The Next Frontier in ART: Harnessing the Uterine Immune Profile for Improved Performance.

Assisted reproduction techniques have improved considerably in recent decades, but despite these advances, success rates remain relatively low. Endometrial immune profiling involves the analysis of cytokine biomarkers in the endometrium during the mid-luteal phase. This profiling aims to provide insights into the immune environment of the uterus. The aim is to identify immune disturbances and thus guide the development of personalized therapeutic approaches. The first part of the review looks back at the emergence of innovative concepts, highlighting the specificity of the human uterine environment at the time of implantation. Based on this new knowledge, biomarkers have been selected for endometrial immune profiling. The second part details the results of clinical studies conducted over the last ten years. These clinical results suggest that this approach can increase the rate of live births in patients suffering from repeated implantation failures or repeated pregnancy loss. Uterine immune profiling represents a clinical innovation that can significantly improve the performance of medically assisted reproduction treatments through personalized strategies tailored to the local immune profile. Innovation in personalized medicine for assisted reproduction is crucial to improving the success rates of fertility treatments, while reducing the risks and costs associated with ineffective or unnecessary interventions.

The Endometrial Immune Profiling May Positively Affect the Management of Recurrent Pregnancy Loss.

Introduction: The endometrial immune profiling is an innovative approach based on the analysis of the local immune reaction occurring in the endometrium at the time of the embryo implantation. By documenting the local immune activation during the period of uterine receptivity, we aim to detect and correct potential imbalances before and at the very beginning of placentation. The main objective of the study was to analyze in women with a history of repeated pregnancy loss (RPL) the association of personalized strategies based on immune dysregulations with live birth rates. The secondary objective was to highlight the main prognostic factors for live births. Methods: This is an observational retrospective analysis of 104 patients with RPL, included between January 2012 and December 2019. Inclusion criteria included a spontaneous fertility with at least three miscarriages, an assessment including a three-dimension ultrasound scan, an endometrial biopsy for uterine immune profiling and a follow-up over at least 6 months with personalized care if indicated after the complete assessment. We defined as a success if the patients had a live birth after the suggested plan, as a failure if the patient either did not get pregnant or experienced a new miscarriage after the targeted therapies. Results: Uterine immune profiling was the only exploration to be significantly associated with a higher live birth rate (LBR) if a dysregulation was identified and treated accordingly (55% vs 45%, p=0.01). On the contrary, an absence of local dysregulation (resulting in an apparently balanced immune environment) was associated with a higher risk of a new miscarriage, suggesting that the cause inducing RPL still needed to be identified. Independently of age and AMH level, dysregulated immune profile is significatively associated with 3 times higher LBR than a non-deregulated profile (OR=3.4 CI 95%1.27-9.84) or five times in case of an overactive profile treated by immunotherapy (OR=5 CI 95% 1.65-16.5). The usage of ART was significantly associated with lower LBR regardless of the presence of a subfertility factor (p=0.012). Personalization of medical care using natural cycle or simple hormonal stimulation is associated with a significantly higher LBR than personalization including ART treatments regardless of maternal age and AMH level (OR= 2.9 CI 95% 1.03-8.88). Conclusion: Our study suggests that some endometrial immune profiles with targeted management of RPL are associated with a higher rate of LBR. ART may be negatively associated with LBR.

Endometrial Immune Profiling: A Method to Design Personalized Care in Assisted Reproductive Medicine.

Objective: To assess the efficiency of the endometrial immune profiling as a method to design personalized care to enhance the pregnancy rate in a large heterogeneous infertile population. We hypothesized that some reproductive failures could be induced by a uterine immune dysregulation which could be identified and corrected with a targeted plan. Design: Prospective cohort study. Setting: Multicentric study. Intervention(s) and Main outcome measure(s): One thousand and seven hundred thirty-eight infertile patients had an immune profiling on a timed endometrial biopsy between 2012 and 2018. This test documented the absence or the presence of an endometrial immune dysregulation and identified its type. In case of dysregulation, a targeted personalized plan was suggested to the treating clinician aiming to supply the anomaly. One year after the test, the clinician was contacted to provide the outcome of the subsequent embryo transfer with the applied suggested plan. Result(s): After testing, 16.5% of the patients showed no endometrial immune dysregulation, 28% had a local immune under-activation, 45% had a local immune over-activation, and 10.5% had a mixed endometrial immune profile. In patients with a history of repeated implantation failures (RIF) or recurrent miscarriages (RM), the pregnancy rate was significantly higher if an endometrial dysregulation was found and the personalized plan applied, compared to the patients with an apparent balanced immune profile (respectively 37.7 and 56% vs. 26.9 and 24%, p < 0.001). In contrast, in good prognosis IVF (in vitro fertilization) subgroup and patients using donor eggs, this difference was not significant between dysregulated and balanced subgroups, but higher pregnancy rates were observed in absence of dysregulation. For patients with immune over-activation, pregnancy rates were significantly higher for patients who had a test of sensitivity, regarding the type of immunotherapy introduced, when compared to the ones who did not (51 vs. 39.9%, p = 0.012). Conclusion(s): Local endometrial immunity appears to be a new and important parameter able to influence the prognosis of pregnancy. Targeted medical care in case of local immune dysregulation resulted in significantly higher pregnancy rates in RIF and RM patients.

Intralipid® may represent a new hope for patients with reproductive failures and simultaneously an over-immune endometrial activation.

PROBLEM: Continuous failures to achieve a pregnancy despite effective embryo transfers is extremely distressing for couples. In consequence, many adjuvant therapies to IVF have been proposed to achieve an "ideal" immune environment. We here focus on Intralipid® therapy (IL) reported to have immunosuppressive properties on NK cells. METHOD OF STUDY: 94 patients exhibited an immune profile of endometrial over-immune activation and an history of repeated implantation failures despite multiple embryos transfers (RIF). They received a slow perfusion of Intralipid®. We here report the live birth rate following the procedure at the next embryo transfer. To get new insight on its mechanism of action, a second immune profiling had been performed under Intralipid® before the embryo transfer. RESULTS: The live birth rate of the RIF cohort treated with Intralipid® reached 54% (51/94) at the next embryo transfer. In patients successfully pregnant under Intralipid® who benefitted of a test of sensibility before the embryo transfer, we observed a significant decrease of the three biomarkers used to diagnose the over-immune endometrial activation (CD56 cells; IL-18/TWEAK, IL-14/FN-14). CONCLUSIONS: Double blind placebo versus Intralipid® studies should be conducted. Intralipid® may be an option to explore in RIF patients who exhibit an over-immune activation of uNK cells.

Impact of high serum progesterone during the late follicular phase on IVF outcome.

With ovarian stimulation for IVF, serum progesterone concentration may increase during the last few days of stimulation. Several factors, mainly the intensity of the ovarian response to gonadotrophins, have been identified to explain progesterone elevation but many other issues remain uncertain. The aim of this narrative, nonsystematic review is to address the nonconsensual issues of the reasons and consequences of premature progesterone elevation during ovarian stimulation. The determination of the optimal threshold above which progesterone elevation may have an impact on IVF outcome is still a matter of debate because it is likely related to the patient's profile. Additionally, it is still uncertain whether the duration of progesterone elevation negatively affects IVF outcome. Recommendations for both prevention and management of progesterone elevation are here suggested by a group of experts. Nevertheless, before being implemented in clinical practice, they require new assessment through additional clinical trials.