Intrauterine Infusion Research Articles

Intrauterine infusion of autologous platelet rich plasma can be an efficient treatment for patients with unexplained recurrent implantation failure

The studies posits that there is not sufficient evidence to support the use of intrauterine platelet-rich plasma (PRP) infusion in patients with recurrent implantation failure (RIF). This study aims to investigate the effects of infusion of PRP on patients with unexplained-RIF in fresh and frozen embryo transfer (ET) cycles. A total of 80 participants were included in this study. The participants were randomly assigned to one of two groups with and without PRP infusion. Each of the PRP and control groups were also divided into fresh and frozen ET subgroups. ET outcomes were compared between groups. Clinical pregnancy rate was significantly higher in Frozen ET in PRP group than other subgroups (p < 0.0001). Miscarriage rate were significantly lower in PRP group than control group. Pregnancy complications and preterm labor were significantly higher in PRP group than control group (p < 0.0001). Live birth and healthy baby rate were significantly higher in PRP group than control group (p < 0.0001). The intrauterine infusion of 0.8-1 ml of PRP 48 h before blastocyst ET at fresh and frozen cycles can be an efficient treatment option for u-RIF patients. Also, results indicated that the clinical pregnancy rate was equal to the live birth rate at fresh ET cycles, whereas the live birth rate was lower than the clinical pregnancy rate at frozen ET cycles. Therefore, considering the superiority of fresh cycles over freeze cycles, the infusion of PRP into the uterus of patients with RIF is recommended to be done at fresh ET cycles.Trial registration: NCT, NCT03996837. Registered 25/06/2019. Retrospectively registered, http://www.clinicaltrial.gov/ NCT03996837.

107 Intrauterine infusions of Flunixin Meglumine on gestational day 30 resulted in pregnancy loss in beef cows

Abstract The physiological mechanisms underlying late embryonic/early fetal mortality in beef cows are largely unknown. Our lab, as well as others, have documented that cows undergoing late embryonic mortality have significantly decreased circulating concentrations of prostaglandin F2a metabolite (PGFM) and increased concentrations of prostaglandin E2 metabolite (PGEM) during gestational d 30 to 38, coinciding with the time of active placentation. Thus, the overall objective of this study was to analyze the physiological effect of inhibiting local prostaglandin synthesis during late embryonic development in beef cows. To determine the appropriate dosage and drug required for the sufficient knockdown of uterine-derived prostaglandins, three pilot studies were conducted. In pilot study one and two, indomethacin was administered intravenously or intrauterine into cyclic cows at a dose of 80 mg/d (n = 4) or, 160 mg/d (n = 4), directly into the jugular of pregnant cows at a dose of 270 mg/d (n = 1) or directly into the uterine artery of pregnant cows at a dose 360 mg/d (n = 2). Administration of indomethacin did not significantly knockdown PGFM or PGEM (P &amp;gt; 0.05). However, in pilot study three, a 720 mg/d dose of flunixin meglumine (FM; Banamine, Merck Animal Health, NJ) infused intrauterine into cyclic beef cows (n = 5) resulted in a treatment by day interaction (P &amp;lt; 0.001) in which luteolysis in treatment cows was inhibited as well as the synthesis of both prostaglandin F2a and prostaglandin E2. Following this validation, the next study was performed using multiparous beef cows that were subjected to a 7-d CO-Synch + CIDR synchronization protocol with insemination occurring on d 0. Pregnancy was confirmed by the presence of a fetal heartbeat on d 28 via ultrasonography and subsequent blood collections every 8 h via venipuncture (n = 9). Intrauterine infusions began on d 29 and occurred every 8 h via infusette catheter consisting of either 240 mg of FM diluted in 10 mL of flush media (ABT; FMTrt; n = 6), or 10 mL of flush media (CON; n = 3). Both infusion solutions were corrected to a pH of 7.4. Serum concentrations of PGFM were measured with a validated commercial ELISA (Cayman Chemical, MI). Though all cows were confirmed pregnant on d 28, concentrations of PGFM were significantly greater on d 28 (P &amp;lt; 0.01) and d 29 (P &amp;lt; 0.05) in the FMTrt cows than the CON cows. There was a significant decline in circulating PGFM within the FMTrt cows (P &amp;lt; 0.05) post infusion on d 29. After two infusions, CON cows had significantly greater PGFM concentrations compared with the FMTrt group (P &amp;lt; 0.01). By d 30, after three infusions, all FMTrt cows had terminated their pregnancies; however, CON cows maintained their pregnancies. Perhaps, these data indicate the importance of prostaglandins during this critical period of pregnancy. Further research is required to fully understand the physiological contribution that prostaglandins elicit in regard to pregnancy.

Effects of intrauterine infusion of autologous platelet-rich plasma gel on endometrial thickness and outcomes of frozen-thawed embryo transfer in women with thin endometrium.

The purpose of this study is to determine whether intrauterine infusion of autologous platelet-rich plasma (PRP) gel increases endometrial thickness (EMT) and improves the outcomes of frozen-thawed embryo transfer (FET) in women with thin endometrium. This study included 111 women (aged 25-44years) who had thin endometrium. All patients had at least one previous cycle canceled because of thin endometrium or previous embryo transfer cycles and an EMT < 7mm. Forty-seven women underwent intrauterine infusion of autologous PRP gel on three occasions during endometrial preparation and the remaining women served as controls. The final EMT was measured by ultrasound before the start of the luteal phase, and FET-related outcome parameters were monitored. Mean EMT was greater in women who received PRP gel than in those who did not (6.7mm vs. 6.3mm, respectively, p < 0.05). FET was attempted in all women. The 47 women who underwent infusion of PRP had a significantly higher pregnancy rate (18 pregnancies (38.3%), with 17 (36.2%) ongoing) compared with 64 control women (ten pregnancies (18.5%), nine (16.7%) ongoing). However, there was no significant reduction in the miscarriage rate. Intrauterine infusion of autologous PRP gel during endometrial preparation for FET cycles can improve the EMT, clinical pregnancy rate, and ongoing pregnancy rate in women with thin endometrium.

Efficacy of intrauterine autologous blood cell derivatives in enhancing endometrial thickness and IVF outcomes for women with recurrent implantation failure: a retrospective cohort study

PurposeThe purpose of this study was to determine the effects of intrauterine infusion of autologous blood cell derivative (ABCD) on endometrial thickness and pregnancy outcomes in a group of patients who underwent IVF with recurrent implantation failure (RIF) and who had either a normal endometrium or thin endometrium.MethodsThis retrospective study included 63 patients who experienced RIF at the Department of Reproductive Medicine and Surgery, KMC, Manipal, between January 2021 and March 2024 and who received three doses of intrauterine ABCD infusion to prepare the endometrium for frozen embryo transfer (FET).ResultsWe enrolled 63 RIF patients, 30 with a normal endometrium (NEM) and 33 with a thin endometrium (TEM). The endometrial thickness (EMT) significantly increased across all the groups. After 3 cycles of intrauterine ABCD infusion, the mean increases in EMT in the NEM and TEM groups were 0.77 mm and 1.36 mm, respectively, which were statistically significant. Among the 62 completed FET cycles, 40.3% were positive for beta-hCG. The clinical pregnancy rate was 33.8% (40% in the NEM group, 28.1% in the TEM group), and the live birth rate was 24.2% (30% in the NEM group, 18.8% in the TEM group). A total of 9.7% of pregnancies had spontaneous miscarriages. Moreover, the EMT did not differ between the pregnant and nonpregnant groups.ConclusionIntrauterine ABCD infusion improves the pregnancy outcomes of patients with RIF, regardless of the EMT. The results of this study revealed that endometrial receptivity improved significantly along with the EMT.

Angiogenic factor-driven improvement of refractory thin endometrium with autologous platelet-rich plasma intrauterine infusion in frozen embryo transfer cycles.

A beneficial effect on endometrial thickness (EMT) and improvement of pregnancy outcome after intrauterine infusion of platelet-rich plasma (PRP) has been suggested. This study assessed the effect of intrauterine PRP infusion on live birth rate and obstetrical outcomes and analyzed cytokines that can potentially improve pregnancy outcomes through PRP. This study was a prospective cohort study conducted in a university hospital fertility center. The study included ninety-one patients who had a history of two or more failed in vitro fertilization (IVF) attempts and refractory thin endometrium that remained unresponsive after at least two conventional treatments for thin endometrium. Patients were treated with an intrauterine infusion of autologous PRP between days 7 and 14 of their hormone replacement therapy-frozen embryo transfer (HRT-FET) cycle. PRP was administered at 3-day intervals until their EMT reached 7mm. After a maximum of three PRP administrations, embryo transfer (ET) was performed. The primary outcome was the live birth rate. Secondary outcomes included the implantation rate and increase in EMT compared to the previous cycle. We compared the cytokines related to angiogenesis in a patient's whole blood (WB) and PRP by utilizing a commercial screening kit. The live birth rate in the PRP treatment cycle was 20.9% (19 of 91 patients), significantly superior to the previous cycle without PRP infusion (p < 0.001). The implantation rate was also significantly higher during the PRP treatment cycle (16.4%) compared to the previous cycle (3.1%) (p < 0.001). The mean EMT post-PRP treatment was 6.1 mm, showing a significant increase of 0.8 mm (p < 0.001). Nonetheless, an increase in EMT was also observed in the non-pregnancy group. No adverse effects were reported by patients treated with autologous PRP. Cytokine array analysis confirmed marked increases in well-known pro-angiogenic factors such as Ang-1, EGF, LAP (TGF-b1), MMP-8, PDGF-AA, and PDGF-AB/PDGF-BB. Intrauterine PRP infusion offers a safe and effective treatment for patients with refractory thin endometrium and implantation failures. The angiogenic cytokines present in PRP are the primary drivers of this improvement.

Efficacy of platelet-rich plasma in the treatment of thin endometrium: a meta-analysis of randomized controlled trials

BackgroundThin endometrium (TE) is a common cause of female infertility in clinical practice. Platelet-rich Plasma (PRP) therapy becomes a novel treatment for thin endometrium; however, its clinical application remains controversial. This meta-analysis aims to evaluate the therapeutic effects of intrauterine autologous PRP infusion in women with thin endometrium through relevant randomized controlled trials (RCTs).MethodsWe systematically searched studies published in English from inception until June 2024 in databases such as PubMed, The Cochrane Library, Embase, Web of Science, and MEDLINE. Search terms included “Platelet-Rich Plasma,” “thin endometrium,” “endometrial thickness,” “infertility,” “pregnancy,” “reproduction,” and “adverse reactions”. RCTs identified through the search were subjected to systematic review and meta-analysis, and data were analyzed using fixed-effects or random-effects models based on heterogeneity.ResultsEight RCTs involving 678 patients with thin endometrium were included. Patients receiving PRP infusion demonstrated significantly superior outcomes compared to the control group in endometrial thickness (MD: 1.23, 95%CI: 0.87 to 1.59, P = 0.000), clinical pregnancy rate (RR: 2.04, 95%CI: 1.52 to 2.76, P = 0.000), live birth rate (RR: 2.46; 95%CI: 1.57 to 3.85, P = 0.000), cycle cancellation rate (RR: 0.46, 95%CI: 0.23 to 0.93, P = 0.000), and embryo implantation rate (RR: 2.71; 95%CI: 1.91 to 3.84, P = 0.000). There were no statistically significance in spontaneous abortion rate (RR: 0.85, 95%CI: 0.40 to 1.78, P = 0.659), chemical pregnancy rate (RR: 1.84, 95%CI: 0.72 to 4.72, P = 0.204) and endometrial vascular improvement rate (RR: 1.10; 95%CI: 0.89 to 1.38, P = 0.367) between the two groups. The limitations of this study includes that, we only included single lauguage for literature research, the sample size and heterogeneity which could cause criteria bias.ConclusionIntrauterine PRP infusion may be an effective and safe treatment for women with thin endometrium. Further high-quality, large-sample, randomized controlled trials are needed to validate the reliability of our results.Trial registrationThe review protocol is registered on PROSPERO with registration number CRD42023490421, and no modifications were made to the information provided at registration.

Injectable GelMA Hydrogel Microspheres with Sustained Release of Platelet-Rich Plasma for the Treatment of Thin Endometrium.

Platelet-rich plasma (PRP) intrauterine infusion has been demonstrated to be effective in treating thin endometrium and achieving pregnancy. However, the rapid release of growth factors limits its effectiveness in clinical applications, and thus, multiple intrauterine infusions are often required to achieve therapeutic efficacy. In this study, a GelMA hydrogel microsphere biomaterial is developed using droplet microfluidics to modify the delivery mode of PRP and thus prolong its duration of action. Its biocompatibility is confirmed through both in vivo and in vitro studies. Cell experiments show that PRP-loaded microspheres significantly enhance cell proliferation, migration, and angiogenesis. In vivo experiments show that the effects of PRP-loaded microspheres on repairing the endometrium and restoring fertility in mice could achieve the impact of triple PRP intrauterine infusions. Further mechanistic investigations reveal that PRP could facilitate endometrial repair by regulating the expression of E2Fs, a group of transcription factors. This study demonstrates that hydrogel microspheres could modify the delivery of PRP and prolong its duration of action, enabling endometrial repair and functional reconstruction. This design avoids repeated intrauterine injections of PRP in the clinic, reduces the number of patient visits, and provides a new avenue for clinical treatment of thin endometrium.

Berberine Alleviates Uterine Inflammation in Rats via Modulating the TLR-2/p-PI3K/p-AKT Axis

Uterine inflammation affects 8% of women in the United States and 32% in developing nations, often caused by uncontrolled inflammation and oxidative stress. This condition significantly impacts women’s health, productivity, and quality of life, and increases the risk of related morbidities leading to higher healthcare costs. Research now focuses on natural antioxidants and anti-inflammatory, particularly berberine (BBR), an isoquinoline alkaloid known for its antioxidant, anti-inflammatory, and antiapoptotic activities. The present study sought to examine the potential therapeutic efficacy of BBR against uterine inflammation induced by the intrauterine infusion of an iodine (I2) mixture in an experimental setting. Female Sprague Dawley rats (n = 6) were divided into five groups, control, sham, I2, I2 and BBR 10 mg/kg, and I2 and BBR 25 mg/kg-treated groups. Compared to I2 infusion, BBR treatment effectively restored normal uterine histopathology and reduced inflammatory markers such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), nuclear factor- kappa B (NF-κB), monocyte chemoattractant protein 1 (MCP1), and myeloperoxidase (MPO). It lowered oxidative markers like malondialdehyde (MDA), and increased antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD). It balanced apoptotic genes by upregulating B-cell lymphoma 2 (Bcl-2) and downregulating Bcl-2-associated X protein (Bax). Furthermore, BBR reduced the expression of Toll-like receptor 2 (TLR-2), phosphorylated phosphatidylinositol 3‑kinase (p-PI3K), and phosphorylated protein kinase B (p-AKT) in the rats treated with intrauterine I2. Ultimately, the therapeutic benefits of BBR can be attributed, to some extent, to its antioxidant, anti-inflammatory, and antiapoptotic properties, in addition to its ability to modulate the TLR-2/p-PI3K/p-AKT axis.

The Efficiency of Introducing Intrauterine Infusion of Autologous Platelet-Rich Plasma versus Granulocyte Colony-Stimulating Factor in Repeated Implantation Failure Patients: An Unblinded Randomised Clinical Trial.

Repeated implantation failure (RIF) refers to the condition where high quality embryos are unable to successfully implant after multiple cycles of in vitro fertilization (IVF) treatment. The aim of this study is to investigate the impact of intrauterine granulocyte colony-stimulating factor (G-CSF) and platelet-rich plasma (PRP) on pregnancy rate in patients with RIF. The present randomised clinical trial study was conducted at the IVF Centre of Mehr Medical Institute in Rasht, Iran, from 2020 to 2022. The research consisted of 200 individuals who had experienced multiple failed cycles. These patients were randomised into two groups: intrauterine infusion of 1 ml of G-CSF and intrauterine infusion of 1 ml autologous PRP at least 48 hours before embryo transfer (ET). The groups were compared in terms of implantation rate, and chemical, clinical, and ongoing pregnancy. The implantation rate was significantly higher in patients who received PRP (P=0.016). Chemical pregnancy in the PRP group was significantly higher than G-CSF group (P=0.003). Both clinical pregnancy and ongoing pregnancy rates were significantly higher in the PRP group (P=0.001) compared to the G-CSF group (P=0.02). The utilisation of PRP via intrauterine infusion is considerably more successful than G-CSF in enhancing pregnancy and live birth rates among patients with RIF.

P-405 Effects of intrauterine perfusion of autologous platelet-rich plasma on recurrent implantation failure in frozen-thawed embryo transfer: a meta-analysis of randomized controlled trials

Abstract Study question We aimed to evaluate the effect of the platelet-rich plasma （PRP) on pregnancy outcomes in patients with RIF undergoing frozen-thawed embryo transfer (FET). Summary answer Intrauterine infusion of PRP might have more beneficial effects on pregnancy outcomes in RIF patients undergoing FET. What is known already Immunological therapies are of great interest to specialists in reproductive medicine. The immune therapies use intrauterine infusion (i.e., PRP, PBMC, G-CSF, and hCG) for endometrial immunomodulation. Despite the limited number of publications available, the results are encouraging. In the network meta-analysis, PRP, PBMC, C-GCSF, and hCG administration all significantly increased embryo implantation and clinical pregnancy compared to controls. Additionally, PRP administration resulted in a higher live birth rate than the control. This year, more research has focused on PRP as an innovative method to treat RIF. Study design, size, duration Medline, Embase, and Cochrane Controlled Register of Trials (CENTRAL) were searched from inception to July 29, 2023. The randomized controlled trials (RCTs) reporting on pregnancy outcomes of women with RIF who were administered PRP undergoing FET were included. We conducted a meta-analysis where possible using a fixed effects model. The Cochrane Handbook was used to assess the risk of bias for RCTs. Binary outcomes were pooled using risk ratio (RR) with 95% confidence intervals (CIs). Participants/materials, setting, methods Seven RCTs were included with 1,014 RIF women. The final number of women analyzed was 508 with intrauterine infusion PRP and 506 without it. Main results and the role of chance Meta-analysis showed that compared to the controls, the women who received PRP had a significantly higher embryo implantation rate (n = 2, risk ratio (RR) 2.34, 95% CI 1.65 to 3.32; P &amp;lt; 0.00001, I2 = 0%), biochemical pregnancy rate (n = 5, RR 1.94, 95% CI 1.60 to 2.36; P &amp;lt; 0.00001, I2 = 0%), clinical pregnancy rate (n = 7, RR 2.31, 95% CI 1.89 to 2.82; P &amp;lt; 0.00001, I2 = 0%), ongoing pregnancy rate (n = 3, RR 2.70, 95% CI 1.79 to 4.05, P = 0.0004, I2 = 31%), and multiple pregnancy rate (n = 3, RR 2.67, 95% CI 1.07 to 6.68, P = 0.04, I2 = 0%). However, PRP was not attributable to reduce the miscarriage rate (n = 3, RR 1.15, 95% CI 0.40 to 3.35; P = 0.80, I2 = 0%). Limitations, reasons for caution The proportion of small-sample studies included has to some extent affected the validity of the results. There were some variations regarding the PRP preparation process, which may result in a variable composition and concentrations of its different contents. Wider implications of the findings Intrauterine infusion PRP in patients with RIF who underwent FET may improve the pregnancy outcomes assessed in RCTs, including clinical pregnancy and ongoing pregnancy. Therefore, we suggest that PRP be included in endometrial preparation protocols. Trial registration number not applicable

P-294 Intrauterine infusion of autologous platelet-rich plasma(PRP) for patients with refractory thin endometrium in euploid frozen embryo transfer cycles improve pregnancy outcomes

Abstract Study question Can intrauterine infusion of autologous platelet-rich plasma(PRP) for patients with refractory thin endometrium in euploid frozen embryo transfer(FET) cycles improve pregnancy outcomes? Summary answer Intrauterine infusion of autologous platelet-rich plasma(PRP) for patients with refractory thin endometrium in euploid FET cycles improve pregnancy outcomes. What is known already Previous studies have reported a positive correlation between endometrial thickness and pregnancy rate, which has led to the common clinical practice of canceling embryo transfer in cycles where the patient’s endometrial thickness remains below 7mm.One of the novel and promising treatments to improve pregnancy outcomes in patients with refractory thin endometrium is intrauterine infusion of autologous PRP.Recent studies demonstrated that intrauterine infusion of PRP improve pregnancy outcomes in these patients.Thus, to better assess the efficacy of intrauterine PRP treatment, further studies involving euploid embryos are necessary to rule out failed implantation or pregnancy loss due to aneuploidy of the embryos. Study design, size, duration This retrospective study analyzed all cycles(n = 131) of euploid FET in women with refractory thin endometrium at the CHA Fertility Center in Seoul Station from January 2022 to August 2023.Patients were divided into two groups according to whether they received PRP intrauterine infusion before embryo transfer in euploid FET cycles.Group A(n = 88) received intrauterine infusion of PRP at least once before transfer of euploid FET,and Group B(n = 43) underwent euploid FET without PRP infusion. Participants/materials, setting, methods Intrauterine infusion of autologous PRP was performed on patients who had more than two canceled FET cycles due to thin endometrial thickness(&amp;lt;7mm). Endometrial preparation was executed according to a standardized protocol for hormone replacement therapy. Group A received the last autologous PRP infusion 48 hours before euploid FET. PRP preparation was carried using an aseptic PRP centrifuge kit (PROSYS PRP; Prodizen, Korea). All embryos transferred were tested for genetic abnormalities using next-generation sequencing. Main results and the role of chance There was no significant difference in mean age and maximum endometrial thickness between the two groups. (38.1±3.1 vs. 38.3±3.2, p = 0.986 and 6.6±1.1 vs. 6.0±0.8, p = 0.320, respectively) Group A had significantly higher clinical pregnancy rates and ongoing pregnancy rates than Group B. (51.1% vs. 30.2%, p = 0.024 and 44.3 vs. 16.3%, p = 0.0017, respectively) Implantation rate and beta HCG positivity were also higher in group A, but there was no statistical difference. (63.6% vs. 46.5%, p = 0.063 and 37.2 vs. 23.2%, p = 0.064, respectively) Limitations, reasons for caution This is a retrospective study and results must be confirmed on a well-designed randomized controlled study. Also, follow-up study consisting of larger number of patients is necessary. Wider implications of the findings Autologous PRP intrauterine infusion has shown positive effects in assisting implantation in patients with refractory thin endometrium. In particular, euploid frozen embryo transfer in these patients excludes failed implantation and pregnancy loss due to embryo aneuploidy, suggesting that intrauterine PRP treatment contributes to successful implantation and pregnancy. Trial registration number not applicable

P-635 Effect of intrauterine autologous platelet-rich plasma on women with repeated implantation failure undergoing IVF: a systematic review

Abstract Study question In women with repeated implantation failure(RIF), according to the ESHRE definition, does intrauterine autologous platelet-rich plasma(PRP) increase the probability of pregnancy after IVF? Summary answer Using the ESHRE definition of RIF, no RCTs exist to accept or refute a beneficial role of intrauterine PRP on the probability of pregnancy. What is known already Ten meta-analyses of RCTs evaluating intrauterine infusion of PRP in patients reported as being RIF have been published until today, suggesting an increase in pregnancy rates. However, due to the significant heterogeneity and low quality of the included studies, no solid conclusions can be drawn. Importantly, the variability in the definition of RIF in the literature renders extrapolation of research results problematic. In this respect, ESHRE has recently published a RIF definition to facilitate evaluation of interventions in these patients. A systematic review on the effect PRP in patients meeting the ESHRE criteria for RIF has not yet been performed. Study design, size, duration A literature search (according to a predefined search protocol) in MEDLINE, Embase and CENTRAL was performed until 12/2023 aiming to identify eligible RCTs. Subsequently, the search results were scrutinized independently by two reviewers and demographic, methodological and clinical data from eligible RCTs were extracted. The main outcome measure was achievement of live birth. Secondary outcomes measures included clinical pregnancy, ongoing pregnancy, implantation and miscarriage rates. Study quality was assessed using the RoB2 tool by Cochrane. Participants/materials, setting, methods Data from the identified RCTs were extracted to examine whether the ESHRE definition of RIF was met. Specifically, whether RCTs were performed in patients &amp;lt;35 years of age with three unsuccessful embryo transfers(ETs) or in patients between 35 and 39 years of age with four unsuccessful ETs, or in patients aged 40 and above with six unsuccessful ETs, when embryos of unknown euploidy were used or in patients with &amp;gt;2 failed ETs of euploid embryos. Main results and the role of chance Systematic review: Twelve RCTs published between 2019 and 2022 were identified, evaluating the effect of intrauterine infusion of PRP in women with RIF, undergoing IVF, transferring embryos of unknown euploidy(1596 women). Although, the majority of the RCTs identified suggested a positive effect of intrauterine PRP infusion on the probability of pregnancy in patients with RIF, a great heterogeneity was present regarding the definition of RIF, especially considering the number of previous failed ETs, that range from at least one to more than three. Moreover, the number of failed ETs used to define RIF did not take into consideration female age, as suggested in the ESHRE definition of RIF. In two out of the twelve RCTs, patients evaluated were less than 35 years of age, which is one the age groups used by ESHRE for the definition of RIF. However, in these studies, patient with less than three failed ETs were included (1-5). Overall, in none of the RCTs identified, the ESHRE definition of RIF was met and thus, a meta-analysis to accept or refute a beneficial role of intrauterine infusion of PRP was not possible. Limitations, reasons for caution Although it is expected that RCTs published prior to the ESHRE definition of RIF are unlikely to meet the criteria proposed, it should be clear that currently no RCTs exist to accept or refute the beneficial role of intrauterine PRP on the probability of pregnancy in these patients. Wider implications of the findings It is likely that the beneficial role of intrauterine PRP infusion on the probability of pregnancy, observed in the relevant RCTs, included in previously published meta-analyses, does not apply to patients with RIF, according to the definition criteria proposed by ESHRE. Therefore, additional RCTs conforming to this definition are required. Trial registration number Under process in Prospero

P-799 Augmenting endometrial thickness and implantation rates: investigating the efficacy of autologous blood cell derivative - endosera in women struggling with thin endometrium and infertility

Abstract Study question Could autologous platelet derived growth factor based strategies promote endometrial growth in women with refractory thin endometrium resulting in sustained implantation and live births? Summary answer Autologous platelet derived growth factor based strategies remarkably promote endometrial thickness and receptivity in women with refractory thin endometrium and pregnancy outcomes What is known already Repeated implantation failure (RIF) attributed to thin endometrium poses significant challenge in reproductive medicine. In cases where conventional treatments prove ineffective, couples often contemplate stressful option of surrogacy. Regenerative strategies, such as platelet-rich plasma (PRP), exhibit promise by capitalizing on anti-inflammatory and pro-regenerative attributes of platelet-derived growth factors. Recognizing the imperative for anti-inflammatory microenvironment conducive to successful implantation, Endosera, a cell-free growth factors concentrate tailored for implantation has been formulated. This study seeks to evaluate the effectiveness of Endosera in augmenting endometrial thickness and implantation rates, offering potential remedies for RIF and thin endometrium. Study design, size, duration In this prospective self-controlled study 62 women (24-47 years) were enrolled spanning May 2021 to December 2023. Women experienced &amp;gt;2 failed IVF cycles and multiple cycle cancellations due to refractory thin endometrium with poor endometrial receptivity defined as endometrial thickness of &amp;lt; 7mm despite standard medical therapy, abnormal endometrial pattern and suboptimal endometrialvascularity, negative hysteroscopic screening for endometrial pathology, and negative bacteriologicscreening and despite multiple failed conventional therapies were selected to undergo Endosera treatment. Participants/materials, setting, methods After obtaining informed consent, patients underwent three intrauterine infusions of Endosera on menstrual cycle Day 7, Day 12, and 2 days before frozen embryo transfer (FET). Alongside standard hormone replacement therapy (HRT), 0.8 ml of Endosera was introduced into the uterine cavity. Pregnancy confirmation relied on a positive serum β-HCG test two weeks post-ET, while clinical pregnancy was established by detecting fetal heartbeat through transvaginal ultrasound four weeks post-ET. Main results and the role of chance In this study involving 62 patients facing multiple cancelled IVF cycles due to refractory thin endometrium, the administration of three doses of Endosera demonstrated significant positive outcomes. Average endometrial thickness notably increased from 6.2 ± 1.2 mm to 8.4 ± 1.2 mm (P &amp;lt; 0.0001) after the 2nd Endosera dose, reaching an optimal thickness of ≥ 8mm. Among the participants, 43 achieved positive pregnancy result (69.4%), with 26 (41.9%) delivering healthy babies and 7 (11.3%) uneventful ongoing pregnancies. Poor outcomes included for 2 (3.2%) patients cycle was cancelled due to no endometrial improvement 5(8.1%) miscarriages before 10 weeks, while 12 (19.4%) women didn’t conceive and for 4.8%(3) patients results awaited post ET. No adverse effects were reported, indicating safety of Endosera.Cumulative positive pregnancy outcomes recorded to be 53.2% (33). The formulation, standardized to contain 6-9 times higher growth factor levels than peripheral blood, emphasizes implantation-friendly and anti-inflammatory cytokines. This optimized composition aligns with cyclical requirements of the endometrial phases (proliferation, secretion, and implantation), creating an angiogenic and anti-inflammatory environment crucial for successful implantation. Endosera’s safety, reproducibility, and efficacy in mimicking natural tissue repair and regeneration processes position it as promising solution for refractory thin endometrium-related challenges. Limitations, reasons for caution This study, though demonstrating improved outcomes in refractory thin endometrium cases with Endosera treatment, acknowledges limitations such as a small sample size and absence of a randomized control group. To establish Endosera as a routine adjuvant in IVF, larger study with stringent inclusion criteria for refractory thin endometrium is recommended. Wider implications of the findings Endosera demonstrated notable success with significant improvement in implantation, pregnancy, and live birth rates for refractory thin endometrium patients prompts rigorous randomized controlled studies. These will include diverse populations, validating results and offering patients hope to reduce financial and psychological stress and challenges associated with cycle cancellations and surrogacy. Trial registration number Not Applicable

P-329 Evaluating Implansera, autologous platelet-derived growth factors, to improve clinical pregnancy and live birth rates in frozen embryo transfer for women with recurrent implantation failure

Abstract Study question Can Implansera, Autologous Platelet-Derived Growth Factors, serve as a promising adjuvant therapy in assisted reproductive techniques to enhance endometrial thickness and implantation rates? Summary answer Use of Implansera significantly increased clinical pregnancy and Live Birth Rate In Patients With repeated implantation failure during FET cycles. What is known already Insufficient endometrial thickness and receptivity contribute to Recurrent Implantation Failure (RIF), prompting consideration of surrogacy. Despite global rise in Frozen Embryo Transfer (FET), quest for an optimal implantation protocol persists. Recent research highlights platelet-rich plasma (PRP) as promising solution for thin endometrium and RIF cases, attributing positive outcomes to PRP’s high growth factor concentration. Recognizing the need for precise platelet and growth factor concentrations, Implansera—a specialized platelet-derived growth factor concentrate—was developed. This innovation addresses the challenge of unresponsive endometrium, offering tailored solution to maximize therapeutic efficacy and improve pregnancy outcomes for patients facing RIF issues. Study design, size, duration Conducted from May 2021 to December 2023, this prospective interventional self-controlled study focused on 21 women (aged 30-48) experiencing recurrent IVF failure due to stubborn thin endometrium. Selected after negative hysteroscopic and bacteriologic screenings, and unsuccessful pregnancies despite multiple immune therapy regimens, such as intralipid and granulocyte colony-stimulating factor infusions, steroids, and endometrial scratching. The subjects underwent Implansera treatment, aiming to address refractory thin endometrium and potentially enhance their chances of successful conception. Participants/materials, setting, methods After obtaining informed consent women with at least two previous unexplained RIF, who were candidates for frozen-thawed embryo transfer were treated with intrauterine infusion of 0.8 ml of Implansera was infused into uterine cavity in addition to standard HRT protocols 2 days before ET. Clinical pregnancy was determined by positive serum β-HCG, 2weeks after ET and presence of fetal heart beat in trans-vaginal ultrasound 5weeks after ET. Main results and the role of chance Among 21 women, 10 achieved pregnancy (47.6%), while 11 did not conceive (52.4%). Clinical outcomes varied: 1 woman (4.8%) experienced chemical pregnancy, 3 (14.3%) miscarried before 6-12 weeks, 3 (14.3%) delivered healthy full-term babies, and 3 (14.3%) are in the 24th week of uneventful gestation accounts for 28.6% cumulative successful pregnancy outcomes. Implansera treatment yielded no reported adverse effects.Implansera, prepared through a patented proprietary process, standardized to contain 6-9 times higher growth factors than peripheral blood, particularly implantation-friendly and anti-inflammatory cytokines, addresses the crucial angiogenic and anti-inflammatory requirements for successful implantation. Tailored for the cyclical demands of endometrial proliferation, secretion, and implantation phases, it efficiently restores impaired uterine environments.Beyond efficacy, Implansera’s safety, reproducibility, and effectiveness in emulating natural tissue repair and regeneration processes are noteworthy. Studies underscore the significance of creating an environment conducive to successful implantation, and Implansera’s composition aligns with these requirements. Its capacity to mimic natural processes positions it as a promising solution, offering a comprehensive approach to enhancing endometrial receptivity, thus optimizing conditions for successful pregnancies. Limitations, reasons for caution This self-controlled prospective study, albeit with small sample size and lacking randomized control group, aligns with published data in demonstrating Implansera’s benefits. Proposing larger studies, particularly with unexplained RIF, to establish Implansera as routine IVF adjuvant. Further investigations aim to identify active molecules influencing implantation and suggest targeted recommendations. Wider implications of the findings Implansera improved implantation, pregnancy, and live birth rates (LBR) in unexplained RIF patients which indicates clearly endometrial thickness and receptivity improvement and motivated us to plan randomized controlled studies to confirm the results and provide opportunity for women with unexplained RIF to conceive and deliver in lesser number of cycles. Trial registration number Not applicable

P-305 Enhancing endometrial thickness and implantation rates: a study on the effectiveness of autologous blood cell derivative - endosera in infertile women with thin endometrium

Abstract Study question Could personalized regenerative medicine based strategies promote endometrial growth and receptivity in women with refractory thin endometrium resulting in successful implantation and live births? Summary answer Personalized regenerative medicine based strategies remarkably promote endometrial growth and receptivity in women with refractory thin endometrium resulting in successful implantation and live births. What is known already Repeated implantation failure (RIF) due to thin endometrium is a formidable challenge in reproductive medicine, often steering couples toward the stressful option of surrogacy. Regenerative approaches like platelet-rich plasma (PRP) have shown promise, leveraging the anti-inflammatory and pro-regenerative properties of platelet-derived growth factors. Recognizing the need for an anti-inflammatory milieu for successful implantation, Endosera, a cell-free implantation-friendly growth factors concentrate, has been developed. This study at Bloom IVF Centre-Mumbai, India, aims to assess Endosera’s efficacy in enhancing endometrial thickness and implantation rates, providing potential solutions for RIF and thin endometrium. Study design, size, duration In this prospective self-controlled study 72 women (27-49 years) were enrolled spanning December 2022 to December 2023. Women experienced two or more failed IVF cycles and multiple cycle cancellations due to refractory thin endometrium, negative hysteroscopic screening for endometrial pathology, and negative bacteriologic screening and despite multiple failed conventional therapies were selected to undergo Endosera treatment. Participants/materials, setting, methods After obtaining informed consent, patients underwent three intrauterine infusions of Endosera on menstrual cycle Day 7, Day 12, and 2 days before frozen embryo transfer (FET). Alongside standard hormone replacement therapy (HRT), Endosera was introduced into the uterine cavity. Pregnancy confirmation relied on a positive serum β-HCG test two weeks post-ET, while clinical pregnancy was established by detecting fetal heartbeat through transvaginal ultrasound four weeks post-ET. Main results and the role of chance In this study involving 72 patients facing recurrent implantation failure due to refractory thin endometrium, the administration of three doses of Endosera demonstrated significant positive outcomes. The average endometrial thickness notably increased from 6.4 ± 1.1 mm to 8.7 ± 1.0 mm (P &amp;lt; 0.0001) after the 2nd Endosera dose, reaching an optimal thickness of ≥ 7mm. Among the participants, 34 achieved a positive pregnancy result (47.2%), with 6 (8.3%) delivering healthy babies and 23 (31.9%) experiencing ongoing clinical pregnancies. Adverse outcomes included 2 (2.8%) ectopic pregnancies and 3 (4.2%) miscarriages before 10 weeks, while 36 (50%) women returned negative HCG results. No adverse effects were reported, indicating the safety of Endosera. The formulation, standardized to contain 6-9 times higher growth factor levels than peripheral blood, emphasizes implantation-friendly and anti-inflammatory cytokines. This optimized composition aligns with the cyclical requirements of the endometrial phases (proliferation, secretion, and implantation), creating an angiogenic and anti-inflammatory environment crucial for successful implantation. Endosera’s safety, reproducibility, and efficacy in mimicking natural tissue repair and regeneration processes position it as a promising solution for refractory thin endometrium-related challenges. Limitations, reasons for caution This study, though demonstrating improved outcomes in refractory thin endometrium cases with Endosera treatment, acknowledges limitations such as small sample size and absence of a randomized control group. To establish Endosera as a routine adjuvant in IVF, a larger study with stringent inclusion criteria for refractory thin endometrium is recommended. Wider implications of the findings Endosera demonstrated notable success with significant improvement in implantation, pregnancy, and live birth rates for refractory thin endometrium patients prompts rigorous randomized controlled studies. These will include diverse populations, validating results and offering patients hope to reduce financial and psychological stress and challenges associated with cycle cancellations and surrogacy. Trial registration number Not applicable

Eff ect of platelet-rich autoplasma on endometrial thickness and receptor sensitivity to estrogen and progesterone.

The effect of platelet-rich autoplasma on endometrial thickness and receptor sensitivity to estrogen and progesterone. This prospective clinical study included 200 patients. The participants in the study were divided into two groups. The first control group received hormone replacement therapy (HRT). The second study group received an intrauterine infusion of platelet-rich autoplasma (PRP group). On the 19th day of the menstrual cycle, an ultrasound examination was performed to assess endometrial thickness, as well as an immunohistochemical analysis to determine receptor sensitivity to estrogen and progesterone. In the course of the study, we found that the use of platelet-rich autoplasma increased the thickness of the endometrium by 0.85 mm; the average thickness of the endometrium in the group who received PRP therapy was 8.25 (8.25-8.61) mm; and in the group of patients who only received HRT, it was 7.40 (7.34-7.65) mm. The sensitivity of receptors to estrogen in the experimental group increased by 3.5, in the experimental group it was 75.00 (71.43-74.22), and in the control group it was 71.50 (67.05-70.85). The sensitivity of receptors to progesterone also increased by 9.0, in the experimental group it was 95.0 (91.4-93.8), and in the control group it was 86.0 (83.47-86.27). Due to the action of platelet factors, PRP therapy has a positive effect on the endometrium, increasing its thickness and improving its receptivity. Therefore, it can be concluded that this method can find great practical application to improve the outcomes of assisted reproductive technology programs.

Autologous platelet-rich plasma as a potential new approach in the endometrial response during in vitro fertilization cycle: A pilot study

Objectives: Infertility is a global health concern, affecting ~13% of couples. Despite assisted reproductive technology (ART) attempts, implantation failure occurs due to inadequate growth of the endometrium. Increasing endometrial thickness (ET) can be increased to improve the rate of pregnancy; implantation necessitates a minimum thickness of 7 mm. Platelet-rich plasma (PRP) is a recommended treatment approach for endometrium and ovarian infertility. This approach minimizes the potential of immunogenic reactions and disease transmission because PRP comes from an autologous source. The purpose of this study was to evaluate the efficacy of PRP intrauterine infusions during the in vitro fertilization (IVF) cycle in patients with thin endometrium. Material and Methods: Ten patients with primary infertility (age: 28–40 years) were chosen for intrauterine PRP infusion at the RiSSA IVF Center, Delhi. This study was carried out between June 2020 and January 2022 over a span of 18-month period. Intrauterine infusion of PRP was an additional procedure to hormone replacement therapy (HRT) treatment cycle. PRP was prepared by centrifugation process from autologous blood. On the 10th day of HRT cycle, 2 mL of PRP was infused into the uterine cavity. In each cycle, PRP infusion was administered 1–3 times if there was no increase in ET 72 hours later. Out of ten patients, four patients received a single infusion, two patients received two infusions, and four patients received three infusions. The embryos were transferred when the ET reached ≥7 mm. ET was measured at the uterine longitudinal axis at the thickest point. To determine ET, three measurements were made, and the average of those measures was noted. The primary outcome measure was ET, determined by transvaginal sonography, and the secondary outcome measure was clinical pregnancy following embryo transfer. Results: The mean increase in ET was 1.8–2.25 mm. In 8 (80%) patients, there was an increase of 7–7.5 mm in ET. ET thickness did not improve in 2 patients (20%), and it was &lt;6 mm after three infusions of PRP. Further, of the eight patients who had embryo transfer and became pregnant, six patients had a clinical pregnancy with visible cardiac activity at 6 weeks, while two patients had a missed abortion in the first trimester. Six patients had a successful delivery. Conclusion: This study revealed that PRP could support endometrial growth, improving pregnancy outcomes in patients who have thin endometrium. PRP is a novel treatment option for endometrial thinning and poor response to IVF. The findings of the current pilot study support the need for large-scale, randomized, controlled trials in this field.

Intrauterine Infusion and Hysteroscopic Injection of Autologous Platelet-Rich Plasma for Patients with a Persistent Thin Endometrium: A Prospective Case-Control Study.

Objectives: To evaluate the effect of intrauterine infusion and hysteroscopic injection of autologous platelet-rich plasma (PRP) in patients with a persistent thin endometrium (EM) undergoing euploid frozen embryo transfer (EFET) cycles. Methods: This prospective case-control study enrolled 116 infertile women with thin EM (<7 mm) who underwent hormone replacement therapy (HRT) for EFET. These women had experienced at least one previous unsuccessful EFET cycle, which either resulted in the cancellation of the cycle or failure of pregnancy. A total of 55 women received an intrauterine infusion of PRP before FET, 38 received a hysteroscopic injection of PRP, and 23 received standard HRT treatment without PRP (control group). Only euploid embryos were transferred in these cycles. The primary outcomes were the implantation rate (IR) and clinical pregnancy rate (CPR) after EFET. Results: After receiving intrauterine infusion and hysteroscopic injection of PRP, 78.2% and 55.3% of patients, respectively, showed an EM thickness exceeding 7 mm, followed by embryo transfer. The hysteroscopic injection group demonstrated significantly higher IR (52%), a higher trend of CPR (52%), and a higher live birth rate (38%) than the control group (18%, 22%, and 4%). Conclusions: Intrauterine infusion and hysteroscopic injection of autologous PRP may be effective methods to increase EM thickness in HRT cycles. According to our results, both methods could increase EM thickness, while hysteroscopic injection appeared to provide more significant assistance in increasing IR, CPR, and live birth rate after EFET in patients with persistent thin EM.

New advances in the treatment of thin endometrium.

Thin endometrium (TE) is defined as a mid-luteal endometrial thickness ≤7mm. TE can affect endometrial tolerance, leading to lower embryo implantation rates and clinical pregnancy rates, and is also associated with impaired outcomes from assisted reproductive treatment. Herein, we systematically review TE causes, mechanisms, and treatments. TE pathogenesis has multiple causes, with the endometrium becoming thinner with age under hormonal influence. In addition, uterine cavity factors are important, as the inflammatory environment may affect expressions of certain genes thereby inhibiting endometrial stromal cell proliferation and promoting apoptosis. Long-term oral contraceptive use or the use of ovulation-promoting drugs are also definite factors contributing to endometrial thinning. Other patients have primary factors, for which the clinical etiology remains unknown. The main therapeutic strategies available for TE are pharmacological (including hormonal and vasoactive drugs), regenerative medicine, intrauterine infusion of growth factor-granulocyte colony-stimulating factor, autologous platelet-rich plasma, and complementary alternative therapies (including traditional Chinese herbal medicine and acupuncture). However, the associated mechanisms of action are currently unclear. Clinical scholars have proposed various approaches to improve treatment outcomes in patients with TE, and are exploring the principles of efficacy, offering potentials for novel treatments. It is hoped that this will improve TE tolerance, increase embryo implantation rates, and help more couples with infertility with effective treatments.

Endometrial responsiveness to interferon-tau and its association with subsequent reproductive performance in dairy heifers

Our objectives were to evaluate the endometrial responsiveness of dairy heifers to an intrauterine infusion of recombinant bovine interferon-tau (rbIFN-τ) and to associate endometrial responses to rbIFN-τ with subsequent reproductive performance. In experiments 1 and 2, cyclic heifers were enrolled in a program for synchronization of the estrous cycle, and blood sampling and ultrasonography examinations were performed on d 0, 4, 7, 11, and 14 of the estrous cycle. In experiment 1, heifers were randomly assigned to receive an intrauterine infusion containing 2 µg of rbIFN-τ (rbIFN-τ = 19) or saline control (CTRL = 19) into the uterine horn ipsilateral to the corpus luteum (CL) on d 14 of the estrous cycle. Then, 6 hours after the infusion, the infused uterine horn was flushed for sampling of the uterine luminal fluid (ULF) for composition analysis, and the endometrium was biopsied for transcriptomics. In experiment 2, 100 heifers received an intrauterine infusion of rbIFN-τ, and the same procedures for uterine sample collection were performed as described in experiment 1. After the intrauterine test, heifers were enrolled in a breeding program and classified as highly fertile (HF; pregnant at first AI) or subfertile (SF; not pregnant at first AI). Statistical analyses were performed using regression models, which included the effects of treatment (experiment 1: CTRL vs. rbIFN-τ) or fertility group (experiment 2: HF vs. SF) and block of samples. Intrauterine infusion of rbIFN-τ increased the expression of classical interferon-stimulated genes in the endometrium (e.g., ISG15, MX1, OAS2, IRF9, and USP18), and an antiviral response was predicted to be the main downstream effect of the transcriptome changes. In addition, rbIFN-τ increased the abundance of cholesterol, glycerol, and the overall concentration of oxylipins in the ULF. Analysis of endometrial transcriptome between HF and SF heifers revealed important differences in the expression of genes associated with cell signaling, metabolism, attachment, and migration, with a large representation of genes encoding extracellular matrix proteins. In general, differentially expressed genes were expected to be downregulated by IFN-τ but seemed to fail to be downregulated in SF heifers, resulting in higher expression in SF compared with HF heifers. Subfertile heifers had lower concentrations of glycerol and an altered profile of oxylipins in the ULF, with a lower abundance of oxylipins derived from arachidonic acid and dihomo-γ-linolenic acid, and a greater abundance of oxylipins derived from linoleic acid. Measurements of ovarian function did not differ between groups and, therefore, did not influence the observed results in uterine biology. Overall, the endometrial responsiveness to IFN-τ is variable among individuals and associated with subsequent fertility of heifers, indicating that communication between conceptus and endometrium is critical for the uterine receptivity and survival of pregnancy.