Experimental Study on the Use of Intrauterine Infusion of Autologous Platelet-rich Plasma (PRGF-IUI) in Patients With Recurrent Implantation Failure and/or Refractory Thin Endometrium

Official title

PMA_PREPAIRE STUDY: Experimental Study on the Use of Intrauterine Infusion of Autologous Platelet-rich Plasma (PRGF-IUI) in Patients With Recurrent Implantation Failure and/or Refractory Thin Endometrium.

Overview

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.

Detailed description

Endometrial receptivity plays a central role in the implantation process and the success of assisted reproductive technologies (ART). A receptive endometrium undergoes synchronized cellular proliferation, vascularization, stromal decidualization, and expression of specific cytokines and adhesion molecules at the time of embryo transfer. Thin endometrium, commonly defined as a transvaginal ultrasound-measured thickness of less than 7 mm, is frequently encountered in patients undergoing ART and is associated with lower implantation and clinical pregnancy rates.

Refractoriness of the endometrium to standard hormone replacement therapy (HRT) represents a persistent clinical challenge. Despite optimization of estrogen administration routes and doses, a significant subset of patients fails to achieve adequate thickness and functional receptivity. These patients often experience repeated implantation failure (RIF), defined by multiple unsuccessful implantation attempts despite transfer of high-quality embryos.

Platelet-Rich Plasma (PRP) is an autologous biological product obtained from peripheral blood through differential centrifugation. PRP contains a high concentration of platelets, which store a complex milieu of growth factors and cytokines, including platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF). These bioactive molecules have mitogenic, angiogenic, and chemotactic properties that facilitate tissue repair and regeneration. The theoretical rationale for PRP application in reproductive medicine is based on its potential to augment stromal proliferation, enhance microvascular growth, and improve the structural and functional characteristics of the endometrium.

Preliminary evidence from observational and interventional clinical studies suggests that intrauterine infusion of autologous PRP may be associated with increased endometrial thickness, improved uterine hemodynamics, and enhanced reproductive outcomes, including implantation and clinical pregnancy rates. In retrospective cohort analyses, patients treated with PRP showed significant improvements in endometrial parameters and pregnancy outcomes compared to conventional therapy. Although variations exist in study designs, inclusion criteria, and infusion protocols, a recurring finding is the promising therapeutic effect of PRP on endometrial receptivity.

Despite these encouraging data, the current literature also highlights the lack of standardized protocols and high-quality, large-scale randomized controlled trials. Systematic reviews and meta-analyses have underscored the need for well-designed clinical trials to establish the reproducibility and clinical validity of PRP therapy in this context. Some guidelines and expert groups note that while the biological rationale is strong, PRP use cannot yet be universally recommended without further evidence from rigorously controlled studies.

The PMA\_PREPAIRE study was designed to address the current lack of robust clinical evidence regarding the use of intrauterine autologous platelet-rich plasma (PRP) in patients with refractory thin endometrium undergoing assisted reproductive technology (ART) treatments.

The study prospectively evaluates the efficacy and safety of intrauterine PRP infusion in a controlled clinical setting, comparing reproductive and endometrial outcomes between patients treated with HRT plus PRP and a prospective control group receiving standard HRT alone.

The trial design aims to combine real-world clinical applicability with methodological rigor through:

\- predefined inclusion and exclusion criteria; standardized PRP preparation and infusion procedures; prospective and structured data collection; controlled comparison between study groups.

Primary and secondary outcomes include:

\- changes in endometrial thickness (EMT); achievement of EMT ≥7 mm; implantation rate; clinical pregnancy rate; safety and tolerability endpoints. By integrating clinical practice with a structured interventional research framework, the PMA\_PREPAIRE study aims to generate high-quality prospective evidence and contribute to the future development of standardized clinical recommendations regarding the use of PRP in reproductive medicine and refractory thin endometrium.

Interventions

• Procedure Intrauterine Platelet-Rich Plasma (PRP) Infusion
  Autologous platelet-rich plasma (PRP) is prepared from peripheral venous blood collected from the participant and processed using a standardized double-centrifugation technique to obtain a platelet-concentrated plasma fraction. The PRP is administered via intrauterine infusion using a sterile flexible catheter in an outpatient setting without anesthesia. Up to three infusions may be performed within a treatment cycle based on endometrial response. The procedure is performed in addition to standa
• Drug Hormone Replacement Therapy (HRT)
  Standard estrogen therapy used for endometrial preparation.

Primary outcome measures

• Endometrial Thickness ≥ 7 mm After PRP Treatment [Time frame: Up to 14 days after initiation of hormone replacement therapy within the treatment cycle.]

Eligibility criteria

Inclusion criteria

• Female patients aged 18 to 45 years
• Body mass index (BMI) between 18 and 30 kg/m
• Undergoing assisted reproductive technology (ART) cycle with hormone replacement therapy
• Endometrial thickness < 7 mm after at least 10 days of hormone replacement therapy
• History of at least one failed embryo transfer
• Normal hematologic and biochemical laboratory results
• Ability to understand and sign written informed consent

Exclusion criteria

• Endometrial hyperplasia or uterine malignancy
• Active pelvic inflammatory disease or untreated sexually transmitted infection
• Coagulation disorders or platelet abnormalities
• Thrombocytopenia (<100,000/mm³)
• Chronic anticoagulant therapy
• Active systemic infection or immunodeficiency
• Contraindications to intrauterine procedures

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Yahyaei A, Madani T, Vesali S, Mashayekhi M. Intrauterine infusion of autologous platelet rich plasma can be an efficient treatment for patients with unexplained recurrent implantation failure. Sci Rep. 2024 Oct 29;14(1):26009. doi: 10.1038/s41598-024-77578-1. PMID 39472511
• Mouanness M, Ali-Bynom S, Jackman J, Seckin S, Merhi Z. Use of Intra-uterine Injection of Platelet-rich Plasma (PRP) for Endometrial Receptivity and Thickness: a Literature Review of the Mechanisms of Action. Reprod Sci. 2021 Jun;28(6):1659-1670. doi: 10.1007/s43032-021-00579-2. Epub 2021 Apr 22. PMID 33886116
• Nazari L, Salehpour S, Hosseini S, Sheibani S, Hosseinirad H. The Effects of Autologous Platelet-Rich Plasma on Pregnancy Outcomes in Repeated Implantation Failure Patients Undergoing Frozen Embryo Transfer: A Randomized Controlled Trial. Reprod Sci. 2022 Mar;29(3):993-1000. doi: 10.1007/s43032-021-00669-1. Epub 2021 Oct 14. PMID 34651260
• Chang Y, Li J, Chen Y, Wei L, Yang X, Shi Y, Liang X. Autologous platelet-rich plasma promotes endometrial growth and improves pregnancy outcome during in vitro fertilization. Int J Clin Exp Med. 2015 Jan 15;8(1):1286-90. eCollection 2015. PMID 25785127
• Kasius A, Smit JG, Torrance HL, Eijkemans MJ, Mol BW, Opmeer BC, Broekmans FJ. Endometrial thickness and pregnancy rates after IVF: a systematic review and meta-analysis. Hum Reprod Update. 2014 Jul-Aug;20(4):530-41. doi: 10.1093/humupd/dmu011. Epub 2014 Mar 23. PMID 24664156

Identifiers

NCT: NCT07455773 · PMA_PREPAIRE STUDY ASL AT

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗