Repeated Implantation Failure Research Articles

Clinical Relevance of Vaginal and Endometrial Microbiome Investigation in Women with Repeated Implantation Failure and Recurrent Pregnancy Loss.

Recent studies have investigated if and how the vaginal and endometrial microbiome might affect endometrial receptivity and reproductive health. Although there is no consensus on the existence of a core uterine microbiome yet, evidence shows that the dominance of Lactobacillus spp. in the female reproductive tract is generally associated with eubiosis and improved chances of successful implantation and an ongoing pregnancy. Conversely, vaginal and endometrial dysbiosis can cause local inflammation and an increase of pro-inflammatory cytokines, compromising the integrity and receptivity of the endometrial mucosa and potentially hampering successful embryonic implantation. This review provides a critical appraisal of the influence of the vaginal and endometrial microbiome as parts of the female reproductive tract on fertility outcomes, focusing on repeated implantation failure (RIF) and recurrent pregnancy loss (RPL). It seems that RIF as well as RPL are both associated with an increase in microbiome diversity and a loss of Lactobacillus dominance in the lower female reproductive system.

Research progress on the STAT signaling pathway in pregnancy and pregnancy-associated disorders.

Signal transducer and activator of transcription (STAT) proteins, pivotal regulators of signaling cascades, undergo activation in response to the stimulation of cytokines and growth factors, and participate in biological processes, including inflammation, immune responses, cell proliferation, and differentiation. During the process of pregnancy, STAT signaling is involved in regulating embryonic implantation, endometrial decidualization, and establishing and maintaining maternal-fetal immune tolerance. Increasing evidence suggests that aberrant STAT signaling contributes to the occurrence and development of pregnancy disorders, including repeated implantation failure (RIF), preeclampsia (PE), recurrent spontaneous abortion (RSA), preterm birth (PTB) and gestational diabetes mellitus (GDM). Elucidating the molecular mechanisms of the STAT signaling pathway holds promise for further understanding the establishment and maintenance of normal pregnancy, and thereby providing potent targets and strategic avenues for the prevention and management of ailments associated with pregnancy. In this review, we summarized the roles of the STAT signaling pathway and its related regulatory function in embryonic implantation, endometrial decidualization, and maternal-fetal immune tolerance. In conclusion, in-depth research on the mechanism of the STAT signaling pathway not only enhances our understanding of normal pregnancy processes but also offers STAT-based therapeutic approaches to protect women from the burden of pregnancy-related disorders.

Basic Research Advances in China on Embryo Implantation, Placentation, and Parturition

Abstract This review aimed to summarize the major progress in maternal-fetal medicine achieved by Chinese scientists in recent years. PubMed was systematically searched from January 2020 to November 2023. Publications that reported the progress in embryo implantation, placentation, and parturition made by Chinese scientists in the last 3 years were selected. The milestone events during gestation, embryo implantation, endometrial decidualization, placentation, and parturition are pivotal to a successful pregnancy. Embryo implantation requires intricate interactions between implantation-competent blastocysts and receptive endometrium. To adapt to pregnancy, endometrial stromal cells transform into specialized decidual cells, which occur spontaneously under the influence of ovarian hormones in humans but require the presence of embryos in mice. With embryonic development, the placenta forms to support fetal growth until parturition. The maternal-fetal interface is composed of diverse cell types, including endometrial decidual cells, placental trophoblast cells, endothelial cells, and various immune cells, a sophisticated interplay among which contributes to the maintenance of pregnancy. Near term, the uterus transitions from quiescence to contractility, in preparation for delivery. Disruptions to these events lead to pregnancy-related disorders such as repeated implantation failure, recurrent pregnancy loss, preeclampsia, fetal growth restriction, preterm birth, and infertility. In recent years, Chinese scientists have made prominent achievements in basic research on the aforementioned pregnancy events. Chinese scientists have made remarkable contributions to reproductive biology and maternal-fetal medicine research in recent years, highlighting future research directions in this field.

Tacrolimus treatment in women with repeated implantation failures.

Tacrolimus is an immunosuppressive drug that works as a calcineurin inhibitor to improve the reproductive outcomes for women who have experienced multiple implantation failures (RIF) and show elevated type 1 helper T (Th1)/Th2 cell ratios. In the first part of this review, we indicate how we re-evaluated the cut-off index for selecting the participants in a tacrolimus regimen via transferred euploid blastocysts. In the second part, we cite cases where tacrolimus has improved the live birth rate for women who have experienced recurrent pregnancy losses (PRL) and we introduce the utility of tacrolimus treatment to prevent obstetrical complications. After reconsideration of the cut-off index (Th1/Th2 ≥ 11.8), however, the pregnancy rates of women with tacrolimus were significantly higher than those of women without tacrolimus. The PRL women treated with tacrolimus showed significantly lower rates of biochemical pregnancy, but higher live-birth rates compared with women who were not treated with tacrolimus. Moreover, prior severe obstetrical complications could be controlled via the administration of tacrolimus during pregnancy. Tacrolimus has become indispensable in the field of solid-organ transplantation, and in the near future, it should become an essential agent in the reproductive field, as well.

Atosiban application in fresh ET cycle is effective for women undergoing repeated embryo implantation failures, especially for advanced-age obese patients

To assess the effect of atosiban in pregnancy outcomes of the fresh embryo transfer (ET), the retrospective cohort study was conducted. Six hundred and eighty-nine cases (using atosiban) and 1377 age and ET cycle-matched controls were collected from the January 2016 to May 2022 to perform the fresh IVF-ET cycle. The essential characteristics and pregnancy outcomes were analyzed. Conditional logistic regression analysis and subgroup analysis were performed. In the whole samples, atosiban had no effects in the pregnancy outcomes. Subgroup analyses suggested that atosiban could improve the clinical pregnancy in more than 3 ET cycles (OR 1.667, 95% CI 1.108–2.509, P = 0.014). Moreover, the improvement of clinical pregnancy was mainly present in the advanced-age women (age ≥ 35 years: OR 1.851, 95% CI 1.136–3.014, P = 0.013), obesity (BMI ≥ 24 kg/m2: OR 2.550, 95% CI 1.105–5.883, P = 0.028) and cleavage stage embryo (D3 embryo: OR 1.721, 95% CI 1.098–2.696, P = 0.018) among the repeated implantation failures (RIF). Atosiban could also improve the live birth for the obese women. Further, in the RIF, atosiban application was strongly recommended for the advanced-age infertility women, who also had the risk of obesity with the implantation of the cleavage stage embryo. In conclusion, atosiban could improve pregnancy outcomes for the advanced-age and obese women in RIF, especially while implanting the cleavage stage embryo in fresh ET cycle.

Effect of sequential embryo transfer on in vitro fertilization and embryo transfer outcomes: a systematic review and meta-analysis.

Sequential embryo transfer has been recognized as a strategy to increase pregnancy rates in women undergoing in vitro fertilization and embryo transfer (IVF-ET). However, its impact on assisted reproductive outcomes remains to be substantiated by robust evidence. This systematic review aims to summarize and analyze the available evidence to investigate the effect of sequential embryo transfer on assisted reproductive outcomes. A comprehensive literature search was executed across the Pubmed, Cochrane Library, Web of Science, and Scopus databases in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data were aggregated utilizing a random effects model, and the resultant outcomes were articulated as odds ratios (ORs) along with their 95% confidence intervals (CIs). The pooled results revealed a statistically significant enhancement in reproductive outcomes for infertile patients undergoing sequential embryo transfer as evidenced by elevated rates of chemical pregnancy (OR = 1.67, 95% CI = 1.23-2.27), clinical pregnancy (OR = 1.78, 95% CI = 1.43-2.21), and ongoing pregnancy (OR = 1.54, 95% CI = 1.03-2.31). Compared with cleavage-stage embryo transfer, sequential transfer yielded superior outcomes in terms of chemical pregnancy rate (OR = 2.08, 95% CI = 1.35-3.19) and clinical pregnancy rate (OR = 1.78, 95% CI = 1.37-2.31). Furthermore, among the repeated implantation failure (RIF) cohort, sequential embryo transfer surpassed blastocyst-stage transfer, delivering a heightened chemical pregnancy rate (OR = 1.66, 95% CI = 1.19-2.53) and clinical pregnancy rate (OR = 1.65, 95% CI = 1.19-2.27). Our meta-analysis indicates that sequential transfer may enhance clinical pregnancy rate in a small subgroup of well-selected women. While promising, further evidence from prospective studies is needed.

Endometrial NK cells in repeated implantation failure – quantity and functional markers

BACKGROUND: Alteration in the composition and function of endometrial immune cells, in particular NK cells, are associated with implantation and placentation pathology, which is considered as one of the causes of reproductive losses. However, data regarding abnormalities in the number and activity of NK cells in repeated implantation failures, including depending on the type of infertility, remain ambiguous.
 AIM: The aim of this study was to evaluate the number of CD56+ and CD16+ cells and the area of expression of CD107a and NKG2D markers in the endometrium of patients with repeated implantation failure (RIF).
 MATERIALS AND METHODS: This prospective comparative study included patients with RIF (main group I, n = 47), who were divided into two subgroups: Ia, patients with primary infertility (n = 29); Ib, patients with secondary infertility (n = 18). Comparison group II included patients with a history of effective ART programs (n = 17). Control group III included healthy fertile women without a history of reproductive loss (n = 12). Endometrial biopsies were obtained on days 19–23 of the menstrual cycle. The expression of CD56+, CD16+, CD107a and NKG2D was assessed by immunohistochemistry.
 RESULTS: In the endometrium of patients in groups I and II, as compared to the control group, the number of CD56+ cells was significantly increased (p 0.001). In patients of subgroup Ia, when compared to the control group, we verified an increase in the number of CD16+ cells (p 0.05) and a decrease in the expression of CD107a (p 0.05). In patients in groups I and II, a negative correlation was revealed between the number of CD56+ and CD16+ cells and the number of pregnancies in history (rs = –0.30 and rs = –0.34, p 0.05), while a positive correlation was found between the expressions of CD56+ and CD107a (rs = 0.66 and rs = 0.75, p 0.05). In patients in group II, a positive correlation was revealed between the expressions of CD16+ and CD107a (rs = 0.75, p 0.05). In the endometrial stroma, CD107a expression increased significantly in patients in group I (p 0.05), while NKG2D expression increased in groups II and III (p 0.01, p 0.05) from the early to the middle stage of the secretion phase. In patients of group II, a positive correlation was established between the expressions of CD56+ and NKG2D (rs = 0.68, p 0.05).
 CONCLUSIONS: In the endometrium of patients with primary infertility and RIF, the number of CD56+ and CD16+ cells is increased with a decrease in the expression of their activation marker CD107a, which may be a potential mechanism for impaired implantation. Further studies of the immune profile of the endometrium may help to personalize diagnostic and therapeutic approaches to management of patients with RIF and to increase the chances of pregnancy in ART programs.

Evaluation of the effectiveness of third-generation lipid emulsion therapy for early pregnancy loss

BACKGROUND: Immune mechanisms play an important role in the pathogenesis of early pregnancy loss. To regulate disorders of immune homeostasis, immunoefferent therapy is used, such as immunocytotherapy, plasmapheresis, and intravenous administration of immunoglobulins and lipid emulsions, which may help to overcome infertility and recurrent miscarriage. Third-generation lipid emulsion (TGLE) is the modern “gold standard” of parenteral lipid therapy. It contains high concentrations of omega-3-polyunsaturated fatty acids, which can directly or indirectly affect the activity of natural killer (NK) cells. The literature comprises contradictory data on the efficacy of TGLE for repeated implantation failure. This may be due to the determination of biochemical parameters for its use and the selection of criteria for assessing the effectiveness of this therapy.
 AIM: The aim of this study was to evaluate the effectiveness of TGLE therapy in patients with a history of early pregnancy loss.
 MATERIALS AND METHODS: This prospective randomized controlled study enrolled 140 patients with early pregnancy loss (recurrent miscarriage and repeated implantation failure) at the Research Institute of Obstetrics, Gynecology and Reproducto logy named after D.O. Ott, Saint Petersburg, Russia from 2021 to 2023. Group 1 consisted of 50 women with TGLE therapy, and group 2 included 90 women without therapy. Patients of group 1 received lipid therapy according to the following regimen: TGLE 20% IV 6 ml per kilogram of body weight once a month for two months on end. Inclusion criteria: women from 18 to 45 years of age with two cases of reproductive failure – pregnancy loss up to 12 weeks of gestation and/or unsuccessful in vitro fertilization attempts (embryo transfers without effect) with normal karyotypes of the spouses. Exclusion criteria: women with miscarriage with an abnormal karyotype of the fetus, with anatomical abnormalities in the development of the reproductive apparatus, with an abnormal karyotype of any of the spouses, with hypersensitivity to omega-3 polyunsaturated fatty acids. We assessed the omega-3 index, functional characteristics of NK cells in the peripheral blood, and the effectiveness of lipid therapy based on biochemical and immunological parameters, as well as the clinical onset of pregnancy.
 RESULTS: The difference in the omega-3 index before and after treatment with TGLE was significant (p = 0.0002), this parameter being increased by 1.23 times compared to the initial level. The functional activity of NK cells in the blood was significantly different after the administration of TGLE: NK (CD3–CD(16+56+)) (p = 0.0041), NKT (CD3+CD(16+56+)) (p = 0.0498), and spontaneously activated NK (CD107a) (p = 0.0498). These parameters decreased by 1.63, 1.29, and 2.07 times relative to their initial levels. In group 1 of patients receiving TGLE therapy, clinical pregnancy occurred twice as often as compared to those who did not receive this therapy (56.41%, n = 22 vs. 31.25%, n = 20; p = 0.01).
 CONCLUSIONS: TGLE has shown effectiveness in pregnancy rates by increasing the omega-3 index and reducing the functional activity of NK cells in women with early pregnancy loss.

Comparison of Doppler ultrasound indices of uterine artery and sub endometrial blood supply in frozen embryo transfer with and without repeated implantation failure: A cross-sectional study.

Background: Uterine blood supply has been identified as a potential factor in implantation failure. Objective: This study aimed to investigate Doppler indices in the uterine artery, including vascular flow and resistance, as well as the amount of sub-endometrial blood supply in women with a history of repeated implantation failure (RIF) compared to the non-RIF group. Materials and Methods: This cross-sectional study was conducted with 139 women candidates for frozen embryo transfer in Yazd Reproductive Sciences Institute, Yazd, Iran from February to July 2023. Group A (n = 68) included women with a history of more than 2 RIF, and group B (n = 71) included women candidates for implantation for the first time without RIF. Doppler ultrasound indices of uterine artery and sub-endometrium, including sub-endometrial flow, uterine artery flow, uterine artery resistance, and peak systolic velocity, were recorded. Results: No significant differences were observed in uterine artery Doppler pulsatility index and peak systolic velocity between groups, but the uterine artery resistance index was significantly higher in the A group (p 0.001). A significant difference was observed in the perfusion area between groups. 60/68 women in the group A had endometrial perfusion in areas 2 and 3 (p 0.001). Conclusion: Our study revealed that women with RIF exhibited higher resistance index in sub-endometrial arteries compared to the non-RIF group.

The efficacy of intrauterine infusion of platelet rich plasma in women undergoing assisted reproduction: a systematic review and meta-analysis

BackgroundPlatelet-rich plasma (PRP) is an autologous platelet concentration recently used in the reproductive field. Studies had conflicting results regarding its effect on pregnancy outcomes. We aimed to solve the debate on the safety and efficacy of PRP in women undergoing assisted reproduction and assess the influence of covariates on the outcomes of PRP infusion.MethodsWe searched PubMed, Scopus, Cochrane, and Web of Science in May 2023. We included randomized and non-randomized clinical trials as well as cohort studies assessing intrauterine PRP in sub fertile women undergoing assisted reproduction (IVF/ICSI). For the quality assessment, We used the Cochrane Risk of Bias Tool 1, the ROBINS-I tool, and the Newcastle–Ottawa Scale. We pooled the data using RevMan version 5.4.ResultsThe data from 23 studies were pooled. PRP had favorable outcomes compared with the control group on clinical pregnancy rate (RR: 1.84, 95% CI 1.62 to 2.09; P < 0.00001), live birth rate (RR: 1.75, 95% CI: 1.24 to 2.47; P = 0.001), and miscarriages (RR: 0.51, 95% CI: 0.36 to 0.72; P = 0.0002). Women with repeated implantation failure had a significantly improved clinical pregnancy rate (RR: 1.83, 95% CI: 1.49 to 2.24; P < 0.00001), live birth rate (RR:1.83, 95% CI: 1.33 to 2.51; P = 0.002), and miscarriage rate (RR: 0.46, 95% CI: 0.31 to 068; P = 0.0001).ConclusionPRP showed promising results in assisted reproductive techniques. Further large and multicenter RCTs are required to compare the doses of PRP while identifying the specific population with the most benefits from PRP.

#237 : The Application of Noninvasive Implantation Capability Screening (NICS®) Resulted in Improved Clinical Outcomes in Patients with Recurrent Pregnancy Loss or Repeated Implantation Failure

Background and Aims: Chromosomal abnormalities are frequently observed in early human embryos, particularly in patients experiencing repeated pregnancy loss (RPL) or repeated implantation failure (RIF). Although preimplantation genetic testing for aneuploidy (PGT-A) is a common technique for screening embryo ploidy, it comes with the risks associated with embryo biopsy. To address this issue, we developed the NICS assay, which evaluates embryos using spent culture medium (SCM) and thus reduces the risks associated with embryo biopsy. However, further evaluation is required to determine the clinical applicability of NICS for patients with RPL or RIF. Method: This retrospective cohort study analyzed 303 patients with RPL or RIF between July 2018 and May 2021. These patients underwent aneuploidy screening using the NICS assay and were thus categorized into the NICS group. The non-NICS group consisted of patients who received conventional morphology embryo transfer during the same period. Routine intracytoplasmic sperm injection (ICSI) was performed, and the embryos were placed in droplets. Approximately 30 [Formula: see text] L of blastocyst medium from each embryo was transferred into cell lysis buffer, followed by DNA library preparation using the ChromInst kit from Yikon Genomics. Results: In patients with RPL, the NICS group demonstrated significantly lower rates of miscarriage per frozen embryo transfer (FET) than the non-NICS group, 17.9% vs 42.6%. Furthermore, the NICS group exhibited significantly higher rates of ongoing pregnancies (40.7% vs 25.0%) and live births (38.9% vs 20.6%) compared to the non-NICS group. In the case of patients with RIF, the NICS group showed higher clinical pregnancy rates per FET compared to the non-NICS group. Specifically, the clinical pregnancy rates, 46.9% vs 28.7%. Conclusion: The present study demonstrates that the use of NICS for selecting euploid embryos can effectively reduce the incidence of miscarriage in patients experiencing RPL, as well as improve the clinical pregnancy rate in those experiencing RIF.

#199 : Does Hysteroscopic Evaluation of Uterine Characteristic Improve Outcome of Thin Endometrium in Patients with a History of Repeated Implantation Failures?

Background: Repeated implantation failure (RIF) is a problem for many patients suffering from infertility and their physicians. Despite numerous developments in the field of assisted reproduction, the implantation rate remains low. Among the various reasons of implantation failure, endometrial regularity has an important role. Recently, hysteroscopy is an accurate method for evaluating the endometrial integrity, with the ability to treat uterine pathology for repeated implantation failure patients. Objective: The aim of this study to evaluate the incidence of uterine pathology among infertile women with a history of two implantation failures after IVF and estimate the effect of diagnostic hysteroscopy and hysteroscopic procedures in uterine cavity on achieving a pregnancy in these patients in Mongolia. Materials and Methods: The retrospective study population included infertile women who attended the outpatient department of the Creation and Love Women’s infertility clinic, between August 2020 and July 2022 in Mongolia. The study inclusion criteria were women who had more than two RIF of IVF/ET cycle. Pregnancy and nonpregnancy rate after hysteroscopic procedures were analyzed included in patients reports archived in clinical data. Results: Hysteroscopy were performed on 35 women who had at least two RIFs. The participants’ mean age was 40.3±5.3 and mean duration of infertility year was evaluated 5.53±3.7. Mean AMH level was 1.4±1.6 ng/ml. All patients were diagnosed abnormal uterine cavity by hysteroscopy. Out of 35 patients participated in this study who underwent hysteroscopic evaluation, 20 patients (57.1%) showed synechiae (mild, moderate and severe synechiae). Second most frequent hysteroscopic finding was the endometrial polyp, accounting for 15 (42.9%) patients. Pregnancy rate after hysteroscopic procedures was 8 patients (23%) in this study group. The duration of infertility year was significantly different in pregnant and nonpregnant women underwent hysteroscopic correction (p&lt;0.05). Conclusion: The intrauterine pathology diagnosed by hysteroscopy in patients with previous IVF failure were found all patients in this study. The synechiolysis was common abnormality in Mongolia may cause by artificial abortion. The correction of abnormalities such as and polyp synechiolysis might improve the outcome of successful pregnancy rate.

#238 : rsERT Guided Personalized Embryo Transfer Improves Clinical Outcomes in RIF Patients

Background and Aims: Narrowed or shifted window of implantation (WOI) is acknowledged to be one of the endometrial origins of embryo implantation failure, especially in patients with repeated implantation failure (RIF). RNA-Seq-based endometrial receptivity test (rsERT) was developed to assess the endometrial receptivity (ER) and guide the personalized embryo transfer (pET). Clinical studies were conducted to evaluate the clinical utility of rsERT in RIF patients. Method: 566 RIF patients with rsERT and pET in multi-centers from 2019-2022 were included in this retrospective study, which was defined as rsERT-pET group. RIF patients without rsERT and pET in the same period was used as control for comparison. rsERT-pET group was further divided into normal WOI (nWOI) and shifted WOI (sWOI) groups. Clinical pregnancy rate and ongoing pregnancy rate were therefore compared among these groups by nonparametric statistical approaches. Results: The intrauterine pregnancy and ongoing pregnancy rates of rsERT-pET group were receptively 55.0% and 46.2%, which were significantly higher than those of the control group (55.0% vs 35.1%, OR = 2.26, p-value = 2.33×10[Formula: see text]; 46.2% vs 19.8%, OR = 3.45, p-value = 4.08×10[Formula: see text] ). We further evaluated the intrauterine pregnancy rates of sWOI and nWOI and found remarkably better pregnancy outcomes in patients from nWOI group compared to those in sWOI group patients (62.4% vs 50.4%, OR = 1.64, p-value = 0.005). Conclusion: The pET guided by the result of rsERT significantly improved the clinical outcomes in patients with RIF based on the intrauterine pregnancy rate and the ongoing pregnancy rate, indicating the clinical potential of rsERT method.

#196 : Office Hysteroscopy Results in Patients with Recurrent Implantation Failure at Tam Anh General Hospital

Background and Aims: To describe the clinical characteristics and evaluate the results of office hysteroscopy in patients with recurrent implantation failure at Tam Anh General Hospital. Methods: A descriptive study on 151 patients at Tam Anh General Hospital who had failed embryo transfer twice or more consecutively was carried out from January 2021 to March 2023. Results: 151 patients were included in the study, 41,1% of which had unexplained infertility. The mean age and duration of infertility were 34,5 ± 5,2 years and 5,7 ± 3,4 years, respectively. 55,0% of patients exhibited uterine cavity abnormalities during office hysteroscopy, with the most common is endometritis accounting for 29.8%. The median time to perform the procedure was 3 (2) minutes, the mean VAS pain score was 3,2 ± 1,1 points. No complications related to office hysteroscopy were noted. Conclusions: A office hysteroscopy was able to detect intrauterine pathologies which were missed by other investigative modalities. In individuals who have experienced repeated implantation failure, office hysteroscopy is a safe and practical approach that should be recognized as a crucial tool for intrauterine evaluation.

#95 : Analysis of the Incidence of and Risk Factors for Chronic Endometritis Recurrence in Infertile Women

Background and Aims: Chronic endometritis (CE) is an inflammatory condition of the endometrium which is related to repeated implantation failure. Recovery from CE can increase opportunities for successful pregnancy; however, some of them remain incapable of conceiving or have a miscarriage and concern CE recurrence. The aim of this study is to identify the incidence rates of and risk factors for the recurrence of CE in infertile women. Method: The study population consisted of 1,897 infertile women from a hospital specializing in reproductive medicine who recovered from CE between December 2018 and August 2021. Among the 152 women (13.0%) who did not conceive or experienced pregnancy loss, 105 consecutive women who underwent repeat endometrial biopsy for CD138 immunostaining and endometrial bacterial culturing within 18 months from CE recovery were recruited. Thereafter, patients with and without CE recurrence were compared. Results: The total recurrence rate of CE was 29.5% (31 women). Multivariable logistic regression analysis to determine risk factors for CE recurrence revealed that hysteroscopic surgery (odds ratio [OR], 0.10; 95% confidence interval [CI], 0.02–0.56) and pregnancy loss (OR, 4.13; 95% CI, 1.31–13.05) were significantly associated with decreased and increased CE recurrence rates, respectively. Also, re-examination with CD138 immunostaining after 16–18 months (OR, 9.75; 95% CI, 1.47–64.64) was significantly associated with increased CE recurrence rates. Among 40 patients without a history of hysteroscopic surgery and pregnancy loss, the cumulative CE recurrence rates after 6, 12, and 18 months were 12.5%, 23.3%, and 30.0%, respectively (Graph 1). Conclusion: We recommend re-examination with endometrial CD138 immunostaining in patients with pregnancy loss or long-term infertility during fertility treatment. Hysteroscopic surgery without antibiotic therapy for CE associated with intrauterine abnormalities is also recommended.

#130 : Food Intolerance and Conception in Women Suffering Repeated Implantation Failure

Background and Aims: Food-specific immunoglobulins, in combination with the elevated reactive oxygen species and other inflammatory components, have been indicated to represent immunological response to food consumed. This study aimed to investigate the relationship of food intolerance and conception in women receiving IVF treatments. Method: Infertile women who had experienced at least two failed embryo transfer treatments were investigated between June 2017 and August 2021 in TUBE Fertility Clinic. The whole blood 20 mL was taken from cubital vein and complete food panel examination employing ELISA analyses were designed to assay food-specific IgG and IgE antibodies. The levels of IgG antibodies were presented through spectrophotometric analysis (Table 1). The IgG tests included 5 dairy components, 25 grains/legumes/nuts, 18 vegetables, 9 egg/meat/poultry, 21 fruits, 9 herbs/spices, 18 fish/crustacea/mollusk, and 9 miscellaneous foods including baker’s yeast. Infertile women were asked to refrain from those foods according to the level of hypersensitivity, six months were required for those with reaction class III to IV, and three months for those with reaction class II. Further IVF and embryo transfer cycles were then carried out afterwards. Results: In total, 67 infertile women enrolled in this study. Their mean age was 38.2 ± 4.3 years old. They had received 2.7 ± 1.6 previous IVF/ET cycles. All 67 women showed positive IgG and 14 (21%) women with positive IgE investigated. Grains/legumes/nuts (90%) and dairy products (86.6%) were the most common hypersensitive foods (Table 2). Thirty-one (46.3%) women conceived in their successive ET cycles after refraining from hypersensitive foods. Lower pregnancy rates were noted in those with hypersensitivity to fish/crustacea/mollusk and eggs/meat/poultry, even after refraining from those foods. Conclusion: High percentage of infertile women suffering repeated failed IVF/ET cycles presented with different levels of hypersensitivity to foods. Avoidance of hypersensitive foods may help them achieve future conception.

Stratified analysis of clinical pregnancy outcomes of sequential embryo transfer in frozen embryo transfer cycles based on different factors: a retrospective study

ObjectiveTo explore the effect of sequential embryo transfer (ET) on the pregnancy outcome of frozen-thawed embryo transfer (FET) cycle and the indications of sequential transfer.MethodsA total of 1440 FET cycles were enrolled in this retrospective study, of which 1080 patients received conventional ET and 360 patients received sequential ET. Further stratified analysis was performed according to the number of previous failed cycles, the number of embryos transferred and the stage of blastocyst (day 5 or 6, denoted D5 or D6) transferred. Comparison of pregnancy rates, implantation rate, miscarriage rate and multiple pregnancy rate among the groups of patients.ResultsThe clinical pregnancy rate and implantation rate of the sequential ET group were higher than those of the conventional ET group (P < 0.01); however, there was no statistical difference in multiple pregnancy rate and miscarriage rate (P > 0.05). In sequential transfer, the number of transferred embryos (2 or 3) and the stage of transferred blastocysts (D5 or D6) had no effect on clinical pregnancy rate, implantation rate, multiple pregnancy rate and miscarriage rate (P > 0.05). In patients with three or more previous failure cycles, the sequential ET group showed higher clinical pregnancy rate and implantation rate (P > 0.05).ConclusionsCompared with conventional ET in FET cycle, sequential ET strategy could significantly improve the clinical pregnancy rate and implantation rate. In sequential transfer, patients with three embryos transferred don’t have higher pregnancy rate and implantation rate. Besides, sequential transfer is more suitable for patients with repeated implantation failures (RIF), and increase the utilization rate of D6 blastocysts.

Clinical application of the endometrial microbiota test combined with personalized treatment in patients with repeated implantation failure

Objective: The objective of this study was to investigate the clinical value of the endometrial microbiota test (EMT) combined with personalized treatment in patients with repeated implantation failure (RIF). Methods: From March 2019 to August 2022, the clinical data of patients with RIF at the Reproductive Medicine Research Center of the Sixth Affiliated Hospital of Sun Yat-sen University were retrospectively analyzed. A total of 356 patients underwent the EMT using 16S rRNA sequencing and were included in the EMT group. The SPSS statistical software propensity score was set at 1:1 to match the age, anti-Müllerian hormone (AMH), antral follicle count (AFC), years of infertility, and body mass index (BMI) of the women who had not undergone the EMT; subsequently, 354 patients were classified in the non-EMT group. We compared the clinical characteristics of the two groups and analyzed the clinical pregnancy outcomes after personalized treatment. Results: The clinical pregnancy rate (CPR) of the EMT group was significantly higher than that of the non-EMT group (47.81% vs. 13.38%, P &lt;0.05). Among 356 patients who underwent the EMT, 55 patients (15.45%) in group A with normal endometrial microbiota composition did not test positive for the pathogenic bacteria causing chronic endometritis, 34 patients (9.55%) in group B with abnormal endometrial microbiota composition did not test positive for the pathogenic bacteria causing chronic endometritis, 35 patients (9.83%) in group C with normal endometrial microbiota composition tested positive for the pathogenic bacteria causing chronic endometritis, and 232 patients (65.17%) in group D with abnormal endometrial microbiota composition tested positive for the pathogenic bacteria causing chronic endometritis. After administration of probiotics or antibiotic plus probiotics treatment, the pregnancy rates of groups C and D were higher than those of group A (44.00% vs. 20.00% and 55.03% vs. 20.00%, respectively; both P &lt;0.05). Conclusion: The EMT combined with personalized treatment in patients with RIF has solid clinical value as a new treatment strategy.

Title: Repeated implantation failure is associated with increased Th17/Treg cell ratio, during the secretory phase of the human endometrium

Repeated implantation failure (RIF) is a significant limiting factor in assisted reproduction. Chronic endometrial inflammation has been noted in RIF women, therefore we sought to investigate the potential association of endometrial Th17/Treg ratio and endometrial inflammation in these cases. Endometrial pipelle biopsies were obtained from volunteers, 29 women with RIF (failure to achieve pregnancy following at least 3 transfers of high-grade embryos in IVF-cycles) and 27 fertile women (at least one child) in total, at the secretory phase of the menstrual cycle. Using tissues from 17 fertile and 18 RIF endometrial samples, stromal and immune cells were isolated and flow cytometry analysis was performed to determine Th17 and CD4+CD25high FOXP3+ cell populations in endometrial stromal cell suspensions. Another group of tissues from 10 fertile and 11 RIF samples were used for mRNA expression levels of Treg and Th17-cell transcription factors, FOXP3 and RORγt respectively. Endometrial inflammatory mediators’ mRNA expression was also analyzed. A statistically significant increase in protein flow cytometry analysis of Th17/Treg ratio (p≤0.05) as well as a reduction in absolute Treg cells in the endometrium (p≤0.05) was noted in women with RIF. Additionally, RNA analysis on the same set of women indicated RORγt/FOXP3 significantly increased in women with RIF compared to fertile ones (p≤0.05). Finally, women with RIF exhibited significantly (p≤0.05) elevated mRNA levels of pro-inflammatory mediators (ΤΝF-a, ΙL-6, IL-8 and CCl2). Women with RIF exhibit elevated Th17/Treg ratio, mostly due to endometrial Treg depletion, as well as a pro-inflammatory state in the endometrium.

The optimal frozen embryo transfer strategy for the recurrent implantation failure patient without blastocyst freezing: thawing day 3 embryos and culturing to day 5 blastocysts.

This study aimed to investigate the optimal frozen embryo transfer (FET) strategy for recurrent implantation failure (RIF) patients with three consecutive failed cleaved embryo implantations and no blastocyst preservation. This retrospective analysis was divided into three groups based on the FET strategy: thawed day 3 embryo transfer (D3 FET group); and extended culture of frozen-thawed day 3 embryos to day 5 blastocysts transfer (D3-D5 FET group); thawed blastocyst transfer (D5 FET group). Transplant cycle data were compared between the three groups. In total, 43.8% of vitrified-thawed cleavage embryos developed into blastocysts. Analysis of the three transplantation strategies showed that, compared with the D3 FET group, D3-D5 had a significantly better hCG-positivity rate and live-birth rate (P < 0.05). Pregnancy outcomes in the D3-D5 FET group and D5 FET group were similar regarding hCG-positivity rate, implantation rate, clinical pregnancy rate, and live-birth rate. Our findings propose two potentially valuable transfer strategies for patients experiencing repeated implantation failures. The D3-D5 FET approach presents a greater potential for selecting promising embryos in cases without blastocyst preservation; however, this strategy does entail the risk of cycle cancellation. Conversely, in instances where blastocyst preservation is an option, prioritizing consideration of the D5 FET strategy is recommended.