm [7]. Coughlan with colleagues in 2014 proposed definition in which they also added the age of women [8]. About the same time, Lukasz with co-workers stated that RIF should be defined as the absence of implantation defined by a negative serum hCG 14 days after oocyte collection, after two consecutive cycles of IVF, ICSI or frozen embryo transfer, where the cumulative number of transferred embryos was no less than four for cleavage-stage embryos and no less than two for blastocysts, with all embryos being of good quality and of appropriate developmental stage [9]. The PGD Consortium, a specialized group of European Society of Human Reproduction and Embryology, suggested one of the last definitions of RIF: it is a failure to achieve pregnancy after ≥3 embryo transfers (ET) of high-quality embryos in women <40 years, or transfers of ≥10 embryos in total in multiple transfers. Presence or absence of pregnancy is diagnosed by an ultrasound examination after the 5th week [8, 10, 11]. Implantation failure can depend on different factors. Successful embryo implantation is an interactive process between the blastocyst and the uterus. Synchronized development of embryos with uterine differentiation to a receptive state is necessary to complete pregnancy. Implantation failure may occur even on early stages during the embryo attachment or migration. As a result, there will be no objective evidence of a pregnancy, i.e. negative urine or blood pregnancy tests (negative hCG) [12]. Another scenario - embryo can migrate through the luminal surface of the endometrium and start to produce hCG, which may be detected in the blood or urine. But even on this stage the process could be disrupted before the formation of an intrauterine gestational sac. In general, implantation failure is usually distinguished into two groups. The first group included women who never shown quantifiable signs of implantation, such as increased levels of hCG. The second group include women who have an evidence of implantation (detectable hCG production) but it did not proceed beyond the formation of a gestational sac visible on ultrasonography 2 weeks later [8]. From the clinical point of view, as defined by the ASRM, implantation is considered successful when there is ultrasonographic evidence of an intrauterine gestational sac or by histopathological examination [2]. With vast numbers of potential causes to consider, to diagnose an etiology of implantation failure is still a complex task for every reproductologist. Some researchers attempted to present summarized reasons of RIF. For example, Timeva et al. have divided RIF causes in three main groups: 1) multifactorial RIF with the subgroups of maternal or paternal factors, hormonal or metabolic disorders, infections and thrombophilias; 2) endometrial RIF that is caused due to thin (≤6 mm) endometrium, with or without variations in vascularity; 3) idiopathic RIF, which is unexplained failure to achieve pregnancy after transfer of good quality embryos, without any anatomical and histological changes in uterine cavity and endometrium, without any other disturbances in patient, patient-partner and embryos [13]. Some other authors, in turn, have distinguished etiologic groups such as decreased endometrial receptivity, defective embryonic development and also multifactorial effectors, including into the multifactorial group endometriosis, hydrosalpinges and suboptimal ovarian stimulation [6]. However, there are two main causes of implantation failure that are always present in the majority of all the classifications: uterine and embryo factors. Therefore, we

will shortly review these two, and will also add some data on the immunological and other factors of interest in the context of RIF.
