Recurrent Implantation Failure

The goal of this clinical trial is to evaluate the efficacy of Zishen Yutai Pill (ZYP) on pregnancy outcomes following embryo transfer and its safety in patients with recurrent implantation failure. The main question it aims to answer is whether ZYP can improve live birth rate in participant's frozen embryo transfer (FET) cycles. Researchers will compare ZYP to a placebo (a look-alike substance with similar characteristics to ZYP) to see if it works to improve pregnancy outcomes. Participants will: 1. Start to receive ZYP or placebo (5g per time, 3 times daily) within the first 5 days of their initial menstrual cycle, and will undergo FET in the following cycle. The medication will be taken without interruption till the day of pregnancy test (2 weeks after embryo transfer). Patients with positive results in β-HCG test will continue to take the drug until clinical pregnancy confirmation by ultrasound three weeks later. For those with a negative β-HCG result, the intervention will be stopped. 2. Baseline visit will be conducted on days 2-4 of the participant's first menstrual cycle. Subsequent clinic visits will follow the standard protocol for FET cycle, as outlined below: Visit 1 (days 2-4 of the second menstrual cycle); Visit 2 (day of ovulation or day of endometrial transformation); Visit 3 (day of embryo transfer); Visit 4 (2 weeks after embryo transfer); Visit 5 (5 weeks after embryo transfer). Follow-up is scheduled at 10 weeks after embryo transfer (Visit 6) and after delivery (Visit 7), and these can be conducted remotely.

Endometrial receptivity is a key determinant of success in assisted reproductive technology (ART). A significant proportion of patients experience repeated implantation failure despite euploid embryos and adequate laboratory conditions. Thin endometrium, often defined as ultrasound-measured thickness \<7 mm at embryo transfer, is frequently refractory to estrogen therapy and associated with low implantation and clinical pregnancy rates. Platelet-Rich Plasma (PRP), obtained from autologous blood by double centrifugation, is rich in growth factors capable of stimulating cell proliferation, angiogenesis, and tissue regeneration, suggesting potential benefits for endometrial function. Preliminary studies indicate improved endometrial thickness and reproductive outcomes following intrauterine PRP infusion, but standardized protocols and systematic data are lacking. The PMA\_PREPAIRE study is a prospective, single-center, controlled, non-randomized interventional clinical trial conducted at the Reproductive Medicine Center of Cardinal Massaia Hospital, Asti. The study aims to evaluate the efficacy and safety of intrauterine infusion of autologous platelet-rich plasma (PRP), in association with hormone replacement therapy (HRT), in improving endometrial receptivity and reproductive outcomes in women with thin or refractory endometrium. The study includes a prospective control group treated with standard HRT alone. Eligible women will be treated with standard clinical care, with PRP infusion offered to those with insufficient response to HRT. Inclusion criteria include age 18-45, BMI 18-30 kg/m², history of ≥1 failed embryo transfer, EMT \<5 mm after ≥10 days of HRT, and normal routine lab tests. Exclusion criteria include endometrial disease, recent gynecological infection, and systemic conditions such as thrombocytopenia or coagulopathies. Procedures include standard HRT from cycle days 1-2, serial ultrasound monitoring of endometrial thickness from days 6-8, intrauterine PRP infusion if EMT ≤7 mm (up to three infusions per cycle), embryo transfer once EMT ≥7 mm, and follow-up through pregnancy testing and confirmatory ultrasound. Collected data will be analyzed using descriptive statistics, paired and unpaired comparative analyses, and multivariate logistic regression models to evaluate predictors of treatment response and reproductive outcomes (significance level p \< 0.05). A sample size of 34 patients per group was estimated to detect a 1.5 mm difference in endometrial thickness (EMT) with 90% statistical power. Considering an anticipated dropout rate of 15%, a total of 40 patients per group will be enrolled. The study includes: an intervention group consisting of 40 patients treated with HRT plus intrauterine PRP infusion; a prospective control group consisting of 40 patients with refractory thin endometrium treated with standard HRT alone, without PRP.

The IMERR study aims to improve understanding of certain causes of infertility related to recurrent implantation failure (RIF) and/or recurrent pregnancy loss (RPL), conditions that affect many women undergoing assisted reproductive technology (ART). Despite medical advances, some patients repeatedly fail to achieve pregnancy, or experience repeated miscarriages. These situations may be linked to subtle immune or microbial disturbances in the uterus. This study seeks to identify immune and microbiological profiles in the endometrium during the implantation window-a crucial period when the embryo attaches to the uterine wall. We will compare women who have experienced RIF and/or RPL with women who have had no such history. Blood and uterine samples will be analyzed to investigate whether certain immune or microbial features are associated with these reproductive failures. The ultimate goal is to uncover predictive factors that may explain why some women experience implantation failure or pregnancy loss, and to lay the foundation for future personalized treatments to improve reproductive outcomes.

The goal of this clinical trial aims to investigate whether a non-invasive implantation window prediction model, constructed based on characteristic changes in peripheral blood miRNAs during the peri-implantation period, can improve pregnancy outcomes in patients with unexplained recurrent implantation failure undergoing frozen embryo transfer. Researchers will compare the clinical pregnancy outcomes between individualized embryo transfer guided by implantation window results and conventional embryo transfer, to observe whether implantation window-guided individualized embryo transfer can improve the clinical efficacy for patients with recurrent implantation failure (RIF). Participants will complete implantation window testing as required by the study protocol, undergo randomization and blinding, and proceed with embryo transfer according to their assigned group.

A low plasma level of mannose binding lectin (p-MBL) is associated with unexplained recurrent pregnancy loss (RPL), but it is not investigated if it is associated with unexplained reproductive failure in general, including recurrent implantation failure (RIF) after assisted reproductive technology (ART) (including IVF, ICSI and FET), recurrent pregnancy loss (RPL) after spontaneous conception, and RPL after ART.

This study will assess the use of autologous bone marrow stem cells mobilization using 1,1'-\[1,4-phenylenebis-(methylene)\]-bis-1,4,8,11-tetraazacyclotetradecane (PLERIXAFOR) as an effective medical therapy for the treatment of Asherman's Syndrome (AS), Atrophic Endometrium (AE) and Recurrent Implantation Failure (RIF).

The pregnancy rate of in vitro fertilisation (IVF) remains around 35% per transfer. Women who are not pregnant following several embryo transfers are regarded as having recurrent implantation failure (RIF), with one of the causes being the asynchronization of the embryo and endometrium. Endometrial receptivity analysis (ERA) may identify the window of implantation and guide the timing of embryo transfer to improve the pregnancy outcomes. However, there is no randomized controlled trial on the clinical effectiveness of ERA in women with RIF. This is a multicenter double-blind randomized controlled trial. All participants will have an endometrial biopsy for ERA in a standard hormonal treatment cycle. They will then be randomly assigned in the central laboratory into the intervention or control group in a 1:1 ratio. At the transfer cycle, participants in the intervention group will have frozen embryo transfer timed according to the results of ERA while those in the control group will have the transfer according to the standard timing. The primary outcome is the ongoing pregnancy rate at 10-12 weeks at their first frozen embryo transfer.

Assessing whether Preimplantation Genetic Testing for Aneuploidy (PGT-A) can increase the ongoing pregnancy rate per transferred embryo and can decrease the time to pregnancy and miscarriage rate in patients with Recurrent Implantation Failure (RIF)