Recurrent implantation failure: reality or a statistical mirage?: consensus statement from the July 1, 2022 Lugano workshop on recurrent implantation failure comment

Abstract

Despite advancements in assisted reproductive technologies over the past few decades, a 35% failure rate is still observed for unexplained reasons when transferring euploid embryos to an anatomically normal uterus. Recurrent implantation failure (RIF) is defined based on cumulative ART cycles failing; however, there is an absence in consensus on the diagnostic criteria, which leads to the risk of overdiagnosing and overtreating the condition. This consensus statement by the Lugano RIF Workshop aimed to merge variation in the clinical concept and management of RIF, focusing primarily on euploid blastocyst transfers in hormone replacement-primed cycles. The workshop comprised a panel of 27 international experts selected on the basis of overall research activities and publications on the subject. A literature search as conducted for all relevant titles and abstracts published between January 2015 and May 2022 for review. Consensus conclusions were based on the literature search and expert opinions. Consideration of an RIF diagnosis was determined to focus on failure to achieve sustained implantation (defined as a gestational sac identified on ultrasound). Historically, RIF was defined as the failed transfer of >10 embryos; however, today, a common number used is 3, which is also similar to the rate of failure based on a 95% confidence interval. Based on large clinical data sets, approximately 2%–5% of patients pursuing ART treatment may have RIF, and the decline in future implantation rate with each cycle fits more to an exponential delay curve than a linear decrease. The diagnosis of RIF should not be considered based on a single cohort of embryos, but rather on the number of euploid blastocyst transferred adjusted to patient’s age. In the absence of abnormal uterine bleeding and normal uterine size, further evaluation of asymptomatic adenomyosis is not warranted. Testing for biomarkers of endometrial receptivity and the endometrial microbiome have not been validated using RCTs and should not be used. The role of chronic inflammation in RIF remains unclear, but evidence suggests chronic endometritis does not directly play a role in ART outcome as assessed by sustained implantation rate after euploid embryo transfer. Substantial evidence exists that is low progesterone on the day of embryo transfer results in worse ART outcomes, and that IM progesterone may be superior to vaginal progesterone. There are no effective treatments for RIF currently, and immunomodulatory treatments that may be offered including glucocorticoids, IVIG, and GCSF have a lack of comprehensive data. This consensus document finds that RIF is likely present in fewer than 5% of patients undergoing ART and has been overdiagnosed and overtreated without sufficient critical evaluation of the presumed condition. It also highlights areas where future research is needed, both in the pathophysiologic cause of RIF and hypothetical treatment modalities.