Previous Implantation Failures Research Articles

O-029 Atosiban in women with previous single implantation failure undergoing frozen-thawed blastocyst transfer: a placebo-controlled randomized trial

Abstract Study question Does the administration of Atosiban before frozen-thawed blastocyst transfer improve the live birth rate in women with a history of a single implantation failure? Summary answer In women with a single implantation failure undergoing frozen-thawed blastocyst transfer, Atosiban did not improve the ongoing pregnancy rate. What is known already Uterine peristalsis preceding embryo transfer is believed to adversely impact the success rates of IVF. Atosiban can reduce uterine peristalsis and act as a role of oxytocin antagonist. The effectiveness of Atosiban in the general population of IVF patients has not been conclusively shown by randomised clinical trials or meta-analyses. It has been suggested that women with previous implantation failure may potentially benefit from the use of Atosiban, particularly in the presence of uterine peristalsis. We aim to evaluate if Atosiban before embryo transfer increases live birth rate in women undergoing frozen-thawed blastocyst transfer? Study design, size, duration We conducted a single-centre, double-blind placebo randomised controlled trial (RCT) in women with previous single implantation failure undergoing frozen-thawed blastocyst transfer. Between July 2019 and June 2023, we randomised 1,100 participants to either Atosiban or placebo. The primary outcome was live birth (≥20 weeks of gestation) in the first FET after randomization. In this abstract, we present results on ongoing pregnancy. Data on live birth will be available at the conference. Participants/materials, setting, methods We randomised women with a history of one failed fresh or frozen blastocyst, with at least one cryopreserved blastocyst into two groups on the day of transfer. In the Atosiban group, women were administered 37.5mg of Atosiban intravenously 30-min prior to FET. In the placebo group, women received a saline infusion for the same duration. Uterine peristalsis was measured using transvaginal ultrasound prior to administration of study drugs. The analysis was done based on intention-to-treat. Main results and the role of chance The ongoing pregnancy rates were 50.46% (277/549) and 46.82% (258/551) in the Atosiban and control groups, respectively (RR 1.08, 95% CI 0.95 to 1.22, P = .23). Uterine peristalsis was measured in 720 (65%) of all participants. Within this cohort, of the 163 (22%) women with abnormal contractions, the ongoing pregnancy rates were 51.9% and 41.7%, respectively (RR 1.25, 95% CI 0.90 to 1.73, P = .19). Among 208 women (29%) with peristalsis but without abnormal contraction waves, ongoing pregnancy rates were 50.9% and 48.0% (RR 1.06, 95% CI 0.81 to 1.40, P = .67). In 349 women (48%) without peristalsis, the ongoing pregnancy rates were 48.6% in the Atosiban group versus 50.6% in the control group (RR 0.96, 95% CI 0.78 to 1.19, P = .71). Limitations, reasons for caution Our study only included women with previous blastocyst implantation failure. Uterine peristalsis was not initially assessed, resulting in only 65% (720/1,100) of the participants having peristalsis measured. In this abstract, we only report on the ongoing pregnancy rate. We will present data on live birth at the congress. Wider implications of the findings In unselected women undergoing frozen-thawed blastocyst transfer with previous single implantation failure, Atosiban does not enhance the ongoing pregnancy rate. Future research regarding Atosiban in IVF should assess uterine peristalsis and focus on women with abnormal contractions. Trial registration number ChiCTR1900022333

P-307 Evaluation of pregnancy rates post-probiotic treatment in patients with varied Lactobacillus species in pre-transfer endometrial microbiome analysis

Abstract Study question Are there differences in clinical outcomes based on the predominant species of Lactobacillus in the endometrium of patients treated with probiotics? Summary answer No discernible variations in clinical outcomes were noted based on the Lactobacillus species identified in the pre-transfer microbiome analysis after personalized probiotic treatment. What is known already Lactobacillus is the genus with the greatest presence in the female reproductive tract. They are responsible for acidifying the environment and play an important role in the prevention of excessive proliferation of pathogens through different mechanisms (competitive inhibition or production of antimicrobial compounds). Among the species of Lactobacillus, crispatus, iners, jensenii and gasseri are the most frequent in the endometrium. Lactobacillus species share some genus-specific characteristics. However, there are differences in the production of antimicrobial compounds among the species: L. iners has a lower production of hydrogen peroxide and lower anti-inflammatory capacity and therefore has lower protective capacity against pathogens. Study design, size, duration A retrospective study analyzed with 209 endometrial samples from 164 patients with previous implantation failure or miscarriage (average age= 41.47-/+4.66 years). Patients underwent endometrial microbiota testing between May 2021 and December 2022. Following analysis, patients received personalized probiotic treatment based on results, particularly tailored for L. iners overgrowth. One hundred and thirty-five patients underwent an embryo transfer after completing the treatment. Participants/materials, setting, methods DNA from endometrial biopsies was analyzed to detect bacteria, fungi and viruses. To evaluate the potential impact of L. iners presence, clinical outcomes were calculated across patient groups with varying percentages of this Lactobacillus species. These rates were compared to those of L. crispatus, known as the most favourable species. Furthermore, the analysis subdivided the detected percentages of each species into differente ranges to discern potential variations in clinical outcomes based on the percentage levels. Main results and the role of chance The overall implantation rate following probiotic and antibiotic treatment (as needed) was 52.59%, with a clinical pregnancy rate of 46.67%. Notably, no statistically significant differences were observed in between patients with a dominant Lactobacillus microbiome (>90%) and those without prior to the treatments. These findings were anticipated, given the probiotic treatment’s inclusion of Lactobacillus strains, which foster an acidic environment conducive to the establishment of endometrial Lactobacillus species. Interestingly, regardless of the percentage of L. crispatus detected in the endometrial biopsy prior to probiotic treatment, implantation rates remained consistently above 50%, with no statistically significant differences observed. Conversely, patients with a high percentage of L. iners (>75%) exhibited a lower implantation rate of 38%, though this disparity was not statistically significant compared to patients with a high percentage of L. crispatus. No statistically significant differences were observed in the clinical outcomes comparing L. crispatus and L. iners. However, high % of L. crispatus was associated with a lower miscarriage rate compared to high % of L. iners (13%vs22%, respectively). This may be attributed to the treatment administered prior transfer, which aims to rebalance Lactobacillus composition, especially in cases of L. iners dominance. Limitations, reasons for caution All patients included in this study underwent personalized probiotic treatment before embryo transfer, limiting the ability to directly assess the impact of L. iners on pregnancy outcomes. Additionally, increasing the number of patients would strengthen the study’s findings and confirm the observed findings. Wider implications of the findings Microbiota studies can effectively identify various species within the same genus (Lactobacillus spp). Personalized probiotic treatment appeared to balance endometrial microbiota, not only increasing the percentage of Lactobacillus in patients with a non- dominant Lactobacillus environment, but also modify the type of Lactobacillus species that are present in the endometrium. Trial registration number not applicable

P-446 Personalization of the euploid embryo transfer guided by the endometrial receptivity analysis in patients with >1 previous failed transfer

Abstract Study question Does personalized embryo transfer (pET) guided by Endometrial Receptivity Analysis (ERA) increase reproductive outcome in patients with >1 previous failed transfer of an euploid embryo? Summary answer pET guided by ERA resulted in a significantly higher Pregnancy Rate (PR), Ongoing Pregnancy Rate (OGPR) and Live Birth Rate (LBR) versus standard embryo transfer. What is known already pET consists of synchronizing embryo transfer with the optimal endometrial receptivity status by the transcriptomics identification of the personalized window of implantation (WOI). Euploid transfers improve reproductive outcome controlling the embryo contribution in the implantation. Controversial results have been published regarding the clinical usefulness of pET in a range of clinical indications. Here we present data from patients with >1 previous failed embryo transfer (ET) in a subsequent euploid ET. Study design, size, duration Multicenter retrospective study involving 270 patients with at least one previous implantation failure between 2017 and 2021. These patients were divided into two groups according to their subsequent transfer: study group (pET guided by ERA) (n = 200), and control group (standard transfer) (n = 70). All the ET were done in Hormone Replacement Therapy cycles (HRT). PR, OGPR and LBR were compared between the two groups. Participants/materials, setting, methods Age, body mass index, previous failed attempts, inner cell mass (ICM) and trophectoderm (TE) quality of the transferred embryos were compared between the groups. Study group had an ERA result as standard WOI or displaced WOI and pET of an euploid embryo was carried out in a subsequent HRT cycle (following the same conditions and recommendations provided by ERA). Wilcoxon rank sum test was applied to quantitative comparations. Chi-square test was done for categorical variables. Main results and the role of chance Clinical results in terms of PR, OGPR and LBR were significantly higher when pET guided by ERA was performed when compared to the non-ERA group. PR was 65% (130/200) in pET versus 37.14% (26/70) in control group (P = 0.000088); OGPR was 49% (98/200) in pET versus 27.14% (19/70) in control group (P = 0.0024); and LBR was 48.20% (95/197) in pET versus 26.09% (18/69) in control group (P = 0.0022). Control and demographics variables did not show differences between the two groups: Age: 35.27 ± 3.86 versus 35.77 ± 3.35 (P = 0.31); BMI: 22.99 ± 3.02 versus 23.25 ± 3.72 (P = 0.52); Previous failed attempts: 2.42 ±1.78 versus 2.17 ±1.81 (P = 0.32); P values where 0.1 and 0.36 for comparisons of optimal quality of ICM and TE, respectively. Limitations, reasons for caution This is a retrospective study, having the limitations of its nature. Wider implications of the findings These results show that pET guided by the ERA test of an euploid embryo significantly increases the reproductive outcomes (PR, OGPR and LBR) in patients with ≥1 previous failed transfer compared to the standard frozen ET. Trial registration number Hospital Clínico de Valencia Ethic Committee approval nº. 2021/018.

P-109 Non-invasive Genetic Testing (niPGTA) and Laser Assisted Hatching (LAH) may improve pregnancy and ongoing pregnancy rates in patients of advanced maternal age

Abstract Study question Does niPGTA and LAH improve pregnancy and ongoing pregnancy rates in patients of advanced maternal age? Summary answer niPGTA increases pregnancy and clinical pregnancy rates in patients aged ≥38 years compared to those without tested embryos, while LAH may further improve pregnancy outcomes. What is known already Embryos release cell-free DNA (cf-DNA) in the IVF culture media, which can be analyzed for chromosomal constitution. The benefit that niPGTA holds over PGT-A is that it is a non-invasive test and could potentially produce comparable results. Therefore, the time to pregnancy and the risk of miscarriage could be reduced in comparison to an IVF treatment with non-tested embryos. Previous studies have shown high concordance with trophectoderm biopsies in PGT-A patients and improved outcomes with LAH in frozen-thawed cycles. However, there is a lack of studies investigating clinical pregnancy rates with niPGTA. Study design, size, duration Retrospective cohort study including 74 patients aged ≥38 years, who underwent Single Frozen Embryo Transfer (FET) from May 2021 to February 2023. Patients who had Endometrial Receptivity Assay (ERA) were excluded. Participants/materials, setting, methods 32 couples had niPGTA; Spent Blastocyst Media (SBM) for each blastocyst were collected on Day 6 and analyzed using the EMBRACE test. Embryos were vitrified. 42 couples had their blastocysts vitrified on Day 5/6 without testing. LAH was introduced to all patients in October 2021. Before that, no LAH was performed. Embryos were transferred to patients 2 hours post-warming after LAH. Pregnancy test was performed 10 days after FET and clinical pregnancy was established. Main results and the role of chance There was a statistical significant increase of pregnancy rate (p = 0.017, Pearson’s Chi-Squared test) and a trend towards higher clinical pregnancy rate for niPGTA patients versus those who had a transfer of not tested embryos. Regarding LAH, there was a trend towards higher pregnancy and clinical pregnancy rates in both niPGTA and not tested group. Results for pregnancies and clinical pregnancies are presented in Table 1. Limitations, reasons for caution More patients are required to confirm clinical significance of pregnancy and clinical pregnancy rates of niPGTA over not tested embryos and if LAH can improve the outcomes. A review of patients who had previous implantation failures and miscarriages in addition to ERA could yield clearer conclusions. Wider implications of the findings The results of this study are encouraging for niPGTA combined with LAH for patients aged ≥38 years. Further studies on niPGTA and modifications of the protocol for increased concordance rates and shorter time in embryo culture should be explored. Trial registration number Not applicable

Analysis of predictors of clinical pregnancy and live birth in patients with RIF treated with IVF-ET technology: a cohort study based on a propensity score approach.

To investigate the predictors of clinical pregnancy and live birth rate in patients with recurrent embryo implantation failure (RIF) treated with in vitro fertilization-embryo transfer (IVF-ET) technique. This retrospective cohort study was conducted in Jinjiang District Maternal and Child Health Hospital, Chengdu City, Sichuan Province, China. Patients were recruited who were enrolled at this hospital between November 1, 2019 and August 31, 2022, and who met the following criteria: a frozen embryo transfer (FET) at day 5 or 6 blastocyst stage was performed and the number of transfer cycles was not less than two. We collected information on age, height, weight, number of embryo transfer cycles, and information related to clinical outcomes. We used the group of patients who underwent ERA testing as the study group and those who underwent FET only as the control group, and matched baseline characteristics between the two groups by propensity score to make them comparable. We compared the differences in clinical outcomes between the two groups and further explored predictors of pregnancy and live birth using survival analysis and COX regression modeling. The success rate of clinical pregnancy in RIF patients was 50.74% and the live birth rate was 33.09%. Patients in the FET group were less likely to achieve clinical pregnancy compared to the ERA group (HR = 0.788, 95%CI 0.593-0.978, p < 0.05). Patients with >3 previous implantation failures had a lower probability of achieving a clinical pregnancy (HR = 0.058, 95%CI 0.026-0.128, p < 0.05) and a lower likelihood of a live birth (HR = 0.055, 95%CI 0.019-0.160, p < 0.05), compared to patients with ≤3 previous implantation failures. Patients who had two embryos transferred were more likely to achieve a clinical pregnancy (HR = 1.357, 95%CI 1.079-1.889, p < 0.05) and a higher likelihood of a live birth (HR = 1.845, 95%CI 1.170-2.910, p < 0.05) than patients who had a single embryo transfer. Patients with concomitant high-quality embryo transfer were more likely to achieve a clinical pregnancy compared to those without high-quality embryo transfer (HR = 1.917, 95%CI 1.225-1.863, p < 0.05). Not receiving an ERA, having >3 previous implantation failures, using single embryo transfer and not transferring quality embryos are predictors for clinical pregnancy in patients with RIF. Having>3 previous implantation failures and using single embryo transfer were predictors for live birth in patients with RIF.

Clinical effectiveness of spindle-view intracytoplasmic sperm injection compared to conventional intracytoplasmic sperm injection in patients with poor ovarian response and previous implantation failure.

This study aimed to determine the clinical advantage of spindle-view intracytoplasmic sperm injection (SVICSI; a novel technology) over conventional intracytoplasmic sperm injection (cICSI) in patients with poor ovarian response (POR) and previous implantation failure. The study included 37 patients who underwent SVICSI followed by fresh embryo transfer (FET) at a single fertility clinic from January to December 2022, 58 patients who underwent cICSI followed by FET at the same fertility clinic from January to December 2021 as a control group. All study participants met the Bologna criteria for POR and had at least three or more previous failed embryo transfers. The number of blastocyst transfers was significantly higher in the SVICSI group than in the cICSI group. A good-quality cleavage embryo rate, blastocyst rate, and good-quality blastocyst rate were also significantly higher in the SVICSI group than in the cICSI group. There were no significant differences in the rates of fertilization, implantation, clinical pregnancy, or clinical abortion between the two groups. In patients with POR, those who underwent SVICSI appeared to have better embryos than those who underwent cICSI. However, whether SVICSI improved clinical outcomes such as implantation and pregnancy rates cannot be proven.

The number of previous implantation failures is a critical determinant of intrauterine autologous platelet-rich plasma infusion success in women with recurrent implantation failure.

We aimed to identify factors influencing the reproductive outcomes of frozen-thawed embryo transfer (FET) with intrauterine autologous platelet-rich plasma (PRP) infusion in patients with either a thin endometrium or recurrent implantation failure (RIF) despite a normal endometrial appearance. In this retrospective study of women who underwent PRP-FET, factors influencing PRP-FET outcomes were identified using multivariate logistic regression analysis. We enrolled 111 patients (70 with refractory thin endometrium and 41 with RIF but no thin endometrium). For 99 completed FET cycles, the β-hCG positivity rate was 46.7%, clinical pregnancy rate (CPR) was 41.0%, and live birth rate (LBR) was 36.2%. PRP treatment was associated with significant improvements over previous cycles, and participants with thin endometria demonstrated thickening. Multivariate logistic regression analysis showed that the number of previous implantation failures in women with RIF was a significant factor affecting the PRP-FET outcomes. The CPR and LBR of women with RIF were lower when there had been ≥3 previous implantation failures occurred. Intrauterine PRP infusion improves the pregnancy outcomes of patients with RIF or a thin endometrium. The number of previous implantation failures is a critical determinant of successful intrauterine PRP infusions in women with RIF.

Effectiveness of atosiban in women with previous single implantation failure undergoing frozen-thawed blastocyst transfer: study protocol for a randomised controlled trial

BackgroundUterine contractions may interfere with embryo implantation in assisted reproductive technology. To reduce these contractions and improve success rates, the oxytocin antagonist atosiban has been suggested for administration during embryo...

Impact of the number of previous embryo implantation failures on IVF/ICSI-ET pregnancy outcomes in patients younger than 40 years: a retrospective cohort study.

The objective of this study was to examine the influence of repeated embryo implantation failures on pregnancy outcomes among patients under 40 years of age undergoing in vitro fertilization/intracytoplasmic sperm injection embryo transfer (IVF/ICSI-ET). A retrospective analysis was conducted on the clinical data of 13,172 patients who underwent 16,975 IVF/ICSI-ET treatment cycles at Henan Reproductive Hospital between January 1, 2015, and December 31, 2018. Patients were categorized into four groups based on the number of previous embryo implantation failure cycles: Group A=no implantation failure, Group B= 1 implantation failure, Group C=2 implantation failures, Group D=≥3 implantation failures. Baseline characteristics and pregnancy outcomes were compared among the four groups. The impact of the number of previous embryo implantation failures on pregnancy outcomes among IVF/ICSI-ET patients was investigated using univariate and multiple regression analyses. Univariate logistic regression analysis demonstrated that factors such as the number of previous embryo implantation failures, female age, basal follicle count, endometrial thickness, total number of oocytes retrieved, type of cycle, number of high-quality embryos transferred, and stage of embryo development significantly affected implantation rate, clinical pregnancy rate, early spontaneous abortion rate, and live birth rate (all P < 0.05). The duration of infertility and anti-Mullerian hormone (AMH) levels were also found to influence implantation rate, clinical pregnancy rate, and live birth rate (all P < 0.05). Upon conducting multivariate logistic regression analysis and adjusting for confounding factors such as age, AMH levels, basal follicle count, endometrial thickness, total number of oocytes obtained, cycle type, number of high-quality embryos transferred, ovarian stimulation protocol, and stage of embryo development, it was revealed that, compared to Group A, Groups B, C, and D exhibited significantly lower implantation and live birth rates, as well as a significantly higher risk of early spontaneous abortion (all P < 0.05). The number of previous embryo implantation failures is an independent factor affecting implantation rate, clinical pregnancy rate, spontaneous abortion rate and live birth rate of patients underwent IVF/ICSI-ET. With the increase of the number of previous embryo implantation failures, the implantation rate, clinical pregnancy rate and live birth rate of patients underwent IVF/ICSI-ET decreased significantly, and the rate of early spontaneous abortion gradually increased.

P-503 Immunological therapies in women undergoing assisted conception: a systematic review and meta-analysis

Abstract Study question What is the effectiveness and safety of immunological therapies in women undergoing assisted conception? Summary answer The evidence on the overall effectiveness and safety of immunomodulators was scarce and uncertain, although some drugs may lead to improved outcomes in selected women. What is known already Embryo implantation is a pre-requisite for pregnancy success. It requires a state of immune tolerance within the maternal endometrium permitting the attachment and subsequent invasion into the decidua of the semi-allogenic blastocyst. Mechanistic data suggesting that heightened immune responses may impair implantation have led to the widespread use of immunomodulatory therapies in clinical practice. These include drugs such as aspirin, heparin, corticosteroids, intralipid and intravenous immunoglobulin (IVIG). However, despite the common use of immunomodulatory drugs in women having in vitro fertilisation (IVF), there is no consensus on their effectiveness and safety, owing to a paucity of well-designed interventional studies. Study design, size, duration We searched MEDLINE, EMBASE, PubMed and CENTRAL until September 2022. We selected randomised controlled trials (RCTs) investigating immunological therapies in women undergoing IVF, including aspirin, heparin, corticosteroids, granulocyte-colony stimulating factor (G-CSF), intralipid, intravenous immunoglobulin (IVIG), tumour necrosis factor-alpha inhibitors and peripheral blood mononuclear cells (PBMCs), evaluated alone or in combination, versus no intervention, placebo or any other immunomodulator(s). The primary outcomes were the rates of live birth or ongoing pregnancy (LBR/OPR) and miscarriage per participant. Participants/materials, setting, methods Two reviewers independently selected studies and extracted data. We conducted pairwise meta-analyses according to participants’ phenotypes as reported by the trialists, including: good prognosis, previous implantation failure, autoimmunity, high inflammation, thin endometrium, and low ovarian reserve. Using the Cochrane-RoB-1 tool, we restricted our primary analyses to RCTs at low risk of selection and other biases. We presented effect estimates as risk ratio (RR) with 95% confidence interval (CI) and considered I2&amp;gt;50% as representing substantial heterogeneity. Main results and the role of chance Our searches identified 14,893 records. We included a total of 84 studies in the qualitative synthesis, of which 43 contributed to the meta-analyses, evaluating in total 7,301 participants and 12 treatment comparisons. The primary analysis showed that aspirin resulted in little to no difference in LBR (RR 0.97, 95% CI 0.94-1.23; n = 688 women; moderate-certainty evidence) and MR (RR 1.20, 95% CI 0.73-1.99; n = 988 women; low-certainty evidence) compared with placebo. The data did not identify a difference in LBR/OPR in women using subcutaneous heparin (RR 1.30, 95% CI 0.80-2.12; n = 150 women; very low-certainty evidence) or IVIG (RR 1.28, 95% CI 0.32-5.16; n = 51 women; very low-certainty evidence) versus placebo. For the remaining interventions, the primary analysis was uncertain of an effect or insufficient for quantitative synthesis. However, the sensitivity analysis including all studies, irrespective of risk of bias, showed that corticosteroids may improve LBR in women with thyroid autoimmunity (RR 2.33, 95% CI 1.04-5.25; n = 60 women; very low-certainty evidence); intrauterine G-CSF may improve LBR in women with a thin endometrium (RR 2.57, 95% CI 1.24-5.29; n = 304 women; very low-certainty evidence); and intrauterine PBMCs may improve LBR in women with previous implantation failure (RR 2.03, 95% CI 1.33-3.10; n = 312 women; very low-certainty evidence). Limitations, reasons for caution For most of the interventions under study, the evidence was of low or very-low certainty, owing to limitations in study design, imprecision, indirectness and inconsistency. Further, very few studies reported on adverse events, highlighting a worrying lack of data on the safety of immunological therapies for women undergoing assisted conception. Wider implications of the findings A scarcity of well-designed RCTs limits the evidence on immunomodulators in women undergoing IVF. However, we identified positive signals for some therapies in specific conditions (e.g. corticosteroids for thyroid autoimmunity, intrauterine G-CSF for thin endometrium, and PBMCs in women with previous implantation failure). This merits further investigation in high-quality trials. Trial registration number PROSPERO registration number CRD42021294031

P-485 Performance of ERA test after PGT-A in RIF patients defined according to ESHRE 2023 good practice recommendations: a retrospective case-control study

Abstract Study question Is Endometrial-Receptivity-Array (ERA) test clinically-useful among Repeated-Implantation-Failure (RIF) women defined according to ESHRE 2023 good-practice-recommendations (GPR) and undergoing single euploid blastocyst transfer? Summary answer ERA-test showed a higher “non-receptive endometrium” rate among RIF. Nevertheless, the live-birth-rate (LBR) per first euploid transfer was independent from progesterone timing according to ERA-test. What is known already ERA-test evaluates the expression of 238 genes from an endometrial biopsy. It aims at predicting the window of implantation and adjust progesterone timing accordingly. The data are controversial due to poor study design and/or limited sample size. Few studies investigated ERA-test in a setting with euploid transfers and/or among RIF patients. Moreover, RIF definition is largely inconsistent leading to a significant bias in the interpretation of the existing literature and treatment. ESHRE 2023 GPR revised RIF definition. Here, we leveraged this updated definition and PGT-A to assess ERA-test diagnostic/therapeutic performance in these women. Study design, size, duration Retrospective case-control study during 2013-2021 including 2211 patients with at least one euploid blastocyst after PGT-A. Hysteroscopy was conducted in case of suspect uterine pathologies, biopsy in case of suspect inflammation, and therapy in case of endometritis. 265 patients (12%) were classified RIF according to the ESHRE GPR (= no successful implantation despite an estimated cumulative chance ≥60%). 48 RIF patients requested ERA-test before undergoing vitrified-warmed euploid single blastocyst transfer, while 217 did not. Participants/materials, setting, methods qPCR/NGS-based PGT-A was conducted to assess non-mosaic aneuploidies. Normal thyroid function, vitamin-D levels, uterine cavity, and absence of sactosalpynx were confirmed. Whenever the ERA test suggested altered receptivity, progesterone timing was modified accordingly. The primary outcome was LBR per first euploid transfer in the non-ERA versus ERA groups, with a sub-analysis in ERA receptive versus non-receptive. Outcomes were adjusted for confounders assessed via logistic regressions. Main results and the role of chance RIF patients requesting ERA-test were older (39.1±4.5 versus 36.7±3.5 years, p &amp;lt; 0.01), and had already undergone 3.7±2.0 transfers resulted in implantation failures (1.5±1.3 of euploid blastocysts) versus 2.6±1.7 transfers (1.0±0.8 of which of euploid blastocysts) in the control (p &amp;lt; 0.01). Nevertheless, all these variables were not associated with the primary outcome under investigation. 44 non-RIF patients requested ERA-test in the same study period. Notably, the rate of pre-/post-receptive endometria was 39.6% (N = 19/48) among RIF and 13.6% (N = 6/44) among non-RIF women (p &amp;lt; 0.01). In fact, maternal age was not associated with “non-receptive” responses after ERA-test, the number of previous implantation failures showed an Odds-Ratio 1.29, 95%CI 1.03-1.62, p = 0.03. Blastocyst quality and day of full-blastulation were similar in ERA and non-ERA patients, as well as in ERA receptive and non-receptive patients. Positive pregnancy test, biochemical-pregnancy-loss, and miscarriage rates were all similar among non-ERA and ERA, and among ERA receptive and non-receptive patients. Indeed, also the LBR was similar among non-ERA and ERA (N = 98/220, 44.5% versus N = 17/48, 35.4%, p = 0.26; Odds-Ratio adjusted for blastocyst quality and day of full-blastulation: 0.76, 95%CI:0.39.1.48, p = 0.42) and among ERA receptive and non-receptive patients (N = 10/29, 34.5% versus N = 7/19, 36.8%, p = 0.99; Odds-Ratio adjusted for blastocyst quality and day of full-blastulation: 0.99, 95%CI:0.3-3.4, p = 0.99). Limitations, reasons for caution Our standard clinical workflow does not entail ERA-test, but the couple may request it. The study is retrospective with limited sample size. Patients requesting ERA-test were older with more previous failures. Non-ERA and ERA receptive patients underwent either Hormone-Replacement-Therapy or Modified-Natural-Cycle. Cost-effectiveness analyses are missing. Wider implications of the findings A promising association was reported between the novel definition of RIF and “non-receptive” responses, suggesting that ERA-test might unveil endometrial receptivity issues. Nevertheless, positive, and negative predictive values upon implantation are largely missing and its clinical utility as a therapeutic tool in RIF women remains questionable. Trial registration number none

Low Molecular Weight Heparin-Aspirin-Prednisolone Combination Does Not Increase the Live Birth Rate in Recurrent Implantation Failure: A Retrospective Cohort Study.

This study investigates the triple combination of adjuvants (low molecular weight heparin (LMWH)-aspirin-prednisolone) whether it improves the live birth rates of IVF&ICSI patients with previous implantation failure. This retrospective study included 1095 patients with >2 failed either fresh or frozen single embryo transfer cycles between 2014 Jan and 2021 Jan. Patients were divided into two subgroups. Group A consisted of patients with only vaginal progesterone for luteal phase support. Group B consisted of patients with triple (daily subcutaneous LMWH, daily 150 mg aspirin, and daily 16 mg prednisolone) luteal phase supplementation to vaginal progesterone. Demographic parameters, cycle characteristics, embryology, and pregnancy outcomes were compared, and the study's primary outcome was the live birth rate. Demographic parameters were similar between the groups. Positive b-hCG, miscarriage, and live birth rates were similar between groups as Group A vs. Group B, positive b-hCG 30.8% (190/617) vs. 35.4% (169/478), miscarriage rates 4.4% (27/617) vs. 6.7% (32/478), and live birth rates 20.4% (126/617) vs. 23.8% (114/478), respectively. When patients were stratified according to previous failures, live birth rates were still similar. Pregnancy outcomes were significantly improved in only patients with diminished ovarian reserve (Group A vs. Group B, positive b-hCG 24.2% vs. 34.3%, live birth rate 12.1% vs. 21.9%, p < 0.01). Whether the embryo transfer was fresh or frozen-thawed did not affect the results. A combined supplementation of LMWH, aspirin, and prednisolone in the luteal phase does not improve live birth rates of IVF&ICSI patients with previous implantation failure except potentially for patients with diminished ovarian reserve.

Association of rs1570360 and rs2010963 in VEGF and rs2279744 in the MDM2 gene with Recurrent Implantation Failure in Iranian Women.

The embryo implantation includes a complex sequence of signaling events, comprising numerous molecular mediators, such as ovarian hormones, cytokines, adhesion molecules and, growth factors. One of the critical factors in angiogenesis is the vascular endothelial growth factor (VEGF). The VEGF plays a pivotal role in embryonic development, decidua vascularization and placental angiogenesis. Furthermore, the P53 gene and its negative regulator, murine double minute 2 (MDM2), are major players in reproductive processes. This study aimed to assess the association of polymorphisms of the VEGF and the MDM2 genes with idiopathic recurrent implantation failure. We genotyped 60 women with previous idiopathic recurrent implantation failures and 60 fertile women as controls. Restriction Fragment Length Polymorphism (RFLP) and Sanger sequencing were used for genotyping the rs2010963 and the rs1570360 polymorphisms in VEGF; and the rs2279744 in MDM2 genes. Results indicated a higher frequency of the VEGF rs1570360 AA genotype and A allele in patients with a history of idiopathic implantation failure [OR=6.4 (1.22 - 33.64), p-value=0.02)]. However, the frequency of VEGF +405 G/C and MDM2 SNP309 T/G [(OR=3 (0.5 - 16) p-value=0.2, OR=1.18 (0.3 - 3.7) p-value=0.7, respectively)] genotypes were not significantly different between cases and controls. The VEGF polymorphism may influence embryo implantation and the VEGF rs1570360 AA genotype may predispose to the risk of recurrent implantation failure after IVF.

İmplantasyon Başarısızlığı Olan Hastalarda Donmuş Embriyo Transferi Öncesi Histeroskopik Cerrahinin Etkisi

Aim: The aim of this study was to evaluate the benefit of hysteroscopy (HS) before single frozen-thawed embryo transfer (sFET) on patients with previous implantation failure. Material and Methods: A total of 1352 infertile women with a previous implantation failure who underwent their first sFET treatment between January 2015 and December 2017 were included in this study. The patients were classified into two main groups in which HS was omitted (Group 1), and who underwent HS (Group 2). Furthermore, Group 2 was classified into two subgroups as patients without any intrauterine pathology (Group 2a), and those with intrauterine pathology (Group 2b). sFET was performed on all patients within 50 days of hysteroscopy. The major outcome measure was the clinical pregnancy rate. Results: The mean number of mature oocytes and fertilization rates were similar between groups. The clinical pregnancy rate was found to be 33.3% (n=70) in Group 1. Comparatively this rate was statistically significantly higher in patients in Group 2. The clinical pregnancy rate was 44.2% (n=378) in Group 2a, and 44.4% (n=127) in Group 2b (p=0.014). There was a significant difference between Group 1 and Group 2a (OR: 1.58, 95% CI: 1.15-2.17, p=0.004), and also Group 2b (OR: 1.59, 95% CI: 1.10-2.31, p=0.013). However, no significant difference was observed between Group 2a and Group 2b (p=0.896). Conclusion: Our findings demonstrate that HS surgery increases the probability of pregnancy rate at least by 1.58 times in patients having previous implantation failure when the hysteroscopic procedure is followed by sFET.

Adjustment of progesterone administration after endometrial transcriptomic analysis does not improve reproductive outcomes in women with adenomyosis

Research questionDo patients with adenomyosis present a dysregulated endometrial receptivity that can be reversed with personalized embryo transfer (PET) by transcriptomic-based progesterone adjustment, improving IVF outcomes? DesignA multicentre, retrospective, cohort study that transcriptomically analysed the endometrial receptivity of the endometrium in patients with adenomyosis (n = 81) and healthy women (n = 231). Subsequently, implantation, biochemical and clinical miscarriage, and live birth rates between adenomyosis patients with one previous implantation failure using donor oocytes who received (n = 59) or did not receive (n = 66) PET based on endometrial receptivity, were observed to evaluate if adjusted progesterone improves reproductive outcomes of adenomyosis patients. ResultsPatients with adenomyosis significantly presented an altered endometrial receptivity (non-receptive) compared with healthy patients (53.1% versus 37.2%, P = 0.0179), elevating the risk of adenomyosis patients having a non-receptive endometrium 42.59% higher (95% CI 41.50 to 44.45). No significant differences were found in implantation (62.7% versus 78.8%, P = 0.0514), biochemical (13.5% versus 3.9%, P = 0.1223) and clinical (10.8% versus 15.4%, P = 0.7543) miscarriage, or live birth rates (75.7% versus 80.8%, P = 0.6066), in patients with PET compared with those without PET. ConclusionsWomen with adenomyosis presented an altered expression of genes involved in decidualization, and a higher rate of non-receptive endometrial statuses than controls. Although progesterone is indispensable for implantation, adjusting progesterone before PET, using endometrial transcriptomic signatures, does not improve IVF outcomes in patients with adenomyosis. Other molecular mechanisms beyond progesterone regulation may be involved in implantation failure.

Autologous platelet-rich plasma intrauterine perfusion to improve pregnancy outcomes after implantation failure: A systematic review and meta-analysis.

Previous studies have reported inconsistent findings on the efficacy of platelet-rich plasma (PRP) therapy in women with implantation failure. The objective of this review was to evaluate whether PRP administration could improve pregnancy outcomes in women with implantation failure undergoing in vitro fertilization. Electronic databases were searched for studies that explored the effects of PRP for patients with implantation failure. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Based on the available data, we performed subgroup analyses and sensitivity analyses. Eight studies were included. PRP treatment improved pregnancy outcomes for all women compared with no treatment or placebo (clinical pregnancy rate: OR 2.24, 95% CI 1.41-3.54; live birth rate: OR 5.76, 95% CI 1.55-21.44; miscarriage rate: OR 0.18, 95% CI 0.05-0.63), especially in randomized controlled trials. No significant differences were detected in multiple pregnancy rates (OR 2.54, 95% CI 0.67-9.67). Furthermore, subgroup analysis based on the number of previous implantation failures showed that PRP treatment improved pregnancy outcomes in women with recurrent implantation failure (clinical pregnancy rate: OR 2.55, 95% CI 1.49-4.38; live birth rate: OR 5.07, 95% CI 1.15-22.34; miscarriage rate: OR 0.20, 95% CI 0.05-0.78). PRP administration could improve pregnancy outcomes in women with recurrent implantation failure. Due to the limited evidence available, the efficacy of PRP in women with recurrent implantation failure needs to be further verified in high-quality studies with larger sample sizes.

Case Report: Successful Pregnancy and Birth of a Healthy Baby with PGT-A for Woman with Advanced Maternal Age

Introduction: The most common cause of failed implantation and miscarriage is embryonic aneuploidy and the risk of aneuploidy increases significantly with increasing maternal age. Pre-implantation genetic testing for aneuploidy (PGT-A) can be an option to improve the prognosis of women with advanced maternal age by extracting 3-5 trophectoderm cells from Day 5 and Day 6 blastocysts for genetic testing. Case History: A 37 years old patient tried to conceive for 5 years was recruited into our PGS research study initiated by Ministry of Health in Singapore. She had 3 previous implantation failure and one miscarriage between 2015-2018. The patient had regular menses every 30-35 days. Antral follicle count was 48 and her husband’s semen analysis was normal with Density 87 million/ml, motility 34% and morphology 4%. Results: Patient underwent an IVF cycle with PGT-A in December 2018 at our IVF Centre. 23 eggs were retrieved, 21 eggs were mature to undergo ICSI and 11 fertilized. The eggs were cultured in EmbryoGen immediately after ICSI and the embryos were transferred to BlastGen on Day 3 for extended culture. A total of 5 embryos were suitable for biopsy, 3 on Day 5 and 2 on Day 6. Embryos were vitrified while waiting for the genetic results. Chromosomal analysis of the biopsied trophectoderm cells was performed using NGS platform. Out of the 5 embryos tested, 2 embryos were euploid, giving 60% aneuploidy rate. One euploid embryo was thawed and transferred in a regulated frozen-thawed cycle in March 2020. The patient became pregnant and delivered a healthy baby boy. She returned in January 2022 to put back the remaining euploid embryo, she was again pregnant. Conclusion: PGT-A for comprehensive chromosome screening in selecting and transferring euploid embryos in assisted reproduction has an immediate impact on implantation, reduces the rate of clinical miscarriages and results in higher live birth rates.

Contribution of immunology to build precision medicine in reproduction: present and future

Infertility affects millions of people of reproductive age. The failure of a blastocyst to implant is a leading cause of psychological distress. It became increasingly evident that an effective immune dialogue occurs at each step in the fluids surrounding the oocyte, the spermatozoa, the embryo, or the endometrium. Exploring and deciphering this dialogue could potentially help understand why 50% of healthy euploid blastocysts fail to implant. Introducing immunology into reproductive medicine requires a change of mindset to bring immune hypothesis to clinical applications. Implantation of an embryo requires a prepared uterus in order to dialogue with the embryo, which is able to express and repair itself. Exploring the uterine immune profile of patients with previous implantation failures (IF) or recurrent miscarriages (RM) has already been developed and is under evaluation as a precision tool to equilibrate the uterine environment before implantation to increase the subsequent live birth rate after the embryo transfer. Immunology may also be fundamental in the future to identify through non-invasive procedure the competence of oocytes or embryos through reliable immune biomarkers quantified in follicular fluids or embryo supernatants during the in vitro fertilization (IVF) process. Non-invasive biomarkers would allow physicians to identify competent oocytes or embryos based on their ability to communicate with the mother and their energetic potential for all the self-repair processes that should occur during the preimplantation and the implantation period. This area of research is only beginning.

P-419 Does adjuvant usage in the luteal phase improve live birth rates of ICSI - ET patients with previous implantation failure?

Abstract Study question Does adjuvant usage in the luteal phase improve live birth rates of ICSI-ET (intracytoplasmic sperm injection - embryo transfer) patients with previous implantation failure? Summary answer Combination of low molecular weight heparin, aspirin, and prednisolone in the luteal phase doesn't improve live birth rates of ICSI-ET patients with previous implantation failure. What is known already RIF affects around 10% of patients undergoing IVF worldwide. The exact pathology of implantation failure, although transferring a good quality embryo, is still unknown. There are numerous treatment options, However, there is no conclusive evidence that prophylactic treatment improves the pregnancy rate in infertile women during IVF. Study design, size, duration This retrospective study included 1095 patients with &amp;gt; 2 failed either fresh or frozen embryo transfer cycles between 2014 Jan – 2021 Jan. Participants/materials, setting, methods Patients were divided into two groups. Group-A consisted of patients with only vaginal progesterone for luteal phase support. Group-B consisted of patients with triple (daily subcutaneous low molecular weight heparin, daily p.o. 150 mg aspirin, and daily p.o. 16 mg prednisolone) luteal phase supplementation to vaginal progesterone. Demographic parameters, cycle characteristics, embryology, and pregnancy outcomes were compared, and the live birth rate was the study's primary outcome. Main results and the role of chance There were 5910 ICSI&amp;ET cycles between the years Jan 2014 and Jan 2021. A total of 3853 Patients with single day5-6 good quality blastocyst transfer was selected from the database, and appropriate patients for inclusion criteria with at least two previous failure implantation history were included. As a result, a total of 1095 fresh or frozen-thawed ET cycles were included in the study. There were 617 patients without (Group A) and 478 patients with adjuvant use (Group B). Demographic parameters were similar between groups. Although higher embryology outcomes (Group A vs. B, No.of oocyte; 11 (7-17) vs. 13 (8-19), No. of MII; 9(5-14) vs. 10 (6-15), No. of 2PN; 5 (3-9) vs. 6 (4-10), p &amp;lt; 0.01), positive b-hCG rates, miscarriage rates, live birth rates were similar between groups (Group A vs. B, positive b-hCG; 30.8% (190/617) vs. 35.4% (169/478), Miscarriage rates; 4.4% (27/617) vs. 6.7% (32/478), Live Birth Rates; 20.4% (126/617) vs. 23.8% (114/478)). When the live birth rates were stratified depending on the number of previous failed transferred cycles, the live birth rates were still comparable between the groups. Limitations, reasons for caution The study's retrospective design limits the power of the results. The study's main limitation is the lack of the euploidy information of transferred embryos. Wider implications of the findings Our findings suggest that empirical usage of adjuvants such as low molecular weight heparin, aspirin, and prednisolone does not improve live birth rates in patients with previous implantation failure. These results support the present literature. Trial registration number Not applicable

P-340 The endometrial switch following progesterone exposure correlates with uterine peristalsis

Abstract Study question What is the effect of the changes of the endometrium following progesterone exposure on uterine peristalsis? Summary answer Uteri with a greater increase endometrial thickness after progesterone exposure have significantly greater uterine peristalsis (UP). Therefore, endometrial compaction is associated with quieter uteri. What is known already Endometrial compaction is considered a sign of adequate response to progesterone. However, it is not always possible to visualize it. Little is known about endometrial switch following progesterone and its consequences after frozen embryo transfer, although it is hypothesized that increased endometrial growth after the window of implantation may be related to an increase in endogenous or exogenous oestrogen causing impairment of progesterone function. On the other hand, the role of progesterone in inhibiting endometrial contractile function is well known. Consequently, both the change in endometrial thickness and uterine contractility are indicators of progesterone function. Study design, size, duration This retrospective observational was carried out in Instituto Bernabeu of Alicante. The study included 215 patients with at least three previous implantation failures after egg donation treatment, which underwent uterine peristalsis assessment the day of embryo transfer from June 2017 to December 2021. Participants/materials, setting, methods UP assessment was performed using 4D ultrasound, recording a video for 6 minutes. UP variable was split in quartiles, and then the last quartile (UP ≥ 1,5 contractions per minute) was considered the hypercontractility group. All patients had performed an ultrasound to assess endometrial thickness between 7 to 10 days before embryo transfer. Endometrial compaction has been considered when it has decreased. Endometrial switch (ES) is considered the percentage between both endometrial measures. Main results and the role of chance The mean age of patients was 40,11 years who underwent an average of 3,75 embryo transfers. The average UP was 1,09 contractions per minute. The average ES was 9% of increased endometrium. Only 83 (38,6%) patients had endometrial compaction. To assess the association between UP and endometrial switch after progesterone exposure a univariate assessment was performed using Pearson’s correlation resulting in a negative correlation (r=-0,16; p = 0,019). It was used the hypercontractility group for performing bivariate logistic regression was performed to examine the effect of independent variables (previous miscarriages, previous pregnancies, C-section, endometriosis, adenomyosis, myomatosis and endometrial preparation) on ES. Greater ES is statistically associated to greater UP with OR 1,013 (95%IC: 1,002 to 1,025; p = 0,041). Limitations, reasons for caution It is a retrospective study based in patients with multiple implantation failure. It is possible that our conclusions couldn't be the same in patients with good prognosis. Wider implications of the findings Assessment of endometrial changes and uterine peristalsis provide information about the response of the uterus to progesterone exposure. However, more studies assessing it prospectively both would be interesting to define which population has high risk to develop situations with inadequate progesterone response. Trial registration number Not applicable