Recurrent implantation failure in IVF: A Canadian Fertility and Andrology Society Clinical Practice Guideline

Abstract

Recurrent implantation failure (RIF) after IVF is a challenging topic for clinicians and can be a devastating reality for some patients with infertility. The purpose of this guideline from the Canadian Fertility and Andrology Society (CFAS) is to provide the most relevant evidence to date for the assessment and management of RIF. This guideline was developed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. This guideline recognizes the presence of heterogeneity in the definition of RIF. Recommendations are offered here on the investigation of RIF and management options that may increase the chance of a live birth. KEY MESSAGERecurrent implantation failure (RIF) is devastating for both couples and clinicians. The definition of RIF is variable, as are the effects of adjuvant medications and techniques to improve the implantation rate. This guideline provides recommendations on the investigation and management options that may increase the chance of a live birth.

The Pathophysiology of Hypercoagulability and Infertility

“…Even with the successful creation of a blastocyst following IVF, in many cases a clinical pregnancy does not follow, with merely one-third of ETs resulting in implantation, 17 which in the field of ART is determined via ultrasound evidence of a gestational sac. 1 Although the incidence of ART is rising, improvement in implantation rates has remained relatively unchanged. The Society for Assisted Reproductive Technology has reported an overall implantation rate of 29% and livebirth rate of 24%, from a total of 248,086 cycles in 2017.…”

“…17 Contextually, RIF is recognized clinically following multiple episodes of unsuccessful implantation, with repeated failure to reach a stage recognizable by pelvic ultrasonography. 17 However, definitions of RIF have been plagued by significant heterogeneity, 1 with the most recent CFAS guideline describing it vaguely as IF following several ETs, and going on to highlight gaps within existing literature, including (1) absence of a uniformly endorsed definition of RIF; (2) variation in the definition of implantation itself; (3) discrepancies in the criteria comprising the definition, such as IVF cycle (fresh or frozen) and embryo (number, quality, and type [cleavage-stage or blastocyst]) characteristics; and (4) provisos concerning the upper limit of maternal age to qualify for RIF. 1…”

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Setting the Scene

Physiology of ImplantationAttainment of a favorable pregnancy outcome is contingent on a multitude of factors, with the extraordinarily complex process of implantation reflecting an imperative phase in its fulfillment. 1 In this process, once the zona pellucida is discarded, the contactless presentation of the embryo toward the endometrium is accomplished via a process called apposition. Subsequently, in a time-sensitive fashion, embryonal-endometrial adhesion takes place via expression of adhesion molecules on the surfaces of both entities.

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Recurrent Implantation Failure: The Role of Anatomical Causes

“…Firstly, it is difficult to find its clinical standardized definition, despite the various articles on the topic. There is no agreement on issues, such as the number of embryo transfer failures, the embryo development stage, its morphology and aneuploidy, in order to define RIF [1]. There are also inconsistencies on the definition of implantation.…”

“…Some authors consider it a failure when the gestational sac is not seen after the embryo transfer. Others claim that it happens when the β-hCG test is negative [1]. In 2014, some researchers proposed the following definition: it is the transfer of at least four good morphologic quality embryos, with at least three fresh or frozen transfers to women below 40 years old.…”