Recurrent implantation failure – definition
The definition of recurrent implantation failure (RIF) has evolved considerably over the recent decades. Whereas a few decades ago it was defined as the lack of any clinical pregnancy after the several IVF treatment cycles involving the transfer of up to 10 cleavage-stage (day 2-3) embryos in recent years the number of transferred embryos was diminished to 4 (Coughlan, 2014) or even 3 or less good-quality blastocysts (Spanish Fertility Society, 2021). The recent ESHRE professional guideline introduced the concept of RIF threshold: if in a given patient after multiple embryo transfers the cumulative chances of a pregnancy have reached at least 60% without success RIF investigations are warranted. In practical terms this could happen after two unsuccessful attempts involving good-quality (either euploid PGT-A tested blastocysts or those from egg donation), whereas in older patients (35-39 years or ≥40 years) 3-4 or even 6 attempts are needed to reach this threshold.
RIF guidelines
In recent years several guidelines were published that could help to navigate this controversial topic. The most recent ESHRE 2023 guideline was established by an international expert workgroup and have categorized potential investigations and interventions using a traffic light system based on published high-quality scientific evidence. Although very few investigations have received a green light, those in the yellow category could still be considered after appropriate counselling and even red ones are proposed in many clinics to satisfy increasing patient demand or ideally in a research context.
What are the RECOMMENDED (green) investigations and interventions?
According to the recent ESHRE RIF guideline (2023) a green light is attributed to re-assessment and optimization of lifestyle factors (obesity, diet, smoking, alcohol, caffeine, stress), evaluation and optimizing of endometrial thickness (should be at least 7 mm) and thrombophilia screening (evaluation of genetic or acquired predisposition to clots especially antiphospholipid syndrome).
What are the OPTINAL (yellow) investigations or interventions?
A yellow light is attributed to karyotyping of both partners (to assess if there is a chromosomal abnormality in any of the parents), uterine cavity assessment using 2D/3D ultrasound/ hysterosonography/ hysteroscopy, endometrial receptivity testing with an endometrium biopsy (to check if the window of implantation is shifted), chronic endometritis testing (to exclude a chronic inflammation of the uterine lining), thyroid function assessment (to exclude under-, or overactive thyroid), checking adequate progesterone levels (before egg collection or on the day of embryo transfer), PGT-A testing for RIF patient (to check the blastocysts have normal chromosomes), and blastocyst-stage embryo transfer (on day 5-6 instead of day 2-3). Many of the above have entered in routine clinical practice of advanced clinics anyway. Although the ESHRE guideline have categorized these as optional due to the lack of high-quality scientific evidence they still can be considered after appropriate patient counselling.
What are the NOT recommended (red) investigations or interventions?
A red light is attributed to vitamin D testing and supplementation (vitamin D has a positive effect on fertility), uterine microbiome testing (normal bacterial flora is associated with positive outcomes), various immune testing and treatments (including thyroid autoimmunity, uterine and peripheral natural killer cell testing, uterine T cell assessment, blood cytokine levels, KIR-HLA compatibility testing), mitochondrial DNA assessment in the embryo (largely experimental), sperm FISH or sperm DNA fragmentation testing (to evaluate intrinsic sperm quality more deeply) and endometrial scratching (mildly scraping the uterine cavity before embryo transfer). While some of these are promising and need further investigations (e.g. microbiome testing) others are more controversial (immune testing and adjuvant treatments) or have been unequivocally refuted (endometrial scratching).
What is the best approach towards RIF in everyday clinical practice?
Despite big advances in reproductive science and increasing success rates, RIF still represents an everyday clinical practice that has to be managed. Currently many investigations and interventions are offered empirically without a strong scientific rationale, especially in private fertility clinics which are under constant pressure to remain competitive and satisfy increasing patient demand. This is also largely influenced by each country’s legal environment, clinical practices, and each clinics own policy. Currently it is still at each clinician’s own judgment to strike the adequate balance between an increased empirical use of investigations and add-ons or a more evidence-based approach.
