Abstract Study question Does immunotherapy effective in patients with recurrent implantation failure (RIF) according to the type of endometrial immune profile? Summary answer Immunotherapy based on the profile of the endometrial immune system has significant results in increasing the pregnancy rate and live birth rate. What is known already Personalized medicine in the area of infertility is in its early stages, and considering the promising results of personalization of treatment in other disorders, including cancer, it is expected to have acceptable results in infertility as well. Given that one of the key factors that affects the infertility of RIF patients is the imbalance of the endometrial immune system, efforts have been made to correct this disorder to increase the chances of fertility. Studies have classified RIF patients into different groups based on endometrial immune system profiles: Balanced, High, Low, and Mixed endometrial immune system activity. Study design, size, duration The study selected 267 RIF patients who were referred to Valiasr Hospital in Tabriz from Aug 2020-Sep 2023, and divided them into five groups: unclassified RIF patients (n = 89), patients with normal and balanced endometrial immune system profile (n = 63), and patients with high (n = 53), low (n = 38) and mixed (n = 24) profiles of endometrial immune system. Based on type of disorder identified, the appropriate immunotherapy was suggested for each group, including vaginal probiotics, lymphocyte therapy and Tacrolimus. Participants/materials, setting, methods The study classified RIF patients based on the endometrial immune system profiles, by the gene expression level of IL-18, IL-15, TWEAK, Fn-14, and CD56. The study included a group of unclassified RIF patients, who underwent routine IVF/ET cycles without immunotherapy. The Balanced group received no immunotherapy. For the Low endometrial immune group, probiotics and lymphocyte therapy were used. High group received probiotics and Tacrolimus, and for Mixed group, probiotics, Tacrolimus, and lymphocyte therapy were used. Main results and the role of chance The primary and secondary endpoints of this study were clinical pregnancy and delivery of a live born infant, respectively. The results showed that RIF patients without classification based on the profile of the endometrial immune system who went through the routine process of IVF/ET cycles had a 25.8% and 23.5% pregnancy and live birth rates, respectively. The pregnancy and live birth rates of the Balanced group was 28.5% and 25.3% (P=NS) while it was significantly higher in the High (56.6%, 54.7%), Low (47.3%, 44.7%) and Mixed groups (37.5%, 29.1%), respectively. According to the obtained results, it was found that the appropriate immunotherapy treatment based on the endometrial immune activity profiles in RIF patients has significantly increased the effective implantation rate in the IVF/ET cycles (P < 0.05). Limitations, reasons for caution It is necessary to examine a larger number of patients. Further work is needed to explore other parameters that are affected by endometrial immune system disorder and that can help classify RIF patients and recommend the most effective treatment. Wider implications of the findings For RIF patients, accurate identification of the cause of the disorder can be very effective for choosing the best treatment method. Personalized immunotherapy for RIF patients with immunologically abnormalities can lead to very promising and acceptable results while having few complications. Trial registration number Not Applicable
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