In Vitro Fertilization Failure Research Articles

Nurturing Hope: Reproductive Outcomes with Sinosomatics Following Unsuccessful IVF Attempts.

For women who have experienced failed attempts at in vitro fertilization (IVF) and face medical issues leading to infertility, the renewed effort to seek fertility treatment, coupled with decreasing likelihood of success, can exert substantial emotional and physical strains. Consequently, many couples opt to discontinue treatment before attaining pregnancy. The objective of this study was to evaluate the reproductive outcomes in patients with unsuccessful prior IVF attempts who received a complementary treatment designed to alleviate emotional distress and burden. A retrospective analysis of data from infertile patients who initiated the complementary intervention at a private clinic between January 2014 and December 2016 was conducted. Information on diagnosis, history of infertility, prior assisted reproductive technologies treatments, mode of conception, and pregnancy outcomes were retrieved. The data of 133 patients with a history of one or more unsuccessful IVF treatments were analyzed. Patients had an average age of 36.7 years (± 4.4 SD) and had been experiencing infertility for an average of 4.6 years (± 2.7 SD). The two main causes of their infertility were endometriosis (36.1%, 48 patients) and diminished egg quality (31.6%, 42 patients). By May 2020, a significant proportion of the patients, 81.2% (108 patients), had achieved pregnancy, leading to 94 live births, which represents a 70.7% success rate. These pregnancies mostly resulted from natural-cycle IVF (35.1%), donor cycles (23.4%), and conventional IVF (21.3%). The dropout rate was comparatively low at 23.3%. The median time from the start of complementary treatment to delivery was 18 months, with a range of 12 to 28 months. This study highlights the potential value of complementary treatment approaches in conjunction with standard medical care for women who have experienced unsuccessful IVF treatments in the past and thus face a reduced chance of motherhood. The reported 71% live birth rate is notably high, indicating that the inclusion of complementary treatments may provide women with past IVF failures a tangible opportunity for achieving successful pregnancy and childbirth. However, these findings need to be confirmed through randomized controlled studies.

ОТНОШЕНИЕ НАСЕЛЕНИЯ РЕСПУБЛИКИ БЕЛАРУСЬ К ПРИМЕНЕНИЮ ЭКСТРАКОРПОРАЛЬНОГО ОПЛОДОТВОРЕНИЯ

Purpose. To identify the attitude and stereotypical perception of the population about the use of in vitro fertilization (IVF) in the Republic of Belarus. Material and methods. A sociological survey of a representative republican sample, which consisted of 1805 respondents (851 (47%) men, 954 (53%) women) aged 18 to 65 years, was performed. Results. In general, there is a positive attitude on the part of society towards reproductive technologies (21.6% of respondents claimed absolutely positive attitude and 30.2% had rather positive attitude to IVF; a neutral attitude was revealed in 37.1% of respondents). Some of the population retain stereotypes associated with varying degrees of influence of reproductive technologies on the psychophysical health of children (about 34%). Conclusion. A system of measures is needed to improve the preparation of married couples with an established diagnosis of infertility and the ineffectiveness of other treatment methods for artificial conception. This approach will minimize the number of failed IVF cycles and reduce the risk of complications for the mother and child. The effective use of assisted reproductive technologies (ART) with positive outcomes in overcoming infertility will contribute to the formation of a positive attitude towards reproductive technologies on the part of society.

Clinical utility of office hysteroscopy following failed invitro fertilization-embryo transfer: A retrospective cohort study.

Despite its widespread use, invitro fertilization (IVF) outcomes are challenged by implantation failure, largely due to factors such as embryo quality and endometrial receptivity. In this study, we investigated the clinical effect of office hysteroscopy (OH) on the subsequent frozen-thawed embryo transfer (FET) in infertile women who experienced a failed IVF-embryo transfer (IVF-ET) cycle. We included 577 infertile women who underwent OH because of a history of failed ET between October 2019 and September 2021. During OH, visible endometrial polyps (EPs) were diagnosed and removed by curette or biopsy forceps; chronic endometritis (CE) was diagnosed by histopathology and immunohistochemistry and treated with oral doxycycline (0.2 g/d) for 14 days. According to the hysteroscopic findings and endometrial pathology with immunohistochemistry, patients were divided into three groups: group A (n = 161) had CE with or without EPs, group B (n = 156) had EPs only, and group C (n = 260) had no CE or EPs. In the following FET cycle, the implantation rates were 47%, 51%, and 45% (P = 0.411); the clinical pregnancy rates were 56%, 62%, and 55% (P = 0.436); the live birth rates were 45%, 51%, and 42% (P = 0.205); and the miscarriage rates were 18%, 16%, and 22% (P = 0.497) in groups A, B, and C, respectively. There were no significant differences among groups (P > 0.05). OH is helpful for diagnosis and treatment of abnormal intrauterine environment in women with a failed IVF cycle and further improves their pregnancy outcome in the following FET.

Preparation of the endometrium in the programs of auxiliary reproductive technologies for sterility in women

Background. The most important stage in the treatment of infertility is the introduction into clinical practice of the methods of in vitro fertilization (IVF), which made it possible to implement the function of childbirth in almost all forms of female infertility. The introduction of endoscopic technologies made it possible to significantly expand diagnostic possibilities and clarify the nature of intrauterine pathology when using assisted reproductive technologies. Purpose – of the research should be to increase the effectiveness of the treatment of female infertility when using assisted reproductive technologies and hysteroscopy by creating conditions in the endometrium for embryo implantation. Materials and Methods. A study was conducted in 42 patients with infertility aged 32 to 38 years. In all women, the morphological state of the endometrium was determined after diagnostic hysteroscopy. The patients were divided into 2 clinical groups. Group 1 included 28 women who were in a state of preparation for IVF after hysteroscopy with changes characteristic of endometrial pathology, which were found during ultrasound. The second group included 14 patients in whom, according to ultrasound, no structural changes of the endometrium were noted. These patients had a failed IVF attempt. In the next cycle, the women underwent a diagnostic hysteroscopy due to the lack of pregnancy after the first IVF attempt. Results. Group 1 patients (n = 28) with endometrial changes before IVF showed that the causes of pathology were: endometrial hyperplasia (53.6%); chronic endometritis (21.4%), endometriosis (25%). Therefore, before stimulation of superovulation, a hysteroscopy was performed to confirm the morphological diagnosis. In patients of the 2nd group (n = 14) after hysteroscopy and histological examination, pathological changes of the endometrium were found in all patients. Chronic endometritis occurred in 5 cases (35.7%), micropolyposis of the endometrium – in 6 (42.9%), endometriosis – 3 (21.4%). Clinical pregnancy occurred in 17 patients (60.7%) in the first group, in 9 (64.2%) in the second group. Conclusions. Hysteroscopy with morphological examination of the endometrium remains the main method of diagnosing intrauterine pathology. Diagnosis of infertility by hysteroscopy plays a very important role in the normalization of reproductive function during in vitro fertilization (IVF). After an unsuccessful IVF attempt, in the absence of pathological changes in the endometrium, a diagnostic hysteroscopy should be performed to rule out endometrial pathology.

Unlocking Infertility: Enhancing Pregnancy Rates With Personalized Embryo Transfers Using Optimal Time for Endometrial Receptivity Analysis in Recurrent Implantation Failure Patients Undergoing In Vitro Fertilization.

Background Infertility remains a significant global challenge, and recurrent implantation failure (RIF) poses a considerable concern in assisted reproductive technology. Understanding the factors contributing to implantation failure is essential for developing accurate diagnostic tools and treatment strategies. Endometrial receptivity (ER) during the window of implantation is crucial for successful embryo implantation in in vitro fertilization (IVF) procedures. Molecular-based endometrial receptivity analysis and next-generation sequencing provide insights into ER, but there is a lack of research on these in the Indian population, particularly in patients with RIF. This retrospective cohort study evaluates the effectiveness of Optimal Timing for Endometrial Receptivity Analysis (OpERA)-guided personalized embryo transfer (pET) in Indian patients with a history of RIF. Methodology The study includes 158 female patients with a history of failed embryo transfers who underwent OpERA testing before frozen embryo transfer. Patients were categorized based on the number of previous failed transfers. OpERA outcomes were assessed, and clinical outcomes were compared between groups undergoing preimplantation genetic testing for aneuploidy (PGT-A) with and without OpERA. Endometrial preparation involved hormone replacement therapy, and OpERA testing was performed at the Neuberg Centre for Genomic Medicine using RNA extraction, cDNA conversion, and sequencing. Results OpERA outcomes showed no significant differences in receptive rates among patient groups. Group 3, with three or more failed transfers, exhibited significantly higher biochemical pregnancy rates (BPRs), clinical pregnancy rates (CPRs), and abortion rates (ARs) compared to Groups 1 and 2. OpERA with PGT-A showed significantly higher BPR, implantation rate, CPR, and lower AR compared to OpERA without PGT-A. Conclusions OpERA-guided pET, especially with PGT-A, demonstrated improved pregnancy outcomes, particularly in patients with a history of RIF. The study emphasizes the importance of OpERA in determining optimal transfer timing, moving beyond the traditional reliance on embryo quality alone.OpERA presents promise in predicting pregnancy outcomes for Indian patients with previous IVF failures. The integration of OpERA and PGT-A represents a significant advancement in personalized reproductive medicine, offering new hope for individuals grappling with infertility complexities.

Whole-exome sequencing identifies ADGB as a novel causative gene for male infertility in humans: from motility to fertilization.

In male mice, adgb-knockout has been reported to cause male infertility with spermatogenesis defects involving flagella and acrosome. However, this remains unclear for humans. Sequencing studies were conducted in a research hospital on samples from three unrelated infertile men with severe asthenoteratozoospermia from Han Chinese families. Data were collected through rigorous in silico analysis. Sanger sequencing were performed to identify pathogenic mutations. Sperm cells from patients were characterized using electron microscopy and used to verify the pathogenicity of the genetic factors through functional assays. Intracytoplasmic sperm injections (ICSI) assays were performed in ADGB-affected males. Herein, in a cohort of 105 Han Chinese men with idiopathic asthenoteratozoospermia, we reported the identification of bi-allelic deleterious variants of ADGB in three infertile men from unrelated families using whole-exome sequencing. We found one homozygous frameshift ADGB variant (NM_024694.4: c.2801_2802del:p.K934Rfs*33), one homozygous missense ADGB variant (NM_024694.4: c.C3167T:p.T1056I), and one compound heterozygous ADGB variant (NM_024694.4: c.C3167T:p.T1056I; c.C3197T:p.A1066V). These variants were rare in general population and were predicted to be damaging by multiple bioinformatics tools. Further, the spermatozoa from patients harboring ADGB variants showed multiple acrosome and flagellum malformations under light and electron microscopy. Functional assays revealed the structural defects associated with dysregulation of ADGB and multiple spermatogenesis proteins. Notably, the fertilization success via ICSI treatment in all three patients, as well as the normal expression of PLCζ but CaM deficiency in the spermatozoa, suggesting that ICSI other than in vitro fertilization (IVF) is an optimal treatment for ADGB-deficient patients. Our findings provide new information for the molecular diagnosis of asthenoteratozoospermia and valuable reference for personalized genetic counselling and clinical treatment for these patients. The underlying risk of IVF failure behind sperm defects was highlighted.

Role of anti-tubercular treatment in vitro fertilization (IVF)

ObjectiveTo evaluate the role of anti-tubercular treatment (ATT) in vitro fertilization (IVF). DesignRetrospective analysis. MethodsA retrospective study was performed in 45 women suffering from infertility with a diagnosis of thin endometrium, history of repeated IVF failure, recurrent miscarriages or hysteroscopic or laparoscopic adhesiolysis in 4 years duration. Based on composite reference standard (CRS), in all females, Akt 4 Kit (combination of four medicines – Isoniazid 300 mg, rifampicin 450 mg, ethambutol 800 mg and pyrazinamide 750 mg) was started for 2 months with supportive medicines followed by AKT 2 (combination of two medicines – Isoniazid 300 mg and rifampicin 450 mg) for 4 months. Fertility treatment was started after 2 months of Akt 4 medication. In all cases, frozen embryo transfer was planned with tab estradiol valerate 6–8 mg in divided doses followed by endometrial thickness scanning. In all cases, embryo transfer was planned when endometrial thickness >8 mm in transvaginal scanning. The efficacy of ATT in above cases was evaluated by assessing the endometrium thickness before embryo transfer, pregnancy rates and clinical pregnancy rates. ResultsThere was no significant difference regarding demographic variables, egg reserve, sperm parameters, number of embryos transferred and embryo quality in all cases. Out of 45 cases, the pregnancy was positive in 31 cases (Pregnancy rate – 68.8 %). The clinical pregnancy rate was 64.4 % (29/45). ConclusionThere is a significant role of anti-tubercular treatment (ATT) in infertility in case of thin endometrium not responsive to medications, repeated IVF failure, recurrent miscarriages or hysteroscopic or laparoscopic adhesiolysis. It improved the endometrial thickness, pregnancy rate and the clinical pregnancy rate in IVF. But further studies are needed with large sample size to collaborate our findings.

Hysteroscopic hysteroplasty for the treatment of T-shaped uteri in women with reproductive failure.

To evaluate the efficacy of hysteroscopic hysteroplasty in the treatment of uterine malformation complicated by primary reproductive disorders. Women with unexplained primary infertility, repeated in vitro fertilization (IVF) failure or repeated spontaneous abortion, and uterine malformations unrelated to diethylstilbestrol who visited the obstetrics and gynecology department of our hospital from January 2019 to December 2022 were included in the prospective cohort study. Uterine malformation in the patients was confirmed by three-dimensional ultrasound and diagnostic hysteroscopy. Hysteroscopic hysteroplasty was performed using a 5-mm diameter hysteroscope and 5-FR surgical scissors, and after 3 months, palliative care was proposed for patients with unexplained infertility or repeated spontaneous abortion, and after 6 months, IVF treatment was recommended for patients with repeated in vitro fertilization (IVF) failures, with a planned minimum follow-up time of 1 year. A total of 83 women enrolled in the study, including 33 cases of primary infertility, 29 cases of repeated spontaneous abortion, and 21 cases of repeated IVF failure. No complications occurred during the hysteroscopic surgery. During the follow-up period, the clinical pregnancy rate of the women enrolled in the study increased to 77.1%, the live birth rate went up to 79.7%, the fetus delivered at full term accounted for 64.1%, and the cesarean section rate was 27.5%. The miscarriage rate was 9.4%. Hysteroscopic hysteroplasty can improve the reproductive outcomes in women with primary reproductive disorders and uterine malformations.

“In House” assays for the quantification of Annexin V and its autoantibodies in patients with recurrent pregnancy loss and in vitro fertilisation failures

Several studies have been shown that Annexin V (ANXV) autoantibodies concentrations are associated with both early recurrent pregnancy losses (RPLs) or in vitro fertilization failure (IVFf). We investigated the association between ANXV autoantibodies and ANVX levels in RPL, IVFf and normal group women. The study was conducted on 22 female patients with RPLs, 66 patients with IVFf, and 16 normal samples from women who had given birth. ANXV autoantibodies were measured using an ELISA test developed by fixing a homemade recombinant ANXV protein and examined with labeled human antibodies, while ANXV concentrations were measured by a competitive ELISA using a homemade anti ANXV polyclonal antibody. The results showed a clear relationship between the high levels of ANXV autoantibodies and the recurrent abortion. On the other hand, ANXV measurement in those patients showed decreased concentrations compared to normal samples. Negative correlation between ANXV and its autoantibodies levels was reported in almost all patients’ samples. Our data supports the possibility that ANXV autoantibodies are a risk factor for reproductive failures associated with both RPLs and/or IVFf and the significant role for ANXV in the maintenance of pregnancy.

Leukemia Inhibitory Factor, Tissue Factor, Thrombomodulin, P-Selectine, D-Dimer, Thrombin Generation and Procoagulant Phospholipid Dependent Clotting Time Are Predictive for in Vitro Fertilization Outcome. the Prospective Roadmap-IVF Study

Background The link between blood hypercoagulability, endothelial cell activation and infertility or in vitro fertilization (IVF) failure is a puzzling issue. Activation of platelets, endothelial cells and blood coagulation, proinflammatory and angiogenetic potential play important role in implantation and early embryonic development. Biomarkers of cellular hypercoagulability are associated with high risk of IVF failure. Soluble Leukemia Inhibitory Factor (LIF), an interleukin 6 class cytokine expressed in the trophectoderm of the developing embryo is an important regulator in the establishment of pregnancy. Endoglin (Eng), a co-receptor for TGF-β1 and TGF-β3 is implicated in vascular complications of pregnancy and particularly in preeclampsia. Aim: The prospective longitudinal monocentric observational cohort study ROADMAP-IVF, evaluated the synergistic prognostic value of LIF and Eng with the biomarkers of cellular hypercoagulability in predicting the endometrial receptivity of fresh IVF cycles. Materials and Methods. The ROADMAP-IVF enrolled 40 women eligible for IVF with normal blood count, PT, aPTT, Fg, renal and liver function. The control group (CG) consisted of 30 healthy women with history of uncomplicated pregnancies. Exclusion criteria: Use of anticoagulant or antiplatelet agents during the last 30 days before inclusion. Known cardiovascular disease, active cancer. Active corticosteroid treatment. Primary end-point: Echographically documented pregnancy at 7 weeks from implantation. Blood was collected on day 2 (D2) from the natural cycle and 6 days after hormone treatment initiation corresponding to D8 of the cycle. Procoagulant phospholipid-dependent clotting time (PPL-ct), tissue factor (TF), thrombomodulin (TM), von Willebrand factor (vWF) and D-Dimers (DDi) were measured with assays from Diagnostica Stago (Asnieres, France). P- and E-Selectin, LIF and Eng were measured with ELISA. Thrombin generation (TG) with the TF 5 pM PPP-Reagent ® was assessed on Calibrated Automated Thrombogram (Stago, France). The cut-off values for studied biomarkers have been selected on the basis of ROC analysis. Univariate and multivariate logistic regression analysis examined the associations between the biomarkers and the study outcome. Results: 40 women were enrolled in the study. In 11 women pregnancy was confirmed with ultrasound and in 23 women no pregnancy was echographically documented. Age was not significantly different between the IVF (41 ys; range 22 - 48 ys) and the control group (40 ys; range 20 - 46 ys). At D2 and D8 the DDi and LIF were significantly higher in IVFG as compared to the CG. At D2 most of the patients had PPL-ct, DDi and MRI of TG higher than the upper normal limit (UNL). At D8 only TF was significantly increased as compared to the CG. Analytical data are presented in Table 1. Age did not correlate with the levels of the studied biomarkers. Significant correlations (p<0.05) were found between DDi and ETP (r=0.35); TM, TF and P-Selectin (r=0.4) at D2; TF, LIF and Eng (r=0.5) at D2 and D8; P-Selectin and PPL-ct (r=-0.4) at D2; P-Selectin and TM (r=0.4), E-Selectin (r=0.5), LIF (0.4) at D2; E-Selectin and P-Selectin (r=0.5), TF (r=0.3), and LIF (r=0.4) at D2. The ROC analysis showed that IVF failure was associate with DDi increase at D2 (AUC = 0.64); P-Selectin increase at D2(AUC = 0.57) and D8 (AUC = 0.61); TM increase at D8 (AUC = 0.61); TF increase at D8 (AUC = 0.57); LIF increase at D8 (AUC = 0.59); ETP increase at D2 (AUC = 0.67) and D8 (AUC = 0.67); Peak increase at D2 (AUC = 0.64) and D8 (AUC = 0.61). Prolongation of PPL-ct on D8 was predictive for positive pregnancy outcome(AUC 0.64). Conclusion The ROADMAP-IVF study showed that at least one out of four women eligible for IVF present biological evidence of activation of platelets, endothelial cells, blood coagulation or LIF upregulation. Hormone treatment administration does not significantly alter the proinflammatory or the hypercoagulable state. Among the studied biomarkers the levels of LIF, DDi, P-Selectine, TM and TF as well as the status of thrombin generation and PPL-ct showed a significant predictive value for the IVF outcome, particularly when measured at 6 days after hormone treatment administration. These findings will lead to the elaboration of an risk assessment model for IVF failure combining the selected biomarkers of hypercoagulability with LIF.

Oocyte in-vitro maturation primed with letrozole-HCG versus FSH-HCG in women with oocyte maturation abnormalities: a retrospective study

Research QuestionThe objective of this study was to compare letrozole-hCG primed IVM with FSH-hCG primed IVM in women with oocyte maturation abnormalities (OMAs) defined as at least two failed in vitro fertilization (IVF) cycles where immature oocytes were retrieved. DesignThis retrospective study was conducted at a private fertility clinic from January 2009 to April 2023. The final analysis included 75 women in Group 1 (FSH-hCG primed IVM) and 52 women in Group 2 (letrozole-hCG IVM). Result(s)Group 1 demonstrated a significantly higher median number of oocytes obtained [9, (IQR: 1-5) vs. 5 (IQR: 1-18)] (p<0.001). However, the groups had no differences in oocyte maturation stages at collection (p>0.05). At the end of IVM, group 1 had 73/666 mature oocytes, while group 2 had 106/322 mature oocytes, and the median MII oocyte rate per patient was higher in group 2 [33.3%, (IQR: 66.7-100.0%) vs. 0.0%, (IQR: 0.0-22.2%)] (p<0.001). Moreover, Group 2 demonstrated a higher median fertilization rate [66.7%, (IQR: 50.0-100.0%) vs. 50.0%, (IQR: 0.0-66.7%)] (p=0.027). The group 2 had a higher proportion of Grade 1 (17.1% vs. 0%) and Grade 2 (58.5% vs. 6.3%) embryos (p<0.001). Notably, all pregnancies obtained in the study were in Group 2 (5 vs. 0; p=0.042). Conclusion(s)IVM with Letrozole-hCG priming in women with prior failed IVF cycles due to OMAs may result in mature oocytes, clinical pregnancies, and live births. The effectiveness of letrozole priming IVM on the subtypes of OMAs need further investigation with studies including higher number of cases.

Pregnancy Benefit of Acupuncture on in vitro Fertilization: A Systematic Review and Meta-Analysis.

Currently, more and more infertility couples are opting for combined acupuncture to improve success rate of in vitro fertilization (IVF). However, evidence from acupuncture for improving IVF pregnancy outcomes remains a matter of debate. To quantitatively summarized the evidence of the efficacy of acupuncture among women undergoing IVF by means of systematic review and meta-analysis. Four English (PubMed, Web of Science, EMBASE, and Cochrane Register of Controlled Clinical Trials) and Four Chinese databases (Wanfang Databases, Chinese National Knowledge Infrastructure, Chinese Science and Technology Periodical Database, and SinoMed) were searched from database inception until July 2, 2023. Randomized controlled trials (RCTs) that evaluated the acupuncture's effects for women undergoing IVF were included. The subgroup analysis was conducted with respect to the age of participants, different acupuncture types, type of control, acupuncture timing, geographical origin of the study, whether or not repeated IVF failure, and acupuncture sessions. Sensitivity analyses were predefifined to explore the robustness of results. The primary outcomes were clinical pregnancy rate (CPR) and live birth rate (LBR), and the secondary outcomes were ongoing pregnancy rate and miscarriage rate. Random effects model with I2 statistics were used to quantify heterogeneity. Publication bias was estimated by funnel plots and Egger's tests. A total of 58 eligible RCTs representing 10,968 women undergoing IVF for pregnant success were identifified. Pooled CPR and LBR showed a signifificant difference between acupuncture and control groups [69 comparisons, relative risk (RR) 1.19, 95% confifidence intervals (CI) 1.12 to 1.25, I2=0], extremely low evidence; 23 comparisons, RR 1.11, 95%CI 1.02 to 1.21, I2=14.6, low evidence, respectively). Only transcutaneous electrical acupoint stimulation showed a positive effect on both CPR (16 comparisons, RR 1.17, 95%CI 1.06 to 1.29; I2=0, moderate evidence) and LBR (9 comparisons, RR 1.20, 95%CI 1.04 to 1.37; I2=8.5, extremely low evidence). Heterogeneity across studies was found and no studies were graded as high-quality evidence. Results showed that the convincing evidence levels on the associations between acupuncture and IVF pregnant outcomes were relatively low, and the varied methodological design and heterogeneity might inflfluence the fifindings. (Registration No. PROSPERO CRD42021232430).

Risk factors for in vitro fertilization failures in women with adenomyosis-associated infertility

Aim. To identify risk factors for in vitro fertilization (IVF) failures in women with adenomyosis-associated infertility.&#x0D; Materials and methods. The study included 83 patients of reproductive age with adenomyosis. Women were divided into two groups: the main group (n=53) included patients with adenomyosis and a history of 1 or more unsuccessful attempts at embryo transfer, and the comparison group (n=30) included women with adenomyosis without impaired fertile function. The mean age of the patients was 364.0 years.&#x0D; Results. Gynecological conditions such as cervical dysplasia, noninflammatory vaginal diseases, and a history of sexually transmitted infections (STIs) were significantly (5-fold) more common in patients with a history of IVF failures (p0.05). A high prevalence of endocrine and digestive system disorders (27.7 and 7.7 times, respectively) was found in infertile women with adenomyosis (p0.05). Coagulation disorders were identified 4.8 times more often in women with adenomyosis-associated infertility and IVF failures. Inflammatory and proliferative endometrial diseases (hyperplasia, intrauterine synechia, and chronic endometritis) were significantly more common in patients in the main group than in patients with adenomyosis without impaired fertility (p0.05).&#x0D; Conclusion. Risk factors for IVF failure in women with adenomyosis-associated infertility are other specified coagulation defects [D68.8] (antiphospholipid syndrome), odds ratio (OR) 4.8, 95% confidence interval (CI) 1.120.9; dysplasia of cervix uteri, unspecified [N87.9] (OR 10.2, 95% CI 1.292.4), other noninflammatory disorders of vagina [N89.7] (OR 10.2, 95% CI 1.292.4), STIs (OR 12.7, 95% CI 1.4112.5), endocrine system disorders (OR 27.7, 95% CI 1.5516.5), and digestive system disorders (OR 7.8, 95% CI 2.227.8).

The Association of NKp46-Positive uNK Cells With a Higher Risk of Recurrent Miscarriage and IVF Failure

Background: Uterine natural killer (uNK) cells have a significant impact on pregnancy and related complications. Given the importance of receptors in the activity of uNK cells, the present study aimed to determine the number of uNK cells and NKp46 (one of the most important NK cell-activating receptors) expression in the endometrium of women with recurrent miscarriage (RM) or a history of in vitro fertilization (IVF) failure. Materials and Methods: This case-control study was performed on 48 participants, including 16 healthy controls, 27 cases with RM, and 5 cases with repeated implantation failure (RIF) during the mid-luteal phase according to a standardized diagnostic protocol. All participants were assessed using transvaginal ultrasound to determine embryo survival rate and confirm gestational age. Endometrial specimens were collected and subjected to immunohistochemistry (IHC) staining using an anti-human NKp46 antibody expressed by uNK cells. Results: A significantly higher number of cells positive for NKp46 was obtained among two groups of cases versus healthy subjects (patients: 1.46±0.78, controls: 0.82±62, P=0.006), and the number of CD56+cells was significantly higher in patients than in controls (patients: 18.14±7.14, controls: 11.71±6.17, P=0.003). Additionally, there was not a significant difference in the frequency ratio of NKp46+NK cell subset to CD56+uNK cells between the patients (P=0.59) and control healthy group. Conclusion: The increase in the number of uterine NK cells and their cytotoxic activity during implantation and early pregnancy, possibly resulting from an excessive expression of inflammatory cytokines, confirms a significant association between uNK cell activity and a higher risk of RM and RIF. Therefore, immunomodulatory treatments may benefit these patients.

Ribosomal, Telomere, and Mitochondrial Repeat Copy Number Variations in Female Genomes during Ovarian Stimulation and the Prediction of In Vitro Fertilization Outcome: A Pilot Study.

Individual risk assessment of assisted reproductive technologies is essential for personalized treatment strategies. Genetic and genomic indicators of the response to stress by cells could provide individual prognostic indicators for in vitro fertilization (IVF) success. Such indicators include the copy number of ribosomal genes (rDNA), which modulates the level of protein synthesis, and the abundance of mitochondrial DNA (mtDNA), which provides the cell with energy, while the content of telomere repeats (TRs) indicate the biological age. The contents of the three repeats in DNA isolated from blood leukocytes of 40 women before and after ovarian stimulation were assayed prior to IVF. Then, we divided the women into a successful IVF group, IVF+ (N = 17, 7 cases of twins), and a group of failed cases, IVF- (N = 23). The control group included 17 non-pregnant women with natural childbirth in the past. The nonradioactive quantitative hybridization (NQH) method was applied to assay the genome repeat contents. The number of rDNA copies in the IVF+ group was significantly higher than in the IVF- group (p < 10-8). The number of mtDNA copies in the IVF+ group also exceeded those in the IVF- group (p < 0.001), whereas the TR content in the two groups differed, albeit, non-significantly (p < 0.03). Following the ovarian stimulation, the rDNA copy numbers did not change, while the contents of the mtDNA and TR varied significantly. This pilot study has shown that rDNA abundance in blood leukocytes can be considered a stable and effective predictor. Very low numbers of ribosomal repeat copies (<330) entail a high risk of IVF failure. However, a combination of numerous mtDNA and TRs, provided that rDNA content is not very low, increases the probability of multiple pregnancies.

An updated view on the role of the female reproductive tract microbiome in IVF outcomes

Introduction. In the last decade, a high-throughput 16S ribosomal RNA (rRNA) sequencing allowed to markedly extend insights into female reproductive tract microbiome. However, evidence about its role on in vitro fertilization (IVF) outcomes remains scarce and controversial.Aim: to analyze literature data for assessing an impact of the vaginal, uterine, and ovarian microbiome on IVF outcomes.Materials and Methods. The review was carried out based on publications from available in PubMed/MEDLINE, EBSCO, ResearchGate, Google Academy and еLibrary databases released over the last 20 years. For this, there was search for keywords and their combinations in Russian- and English-written publications: «vaginal microbiome», «cervical microbiome», «uterine microbiome», «ovarian microbiome», «microbiome of ovarian follicles», «IVF», «miscarriage», «early pregnancy loss», «implantation failure», «ovarian failure», «inflammasome». Only full-text original articles and reviews published in peer-reviewed journals were included in the review. Exclusion criteria were as follows: studies containing less than 10 observations per group, abstracts of conferences, studies on the male reproductive tract microbiome. Duplicate publicationswere excluded. The publications were selected independently by two co-authors, and in case of discrepancy two other co-authors were involved.Results. Vaginal, uterine, and ovarian microbiomes were characterized by providing relevant classifications and the features related to implantation failures and pregnancy loss after IVF. It was found that a decline in total Lactobacillus level and elevated proportion of L. jensenii, G. vaginalis, and Proteobacteria in the vaginal microbiome were predictors of implantation failure. In addition, IVF failure was also associated with the presence of Atopobium, Bifidobacterium, Chryseobacterium, Gardnerella, Streptococcus, Haemophilus, Staphylococcus, Brevundimonas, and Ralstonia in the uterine cavity as well as Bifidobacterium, Gardnerella, and Klebsiella in the endometrial tissue. On the other hand, Lactobacillus dominance in the uterine microbiome has a favorable effect. The colonization of the follicle by any microorganisms as well as the presence of follicular fluid anaerobic bacteria-derived metabolite trimethylamine-N-oxide (TMAO) associated with bacterial vaginosis additionally alters IVF outcomes. Moreover, the role of infectious cues in lowered ovarian reserve has also been established. Activation of the NLRP3 (NLR Family Pyrin Domain Containing 3) inflammasome by microbe-derived ligands stimulates production of pro-inflammatory cytokines and contributes to reduced follicle number. Blocking NLRP3 in mouse experiments can delay depletion of the follicle pool and result in elevated fertility.Conclusion. Favorable IVF outcomes are associated with Lactobacillus predominance in the vaginal and endometrial microbiome as well as lack of follicular fluid microorganisms. TMAO detected in the follicular fluid as well as activated NLRP3 inflammasome serve as negative predictors of IVF outcomes.

Comparison of dydrogesterone plus progesterone gel with subcutaneous aqueous progesterone plus progesterone gel for luteal phase supplementation of subsequent in vitro cycle in women after previous cycle failure.

The luteal phase supplementation (LPS) of the in vitro fertilization (IVF) cycle is crucial to increase the chance of a live birth. There is no preferred progestogen for use in the general population. The optimal progestogen regimen in the event of prior IVF failure is unknown. The aim was to compare the live birth rate for dydrogesterone plus progesterone gel versus aqueous progesterone plus progesterone gel in LPS of the IVF cycle in women with at least one previous IVF failure. A prospective randomized single-center study enrolled women with at least one previous IVF failure undergoing another IVF cycle. Women were randomly assigned in a 1:1 ratio to 2 arms depending on LPS protocol: dydrogesterone (Duphaston®) + progesterone in vaginal gel (Crinone®) vs aqueous progesterone solution in subcutaneous injection (Prolutex®) + progesterone in vaginal gel (Crinone®). All women underwent fresh embryo transfer. The live birth rate with one prior IVF failure was 26.9% for D + PG vs 21.2% for AP + PG (p = 0.54), and with at least two IVF failures: 16% for D + PG vs 31.1% for AP + PG (p = 0.16). There were no significant differences in live birth rates between protocols, regardless of the number of prior IVF failures. In light of the evidence from this study that neither of the two LPS protocols is more effective in women with prior IVF failure, other factors, such as potential side effects, dosing convenience and patient preference, should be considered when choosing a treatment.

A pathogenic variant in the uncharacterized RNF212B gene results in severe aneuploidy male infertility and repeated IVF failure.

Quantitative and qualitative spermatogenic impairments are major causes of men's infertility. Although invitro fertilization (IVF) is effective, some couples persistently fail to conceive. To identify causal variants in patients with severe male infertility factor and repeated IVF failures, we sequenced the exome of two consanguineous family members who underwent several failed IVF cycles and were diagnosed with low sperm count and motility. We identified a rare homozygous nonsense mutation in a previously uncharacterized gene, RNF212B, as the causative variant. Recurrence was identified in another unrelated, infertile patient who also faced repeated failed IVF treatments. scRNA-seq demonstrated meiosis-specific expression of RNF212B. Sequence analysis located a protein domain known to be associated with aneuploidy, which can explain multiple IVF failures. Accordingly, FISH analysis revealed a high aneuploidy rate in the patients' sperm cells and their IVF embryos. Finally, inactivation of the Drosophila orthologs significantly reduced male fertility. Given that members of the evolutionary conserved RNF212 gene family are involved in meiotic recombination and crossover maturation, our findings indicate a critical role of RNF212B in meiosis, genome stability, and in human fertility. Since recombination is completely absent in Drosophila males, our findings may indicate an additional unrelated role for the RNF212-like paralogs in spermatogenesis.

P-329 Oocyte donation outcomes in endometriosis patients with multiple IVF failures

Abstract Study question What are the reproductive outcomes and the prognostic factors of live birth rates in endometriosis patients referred to oocyte donation after multiple in vitro fertilization(IVF)-failures? Summary answer In this specific population, oocyte donation appears to be a viable option to optimize the reproductive outcomes, as the cumulative live birth rate reaches 63.2%. What is known already Assisted Reproductive Technology(ART) is currently recognized as one of the main therapeutic options to manage endometriosis-related infertility, often resulting in satisfactory outcome. A burning issue in this field remains how to deal with patients undergoing recurrent ART failures. As there appear to be two main factors contributing to the failures, i.e., a deleterious effect of endometriosis on embryo implantation and altered oocyte and embryo quality, two competing therapeutic strategies can be considered:(i) endometriosis surgery and (ii) oocyte donation. However, no data has been published to date in the specific population of endometriosis patients with previous IVF failures, undergoing oocyte donation. Study design, size, duration Observational cohort study including fifty-seven women with endometriosis-related infertility and multiple IVF failures (≥ 2 failed IVF cycles) referred to oocyte donation who consulted at our institution between January 2013 and June 2022. Participants/materials, setting, methods Endometriosis was diagnosed based on published imaging criteria using transvaginal sonography and magnetic resonance imaging and confirmed histologically in women who had a history of surgery for endometriosis. The main outcomes measured were the clinical pregnancy rate (CPR) and the cumulative live birth rate (CLBR). We compared the characteristics of women who had a live birth versus those who did not using univariate and multivariate analysis to identify determinant factors of fertility outcome. Main results and the role of chance Fifty-seven patients underwent 90 oocyte donation cycles, after 244 failed autologous IVF cycles. The mean age of the population was 36.8 ± 3.3 years, with a mean infertility duration of 3.6 ± 2.2 years, and a mean number of autologous IVF/ICSI cycles of 4.4 ± 2.3 cycles per patient. Three patients (5.3%) had superficial endometriosis, 2 patients (3.5%) had ovarian endometriomas, and 52 patients (91.2%) had deep infiltrating endometriosis, among which 30 patients (57.7%) had bowel lesions. Thirty patients (52.6%) had associated adenomyosis. Overall, the CPR and the CLBR per patient were 49/57 (85.9%) and 36/57 (63.2%), respectively. After multivariate analysis, only being nulligravida (p = 0.002) remained an independent negative predictive factor of the live birth rate. Limitations, reasons for caution In 35.1% of patients there was no surgical/histological proof of endometriosis. However, for all the study participants, endometriosis was diagnosed and staged using patient interviews, clinical examination, and imaging techniques to assess for endometriosis phenotypes, which is in line with the structured diagnostic process acknowledged as being appropriate for endometriosis. Wider implications of the findings In this specific population, poor embryo quality may be the main limiting factor of ART success rates, rather than impaired endometrial receptivity. These data are reason for clinicians not to systematically refer infertile endometriosis patients with recurrent IVF failures to surgery. Trial registration number not applicable

Chronic Endometritis in Patients with Failure of IVF

Background: Chronic endometritis (CE) is highly prevalent in patients with unexplained infertility. This study aimed to determine the associations between CE and infertility. Methods and Results: We performed a prospective study of 197 women with implantation failure and pregnancy loss after undergoing in vitro fertilization (IVF). The endometrium was examined with a hysteroscope, and a sample was taken for biopsy in areas suspected of having inflammation. Immunohistochemistry was performed for CD138 antibodies. Diagnostic criterion was more than 5 plasma cells per 10 high-power fields. Patients who were positive for CE were treated with antibiotics. Among the 197 patients in our study, 115(58.4%) were positive for CE. Regarding the success of CE treatment and pregnancy after treatment, among the 115 CD138-positive patients, 32 became pregnant without IVF after treatment, while another 43 had successful pregnancies and childbirth with IVF. Thus, with treated CE, a successful pregnancy and childbirth was detected in 65.2% of cases, including spontaneous pregnancies and IVF. Conclusion: Patients with infertility and those who have pregnancies lost in IVF have a high rate of CE. Failure to treat CE results in infertility and IVF failure. An efficient diagnosis and treatment of CE are important for a successful pregnancy.