Optimization of uterine receptivity for patients increases significantly the subsequent potentiality of pregnancy

Introduction: Implantation rates per transferred embryo after IVF/ICSI still stagnate in Europe at around 20% while decreasing to 5% for patients with repeated previous embryo implantation failures (RIF patients). Identification of local immune mechanisms inducing RIF may allow IVF treatment to be personalized to counteract the documented deleterious endometrial mechanism. Design: Prospective observational cohort study of 287 RIF patients. An endometrial immune uterine check-up is performed during the middle luteal phase of a nonconceptual cycle. In the case of documented poor or over-endometrial immune activation, personalized strategies were recommended. The outcome is the ongoing pregnancy rate occurring after the first embryo transfer following the evaluation. Materials andmethods: The endometrial biopsy is performed with a Cornier pipelle. After histological dating, we quantify the mobilization of uterine natural killer cells (uNK) (immunostaining CD56+), the endometrial mRNA expression of IL-15 (reflecting the maturation state of uNK), of IL-18 (reflecting the Th-1/Th-2 balance) and of TWEAK/Fn-14 (reflecting the TNF-related local immuneregulation) by real-time PCR. Such procedures lead to documentation of either low local reactivity, suggesting a problem of adhesion, or the opposite, an over-immune local activation suggesting the necessity of simultaneous local control to avoid embryo rejection (EP 12177377.42404). Normal ranges were predetermined in fertile controls. Results: 26.5% (76/287) and 58.5% (168/287) of the RIF patients showed endometrial profiles of low or the opposite over-immune activation respectively, while only 15% (43/287) had a profile comparable to fertile controls. Consequently, specific recommendations either to promote the adhesion (local injury, low stimulation, sexual intercourse, supplementationwith luteal HCG) or to control the endometrial activation (no local injury, supplementation with corticosteroids and a high dose of progesterone) were applied. Ongoing pregnancy rates observed after the first embryo transfer were 53.9% (41/76), 40% (67/168), and 9% (4/43) according to their immune profiles of low, overor normal endometrial activation (p<0.001). Conclusion: Immune uterine deregulation was observed in 85%. Optimization of uterine receptivity allowed the unexpected PR to be reached at 44%. In contrast, in the group with no deregulation diagnosed, the ongoing PR was significantly lower, most probably explained by unresolved problems with gametes.