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Abstract Background Currently, there is no consensus on the optimal management of women with low prognosis in ART. In this Delphi consensus, a panel of international experts provided real-world clinical perspectives on a series of literature-supported consensus statements regarding the overall relevance of the POSEIDON criteria for women with low prognosis in ART. Methods Using a Delphi-consensus framework, twelve experts plus two Scientific Coordinators discussed and amended statements and supporting references proposed by the Scientific Coordinators (Round 1). Statements were distributed via an online survey to an extended panel of 53 experts, of whom 36 who voted anonymously on their level of agreement or disagreement with each statement using a six-point Likert-type scale (1 = Absolutely agree; 2 = More than agree; 3 = Agree; 4 = Disagree; 5 = More than disagree; 6 = Absolutely disagree) (Round 2). Consensus was reached if > 66% of participants agreed or disagreed. Results The extended panel voted on seventeen statements and subcategorized them according to relevance. All but one statement reached consensus during the first round; the remaining statement reached consensus after rewording. Statements were categorized according to impact, low-prognosis validation, outcomes and patient management. The POSEIDON criteria are timely and clinically sound. The preferred success measure is cumulative live birth and key management strategies include the use of recombinant FSH preparations, supplementation with r-hLH, dose increases and oocyte/embryo accumulation through vitrification. Tools such as the ART Calculator and Follicle-to-Oocyte Index may be considered. Validation data from large, prospective studies in each POSEIDON group are now needed to corroborate existing retrospective data. Conclusions This Delphi consensus provides an overview of expert opinion on the clinical implications of the POSEIDON criteria for women with low prognosis to ovarian stimulation.

Abstract Objective Ovarian stimulation (OS) with high daily gonadotropin doses are commonly offered to patients attempting social/elective egg freezing. However, the optimal daily gonadotropin dose that would allow a higher oocyte yield in the successive IVF cycle attempt was not settled and should be determined. Patients and methods Data from all women admitted to our IVF unit for social/EEF, who underwent two consecutive IVF cycle attempts, with only those who used in the first attempt a starting daily gonadotropin dose of 300IU were analyzed. Patients characteristics and OS variables were used in an attempt to build a logistic model, helping in determining the daily gonadotropin dose that should be offered to patient during their second EEF attempt, aiming to further increase their oocyte yield. Results Three hundred and thirteen consecutive women undergoing two successive IVF cycle attempts were evaluated. Using logistic regression model, two equations were developed using individual patient-level data that determine the daily gonadotropin dose needed aiming to increase the oocyte yield in the successive cycle. (a): X=-0.514 + 2.87*A1 + 1.733*A2–0.194* (E2/1000) and (b): P = EXP(X) / [1 + EXP(X)]. Conclusions Using the aforementioned equations succeeded in determining the daily gonadotropin dose that might result in increasing oocyte yield, with an AUC of 0.85. Any additional oocyte retrieved to these EEF patients might get them closer to fulfil their desire to parenthood.

Introduction: The aim of this study was to estimate the time to pregnancy and live birth and evaluate the effect of weight regain in women with a history of bariatric surgery (BS) who underwent in vitro fertilization (IVF) treatments. Methods: This is a retrospective cohort study. All patients with previous BS who underwent IVF treatment in a tertiary university-affiliated hospital between 2013 and 2022 were included. Time to pregnancy and live birth were compared between patients who regained less than or greater than three points of body mass index (BMI) from the nadir weight after BS. Kaplan-Meier curves and log-rank tests were used to compare groups. Results: A total of 78 patients were included in this study. The positive β-hCG, clinical pregnancy, and live birth rates following BS were 89.4%, 78.9%, and 50.8%, respectively. The median time from the beginning of IVF treatments to a positive β-hCG test was 2.97 months (95% CI: 1.04–4.89 months), to a clinical pregnancy was 7.1 months (95% CI: 3.56–10.91), and to a live birth was 20.2 months. Women who maintained their nadir BMI following BS had nearly twice the chance of achieving a clinical pregnancy (HR 1.967, 95% CI: 1.026–3.771, p = 0.042) and were approximately three times more likely to achieve a live birth (2.864, 95% CI: 1.196–6.859, p = 0.018) than those who regained at least three points of BMI. Conclusion: Weight regain after BS is associated with a lower rate of live births and prolonged time to achieve clinical pregnancy and live birth.

Abstract Ovarian stimulation (OS) is one of the key factors in the success of in vitro fertilization-embryo transfer (IVF-ET), by enabling the recruitment of numerous healthy fertilizable oocytes and, thereby, multiple embryos. The Stop GnRH-agonist/GnRH-antagonist (GnRH-ag/GnRH-ant), which offers all the advantages of using long suppressive GnRH-ag, with GnRH-ant, is in my opinion a valuable addition to the armamentarium of OS protocols. It allows cycle programming, better follicular synchronization and offers successful outcome in a variety of challenging cases such as poor responders, Poseidon group 4 poor prognosis patients, those with elevated peak progesterone (P) serum levels, poor embryo quality or repeated IVF failures.

Abstract Objective Nowadays, patients attempting social/elective egg freezing has spread globally. Ovarian stimulation (OS) with high daily gonatotropin doses, are commonly offered to this group of patients, aiming to achieve the maximal oocytes cohort with minimum IVF cycle attempts. We aim to assess the IVF-ET outcome, and specifically the oocyte yield, of patients undergoing two successive IVF cycle attempts for elective egg freezing (EEF), and whether changing the daily gonadotropin dose in the second IVF cycle attempt, affect the outcome. Patients and methods All women admitted to our IVF unit for social/EEF, who underwent 2 consecutive IVF cycle attempts, with only those who used in the first attempt a starting daily gonadotropin dose of 300 IU were included. Ovarian stimulation characteristics, duration of OS, number of retrieved oocytes, number of mature oocytes were assessed and compared between the 1st and the 2nd IVF cycle attempts, and between the different daily gonadotropin doses and the oocyte yields in the 2nd cycle attempt (increase, decrease or no change). Main outcome measures Oocytes and mature oocytes yield in the 2nd as compared to the 1st IVF cycle attempt. Results A reduced oocyte yield in the 2nd cycle attempt was observed in those who highly responded in the 1st attempt, regardless the daily dose in the 2nd cycle attempt (whether it was increased, no change and decreased). Moreover, the proportion of patients with same or more oocytes in the 2nd IVF cycle attempt was significantly lower in patients with high peak E2 levels, compared to those with peak E2 levels 9175 pmol/L), those who achieved a lower oocytes yield in the 2nd IVF cycle attempt had lower basal Day-3 FSH/LH ratio (1.5 + 0.5 vs 1.8 + 0.8, p 9 oocytes and 61.8% of those with 9175 pmol/L) in the 1st attempt, and basal Day-3 FSH/LH ratio

Abstract Objective Nowadays, different modes and timing of GnRH-agonist combined with hCG trigger, for final follicular maturation, have been described. While LH + FSH are the naturally occurring final follicular maturation trigger, hCG is commonly use during stimulated cycle, and recently the introduction of the Dual/Double trigger combines LH + FSH + hCG. In the present study we aim to investigate the messenger RNA (mRNA) expression of reproduction-related genes in human granulosa cells (GCs) exposed to the aforementioned different types and combinations of gonadotropins. Material and methods Mural GCs were obtained from follicular fluid aspirated during IVF protocol. GCs were seeded in culture for 4 days with daily medium exchange followed by administration of either hCG (1 U/ml); FSH (1 U/ml) and LH (8 U/ml); or hCG (1 U/ml) and FSH (1 U/ml) and LH (8 U/ml) for 16 h. mRNA was purified from harvested GCs and gene expression was quantitative by qPCR. Main outcome measures The expression of genes related to steroidogenesis (StAR/ CYP19) and oocyte maturation (COX2/Amphiregulin) in cultured GCs. Results The Dual/Double trigger (LH + FSH + hCG) showed higher activation of steroidogenesis (StAR/CYP19) and maturation (COX2/Amphiregulin) as compared to the naturally occurring trigger (LH + FSH) and the hCG triggers. Moreover, while the naturally occurring trigger (LH + FSH) activated maturation significantly and more intensely than the hCG trigger, no in between group differences were observed with regards to steroidogenic related genes. Conclusions Our findings are in agreement with clinical experience, demonstrating the superiority of the double/dual (LH + FSH + hCG) trigger over the naturally occurring and the hCG triggers.

Abstract Background Poor responders to ovarian stimulation are one of the most challenging populations to treat. As a failed cycle can cause a considerable emotional and economical loss, adequate fertility counseling addressing patients’ expectations are highly important when facing patients with poor ovarian response. The study aimed to evaluate reproductive outcomes and to identify factors associated with live birth (LB) after fresh autologous IVF/intracytoplasmic sperm injection (ICSI) cycles of patients fulfilling the Bologna criteria for poor ovarian response (POR). Methods A retrospective study included 751 IVF/ICSI treatment cycles which yielded up to three retrieved oocytes, at a tertiary referral hospital between January 2016 and February 2020. A logistic regression analysis was used to adjust for confounders. Results Clinical pregnancy and LB rate per cycle were significantly higher among women younger versus older than 40 years (9.8% and 6.8% vs 4.5% and 2.1%, p

Summary Embryo transfer is a crucial step in IVF cycle, with increasing trend during the last decade of transferring a single embryo, preferably at the blastocyst stage. Despite increasing evidence supporting Day 5 blastocyst-stage transfer, the optimal day of embryo transfer remains controversial. The crucial questions are therefore, whether the mechanisms responsible to embryos arrest are embryo aneuploidy or others, and whether those embryos arrested in-vitro between the cleavage to the blastocyst stage would survive in-vivo if transferred on the cleavage-stage. We therefore aim to explore whether aneuploidy can directly contribute to embryo development to the blastocyst stage. Thirty Day-5 embryos, that their Day-3 blastomere biopsy revealed a single-gene defect, were donated by 10 couples undergoing preimplantation genetic testing treatment at our center. Affected high quality Day-3 embryos were cultured to Day-5, and were classified to those that developed to the blastocyst-stage and those that were arrested. Each embryo underwent whole genome amplification. Eighteen (60%) embryos were arrested, did not develop to the blastocyst stage and 12 (40%) have developed to the blastocyst stage. Nineteen embryos (63.3%) were found to be euploid. Of them, 12 (66.6%) were arrested embryos and 7 (58.3%) were those that developed to the blastocyst-stage. These figures were not statistically different (p = 0.644). Our observation demonstrated that the mechanism responsible to embryos arrest in vitro is not embryo aneuploidy, but rather other, such as culture conditions. If further studies will confirm that Day-5 blastocyst transfer might cause losses of embryos that would have been survived in vivo, cleavage-stage embryo transfer would be the preferred timing. This might reduce the cycle cancellations due to failure of embryo to develop to the blastocyst stage and will provide the best cumulative live birth-rate per started cycle.

Abstract Background Preimplantation genetic testing (PGT) is offered to a wide range of structural and numerical chromosomal imbalances, with PGT- polymerase chain reaction (PCR), as the method of choice for amplifying the small DNA content achieved from the blastomere biopsy or trophectoderm (TE) biopsy, that might have a detrimental impact on embryonic implantation potential. Since human embryos cultured until Day-5–6 were noticed to expel cell debris/ fragments within the zona pellucida, we aimed to examine whether these cell debris/ fragments might be used for PGT, as an alternative to embryo biopsy. Methods Blastocysts, which their Day-3 blastomere biopsy revealed an affected embryo with single-gene defect, and following hatching leaved cell debris/fragments within the zona pellucida were analyzed. Each blastocyst and its corresponding cell debris/fragments were separated and underwent the same molecular analysis, based on multiplex PCR programs designed for haplotyping using informative microsatellites markers. The main outcome measure was the intra-embryo congruity of Day-3 blastomere biopsy and its corresponding blastocyst and cell debris/fragments. Results Fourteen affected embryos from 9 women were included. Only 8/14 (57.2%) of embryos demonstrated congruent molecular genetic results between Day-3 embryo and its corresponding blastocyst and cell debris/fragments. In additional 6/14 (42.8%) embryos, molecular results of the Day-3 embryos and their corresponding blastocysts were congruent, while the cell debris/fragments yielded no molecular diagnoses (incomplete diagnoses). Conclusions It might be therefore concluded, that in PGT cycles, examining the cell debris/fragments on Day-4, instead of Day-3 blastomere or Day-5 TE biopsies, is feasible and might avoid embryo biopsy with its consequent detrimental effect on embryos’ implantation potential. Whenever the latter results in incomplete diagnosis, TE biopsy should be carried out on Day-5 for final genetic results. Further large well-designed studies are required to validate the aforementioned PGT platform.

Abstract FMR1 premutation (55–200 CGG repeats) results in fragile X-associated primary ovarian insufficiency (FXPOI). We evaluated expression levels of folliculogenesis-related mediators, follicle-stimulating hormone (FSH) receptor and anti-Mullerian hormone (AMH), to gain insights into the mechanisms underlying the reduced ovarian function. Mural granulosa cells (MGCs) were collected from FMR1 premutation carriers and noncarriers undergoing IVF treatments. At baseline, MGCs of carriers demonstrated significantly higher mRNA expression levels of AMH (3.5 ± 2.2, n = 12 and 0.97 ± 0.5, n = 17, respectively; p = 0.0003) and FSH receptor (5.6 ± 2.8 and 2.7 ± 2.8, respectively; p = 0.02) and higher AMH protein expression on immunostaining. Accordingly, FMR1 premutation-transfected COV434 cells exhibited higher AMH protein expression than COV434 cells transfected with 20 CGG repeats. We conclude that FMR1 premutation may lead to dysregulation of AMH expression levels, probably due to a compensatory mechanism. Elucidating the pathophysiology of FXPOI may help in early detection of ovarian dysfunction and tailoring IVF treatments to FMR1 premutation carriers.

Abstract Introduction Several studies suggest that luteinizing hormone (LH) could improve IVF outcome in women of advanced reproductive age by optimizing androgen production. In this review, we assessed the role of recombinant-human LH (r-hLH) and recombinant human follicle stimulating hormone (r-hFSH) co-treatment in ovarian stimulation for assisted reproductive technology in women of advanced reproductive age candidates for assisted reproduction. Material and methods Using a preregistered protocol we systematically searched Medline/PubMed, Scopus and the ISI Web of Science databases to identify randomized controlled trials in which r-hFSH monotherapy protocols were compared with r-hFSH/r-hLH co-treatment in women ≥35 years undergoing fresh IVF cycles. We calculated the pooled odds ratio (OR) for dichotomous data and the weight mean difference (WMD) for continuous data with an associated 95% confidence interval (CI). The meta-analyses were conducted using the random-effect model. P values

Abstract Objective No information exists in the literature regarding the effect of mRNA SARS-CoV-2 vaccine on subsequent IVF cycle attempt. We therefore aim to assess the influence of mRNA SARS-CoV-2 vaccine on IVF treatments. Design An observational study. Setting A tertiary, university-affiliated medical center. Patients and Methods All couples undergoing consecutive ovarian stimulation cycles for IVF before and after receiving mRNA SARS-CoV-2 vaccine, and reached the ovum pick-up (OPU) stage. The stimulation characteristics and embryological variables of couples undergoing IVF treatments after receiving mRNA SARS-CoV-2 vaccine were assessed and compared to their IVF cycles prior to vaccination. Main outcome measures Stimulation characteristics and embryological variables. Results Thirty-six couples resumed IVF treatment 7–85 days after receiving mRNA SARS-CoV-2 vaccine. No in-between cycles differences were observed in ovarian stimulation and embryological variables before and after receiving mRNA SARS-CoV-2 vaccination. Conclusions mRNA SARS-CoV-2 vaccine did not affect patients’ performance or ovarian reserve in their immediate subsequent IVF cycle. Future larger studies with longer follow-up will be needed to validate our observations.

Abstract Background Live birth has increasingly been identified as the standard clinical approach to measure the success of medically assisted reproduction (MAR). However, previous analyses comparing biosimilar preparations of follitropin alfa versus the reference product (GONAL-f®, Merck KGaA, Darmstadt, Germany or GONAL-f® RFF; EMD Serono, Inc., Rockland, MA), have had insufficient power to detect differences in clinically meaningful outcomes such as live birth. Methods Medline, Embase, the Cochrane Library, Web of Science and clinical trial registries were searched for randomised controlled trials (RCTs) and conference abstracts comparing biosimilar follitropin alfa versus the reference product in controlled ovarian stimulation (COS) cycles published before 31 October 2020. Only studies in humans and publications in English were included. Retrieved studies were screened independently by two authors based on titles and abstracts, and then by full text. Inclusion criteria: RCTs comparing follitropin alfa biosimilar preparations with the reference product in infertile patients of any age, with any type of infertility for any duration, undergoing COS for the purposes of MAR treatment (including frozen cycles). The primary outcome was live birth. Combined data for biosimilar preparations were analysed using a fixed-effects model. Results From 292 unique records identified, 17 studies were included in the systematic review, representing five unique RCTs that were included in the meta-analysis. Rates of live birth (RR = 0.83, 95% CI 0.71, 0.97; 4 RCTs, n = 1881, I2 = 0%), clinical pregnancy (RR = 0.82, 95% CI 0.72, 0.94; 4 RCTs, n = 2222, I2 = 0%) and ongoing pregnancy (RR = 0.81, 95% CI 0.68, 0.96; 4 RCTs, n = 1232, I2 = 0%) were significantly lower with biosimilar preparations versus the reference product. Rates of cumulative live birth and cumulative clinical pregnancy were also significantly lower with biosimilars versus the reference product. There was high risk of publication bias. Conclusions This meta-analysis included data from RCTs evaluating the efficacy and safety of the biosimilar follitropin alfa preparations and demonstrated lower probability of live birth and pregnancy (ongoing and clinical) in couples treated with biosimilar preparations compared with the reference product. This study provides more insight into the differences between biosimilar r-hFSH preparations and the reference product than previously reported. Trial registration Registration number: CRD42019121992 .

Abstract Two professional societies recently published opinions on the clinical management of “mosaic” results from preimplantation genetic testing for aneuploidy (PGT-A) in human blastocyst-stage embryos in associations with in vitro fertilization (IVF). We here point out three principal shortcomings: (i) Though a most recent societal opinion states that it should not be understood as an endorsement of the use of PGT-A, any discussion of how PGT-A should be clinically interpreted for all practical purposes does offer such an endorsement. (ii) The same guideline derived much of its opinion from a preceding guidance in favor of utilization of PGT-A that did not follow even minimal professional requirements for establishment of practice guidelines. (iii) Published guidelines on so-called “mosaic” embryos from both societies contradict basic biological characteristics of human preimplantation-stage embryos. They, furthermore, are clinically unvalidated and interpret results of a test, increasingly seen as harmful to IVF outcomes for many infertile women. Qualified professional organizations, therefore, should finally offer transparent guidelines about the utilization of PGT-A in association with IVF in general.

Abstract Human embryogenesis frequently coinciding with cell division mistakes contributing to pervasive embryonic aneuploidy/mosaicism. While embryo self-correction was elegantly demonstrated in mouse models, human studies are lacking. Here we are witness to human embryos ability to eliminate/expel abnormal blastomeres as cell debris/fragments. Each blastocyst and its corresponding debris were separated and underwent whole genome amplification. Seven of the 11 pairs of blastocysts and their corresponding cell debris/fragments revealed discordant results. Of the 9 euploid blastocysts, four showed euploid debris, while in the others, the debris were aneuploid. In the remaining pairs, the debris showed additional aneuploidy to those presented by their corresponding blastocyst. The observed ability of human embryos to self-correction doubts many invasive and non-invasive preimplantation testing for aneuploidy at the blastocyst stage, rendering high rate of false positive (discarding “good” embryos) by identifying the cell-free DNA originated from the expelled cell debris, as aneuploidy/mosaic blastocyst.

Abstract Background Co-administration of letrozole during the first 5 days of ovarian stimulation was suggested to improve IVF outcomes in poor responders. We aimed to determine whether poor/sub-optimal responders might benefit from Letrozole co-treatment throughout the entire stimulation course. Methods We retrospectively reviewed the medical files of women who demonstrated poor (oocyte yield ≤3) and sub-optimal (4 ≤ oocyte yield ≤9) ovarian response during conventional multiple-dose antagonist stimulation protocols and were co-treated in a subsequent cycle with 5 mg Letrozole from the first day of stimulation until trigger day. A self-paired comparison between gonadotropins-only and gonadotropins-letrozole cycles was performed. Results Twenty-four patients were included. Mean patients’ age was 39.83 ± 4.60 and mean day-3-FSH was 12.77 ± 4.49 IU/m. Duration of stimulation and total gonadotropins dose were comparable between the two cycle groups. Peak estradiol levels were significantly lower in gonadotropins-letrozole cycles (2786.74 ± 2118.53 vs 1200.13 ± 535.98, p

Abstract Background The presence of submucous fibroids strongly impacts on IVF results, therefore, these patients should be considered for surgical or medical treatment. The aim of this study was to assess the role of Ulipristal acetate (UPA), a selective progesterone receptor modulator, in restoring uterine cavity deformation due to submucous fibroids, in infertile patients attempting an IVF treatment. The secondary study outcome was to evaluate the impact of preconception UPA treatment on rate of biochemical pregnancy, ongoing pregnancy, and live birth compared to a control group without fibroids. Methods Infertile patients with submucosal fibroid (Type 1 and Type 2 according to FIGO classification) were enrolled in the study as fibroids group and received 1 to 3 treatment cycles of UPA, according to their response, as reflected by fibroid volume reduction and restoration of normal uterine cavity. Patients in control group were randomly selected from a general IVF cohort by a ratio of 2:1 with fibroids group, matched by age, BMI, type and cause of infertility and antral follicle count. The impact of UPA on fibroids volume reduction was evaluated. IVF outcome was compared between groups. Results Twenty-six patients underwent UPA treatment revealed a mean volume reduction of their fibroids of 41%. A total of 15 (57.6%) biochemical pregnancy were obtained, resulting in 13 (50%) ongoing pregnancy and 9 (34.6%) healthy babies were already delivered. Similar results were obtained in control group. Conclusion Restoration of normal uterine cavity by UPA treatment prior to IVF treatment avoids surgery and establishes a pregnancy rate comparable to a control group without fibroids.

Abstract The prolonged lockdown of health services providing high-complexity fertility treatments –as currently recommended by many reproductive medicine entities– is detrimental for society as a whole, and infertility patients in particular. Globally, approximately 0.3% of all infants born every year are conceived using assisted reproductive technology (ART) treatments. By contrast, the total number of COVID-19 deaths reported so far represents approximately 1.0% of the total deaths expected to occur worldwide over the first three months of the current year. It seems, therefore, that the number of infants expected to be conceived and born –but who will not be so due to the lockdown of infertility services– might be as significant as the total number of deaths attributed to the COVID-19 pandemic. We herein propose remedies that include a prognostic-stratification of more vulnerable infertility cases in order to plan a progressive restart of worldwide fertility treatments. At a time when preventing complications and limiting burdens for national health systems represent relevant issues, our viewpoint might help competent authorities and health care providers to identify patients who should be prioritized for the continuation of fertility care in a safe environment.

BackgroundA Delphi consensus was conducted to evaluate global expert opinions on key aspects of assisted reproductive technology (ART) treatment.MethodsTen experts plus the Scientific Coordinator discussed and amended statements plus supporting references proposed by the Scientific Coordinator. The statements were distributed via an online survey to 35 experts, who voted on their level of agreement or disagreement with each statement. Consensus was reached if the proportion of participants agreeing or disagreeing with a statement was >66%.ResultsEighteen statements were developed. All statements reached consensus and the most relevant are summarised here. (1) Follicular development and stimulation with gonadotropins (n = 9 statements): Recombinant human follicle stimulating hormone (r-hFSH) alone is sufficient for follicular development in normogonadotropic patients aged

Despite advances in the field of male reproductive health, idiopathic male infertility, in which a man has altered semen characteristics without an identifiable cause and there is no female factor infertility, remains a challenging condition to diagnose and manage. Increasing evidence suggests that oxidative stress (OS) plays an independent role in the etiology of male infertility, with 30% to 80% of infertile men having elevated seminal reactive oxygen species levels. OS can negatively affect fertility via a number of pathways, including interference with capacitation and possible damage to sperm membrane and DNA, which may impair the sperm’s potential to fertilize an egg and develop into a healthy embryo. Adequate evaluation of male reproductive potential should therefore include an assessment of sperm OS. We propose the term Male Oxidative Stress Infertility, or MOSI, as a novel descriptor for infertile men with abnormal semen characteristics and OS, including many patients who were previously classified as having idiopathic male infertility. Oxidation-reduction potential (ORP) can be a useful clinical biomarker for the classification of MOSI, as it takes into account the levels of both oxidants and reductants (antioxidants). Current treatment protocols for OS, including the use of antioxidants, are not evidence-based and have the potential for complications and increased healthcare-related expenditures. Utilizing an easy, reproducible, and cost-effective test to measure ORP may provide a more targeted, reliable approach for administering antioxidant therapy while minimizing the risk of antioxidant overdose. With the increasing awareness and understanding of MOSI as a distinct male infertility diagnosis, future research endeavors can facilitate the development of evidence-based treatments that target its underlying cause.

Abstract Backgroud In order to maximize In vitro fertilization (IVF) success rates in advanced- age patients, it has been suggested to favor the use of intracytoplasmic sperm injection (ICSI) over conventional insemination (CI), with the notion that ICSI would serve as a tool to overcome interference in sperm oocyte interaction and sperm oocyte penetration issues that can be related to maternal age and are not due to sperm abnormalities. We therefore aim to evaluate the role of ICSI in the treatment of non-male factor infertile patients aged ≥35 in terms of fertilization and top-quality embryo rates. Methods In this retrospective cohort study, data were collected and analyzed for all patients with non-male factor infertility, aged ≥35 treated, undergoing their first IVF cycle attempt with 6 or more oocytes yield, in whom a 50% ICSI-CI division was performed. Results Five hundreds and four oocytes were collected from 52 eligible patients. Overall, 245 oocytes underwent ICSI and 259 oocytes underwent CI. The fertilization rate was 71.0% following ICSI, compared to 50.1% in the CI treated oocytes (P

Abstract Recurrent implantation failure (RIF) refers to cases in which women have had three failed in vitro fertilization (IVF) attempts with good quality embryos. The definition should also take advanced maternal age and embryo stage into consideration. The failure of embryo implantation can be a consequence of uterine, male, or embryo factors, or the specific type of IVF protocol. These cases should be investigated to determine the most likely etiologies of the condition, as this is a complex problem with several variables. There are multiple risk factors for recurrent implantation failure including advanced maternal age, smoking status of both parents, elevated body mass index, and stress levels. Immunological factors such as cytokine levels and presence of specific autoantibodies should be examined, as well as any infectious organisms in the uterus leading to chronic endometritis. Uterine pathologies such as polyps and myomas as well as congenital anatomical anomalies should be ruled out. Sperm analysis, pre-implantation genetic screening and endometrial receptivity should be considered and evaluated, and IVF protocols should be tailored to specific patients or patient populations. Treatment approaches should be directed toward individual patient cases. In addition, we suggest considering a new initial step in approach to patients with RIF, individualized planned activities to activate the brain's reward system in attempt to improve immunological balance in the body.

The POSEIDON (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) criteria were developed to help clinicians identify and classify low-prognosis patients undergoing assisted reproductive technology (ART) and provide guidance for possible therapeutic strategies to overcome infertility. Since its introduction, the number of published studies using the POSEIDON criteria has increased steadily. However, a critical analysis of existing evidence indicates inconsistent and incomplete reporting of critical outcomes. Therefore, we developed guidelines to help researchers improve the quality of reporting in studies applying the POSEIDON criteria. We also discuss the advantages of using the POSEIDON criteria in ART clinical studies and elaborate on possible study designs and critical endpoints. Our ultimate goal is to advance the knowledge concerning the clinical use of the POSEIDON criteria to patients, clinicians, and the infertility community.

PurposeWe aim to estimate the future fertility of patient undergoing their first IVF cycle attempt with no oocyte retrieved, and to identify factors that might predict those who will conceive in subsequent IVF cycle attempt.MethodsA cohort retrospective study of all consecutive women attending our IVF unit, for their first IVF cycle attempt, between January 2013 to December 2019, who reached the ovum pick-up (OPU) stage with zero oocyte retrieved. Patients' characteristics and infertility-treatment-related variables in the first IVF cycle attempt were compared between those who conceived in a subsequent cycle and those who did not. Moreover, infertility-treatment-related variables during successful cycles resulting in pregnancy were compared to those without.Results59 met the study inclusion criteria, yielding zero oocytes. During the follow-up period, 12 (20.3%) women conceived (one conceived twice), and 8 (14%) gave birth to a live infant. Cumulative live-birth rate per OPU and per patients were 4% and 14%, respectively. Clinical pregnancies were achieved after 3.61+1.4 cycle attempts (range: 1-6), with no live-births following the fifth IVF cycle attempt. No in-between group differences were observed in ovarian stimulation variables of their first IVF cycle attempt. Moreover, in those cycles resulting in pregnancy, patients achieved a significantly higher number of fertilized oocytes (2.15+1.5 vs 0.94+1.5, respectively; pConclusionWomen yielding zero oocytes at their first IVF cycle attempt, may achieve 14% cumulative live-birth rate after 5 IVF cycle attempts. Moreover, those who conceived in subsequent IVF cycle attempts were those achieving 2 or more fertilized oocytes/TQE.

Background: To describe the clinical course of women with acute vaginal bleeding and a finding of uterine enhanced myometrial vascularity (EVM) with suspected retained products of conception (RPOC) on vaginal ultrasound examination. Methods: A retrospective cohort study including women with EMV and suspected RPOC attending a single tertiary medical center between April 2018 to May 2020. Women with uterine EMV were identified from medical records of the ultrasound clinics. Demographic and clinical characteristics were retrieved from women’s medical files. Results: During the study period nine women met inclusion criteria. The preceding event in seven and in two of the women was first and second trimester abortions, respectively. Of those who underwent first trimester abortion, three were surgical, two were medical and two were spontaneous. Suspected RPOC and EMV were observed by ultrasound in all cases. Six of nine women (67%) underwent uncomplicated operative hysteroscopy with removal of RPOC, and three (33%), who had severe active bleeding due to vascular malformations (arterio-venous malformation-1, pseudo-aneurysm of uterine artery-1, other vascular malformation-1) were treated with uterine artery embolization prior to operative hysteroscopy. Conclusions: Work-up of women with episodes of uterine bleeding following curettage or abortion should include color/power Doppler ultrasonography for the detection of EMV. Although in most cases EMV is a benign sonographic finding that accompany RPOC and disappear after the removal of RPOC, in women who present with acute vaginal bleeding it might hint for the presence of vascular malformations that might cause life-threatening bleeding during additional surgical interventions.

Objective: To examine whether the Stop GnRH-agonist combined with multiple-dose GnRH-antagonist protocol may improve conventional IVF/intracytoplasmic sperm injection (ICSI) cycle in poor ovarian response (POR) patients.Design: Cohort historical, proof of concept study.Setting: Tertiary, University affiliated Medical Center.Patient(s): Thirty POR patients, defined according to the Bologna criteria, who underwent a subsequent Stop GnRH-agonist combined with multiple-dose GnRH-antagonist controlled ovarian hyperstimulation (COH) protocol, within 3 months of the previous failed conventional IVF/ICSI cycle, were included. For the purposes of this study, we eliminated a bias in this selection by including only “genuine” poor responder patients, defined as those who yielded up to 3 oocytes following COH with a minimal gonadotropin daily dose of 300 IU.Main Outcome Measure(s): Number of oocytes retrieved, number of top-quality embryos, COH variables.Result(s): The Stop GnRH-agonist combined with multiple-dose GnRH-antagonist COH protocol revealed significantly higher numbers of follicles >13 mm on the day of hCG administration, higher numbers of oocytes retrieved, and top-quality embryos (TQE) with an acceptable clinical pregnancy rate (16.6%). Moreover, as expected, patients undergoing the Stop GnRH-agonist combined with multiple-dose GnRH-antagonist COH protocol required significantly higher doses and a longer duration of gonadotropins stimulation.Conclusion(s): The combined Stop GnRH-ag/GnRH-ant COH protocol is a valuable tool in the armamentarium for treating “genuine” poor ovarian responders. Further, large prospective studies are needed to elucidate its role in POR and to characterize the appropriate patients subgroup (before initiating ovarian stimulation) that may benefit from the combined Stop GnRH-ag/GnRH-ant COH protocol.

ObjectiveTo assess the efficacy and clinical outcome of PGT-M undertaken on Day-3, Day-4 and Day-4 "delayed" embryos that were unsuitable for biopsy on Day-3.Design and settingCohort-historical study of all consecutive patients admitted to the IVF-PGT-M program in a large tertiary center.Main outcome measure(s)The pregnancy rates and the percentages of complete, incomplete diagnosis, PCR failure, abnormal embryos in PGT of Day-3 cleavage-stage, Day-4 and Day-4 "delayed" embryos.Patients and methodsWe reviewed the medical files of all consecutive patients admitted to our IVF for a fresh IVF-PGT-M cycle. Patients were divided into 3 groups according to the day of blastomere biopsy: Day 3 cleavage-stage, Day-4 morula and Day-4 "delayed" embryos. The laboratory data, genetic diagnostic and clinical results were collected and compared between the different study groups.ResultsNine hundred and six patients underwent PGT-M cycles in our PGT program: 747, 127 and 32 in the Day-3, Day- 4 and Day-4 "delayed" groups, respectively. Ongoing pregnancy rates per transfer and per patient (15.8% and 9.4%, respectively) were non-significantly lower in the Day-4 "delayed", compared to Day-3 (21.4% and 17.5%, respectively) and Day-4 (24.3% and 19.7%, respectively). When comparing ALL morulas (Day-4 and Day-4 "delayed") to ALL cleavage-stage embryos (Day-3, Day-4 and Day-4 "delayed"), a significantly higher ongoing pregnancy rate was demonstrated following the transfer of embryos derived from morula biopsy, as compared to biopsy at the cleavage-stage (33.3% vs 20.5%, pConclusionDay-4 embryo biopsy is feasible and yields comparable and even higher ongoing pregnancy rate if undertaken at the morula stage. Further studies evaluating the cumulative live-birth rate per started cycles in Day-3 vs Day-4 embryo biopsy for PGT-M are warranted.

The number of embryos transferred during an IVF cycle is directly related to the high incidence of multiple births, which is the culprit of perinatal morbidity. Therefore, single fresh embryo transfer (ET) strategy, or freeze-all, followed by a single frozen-thawed embryo transfer (FET) cycle, may dramatically reduce the rate of multiple births, without compromising the cumulative live birth rates (LBRs). A literature review was conducted for all available evidences assessing obstetrics and perinatal outcomes associated with FET compared to fresh ET and natural conception. While studies comparing fresh and FET cycles in normal responders have yielded conflicting results for pregnancy rate, FET was associated with lower risk of prematurity and low birth weight and increased risk of large for gestational age (LGA) and/or macrosomic in singletons, when compared with fresh ET. Macrosomic/LGA births have a higher risk of fetal hypoxia, stillbirth, shoulder dystocia, perineal lacerations, cesarean section, postpartum hemorrhage and neonatal metabolic disturbances at birth. Nonetheless, it seems that other than higher risk of fetal macrosomia, there are additional obstetric complications associated with FET. The relative risk of hypertensive disorders in pregnancy, as well as perinatal mortality were also demonstrated to be increased in FET compared with singletons from fresh ET and natural conception. Therefore, when considering elective freeze-all policy, in addition to LBR and the risk of ovarian hyperstimulation syndrome, physicians should consider the aforementioned increased FET cycles' pregnancy complications, including LGA/ macrosomia, hypertensive disorders of pregnancy, as well as perinatal mortality.

Abstract Endometriosis is an estrogen-dependent chronic inflammatory condition that affects women in their reproductive period causing infertility and pelvic pain. The disease, especially at the ovarian site has been shown to have a detrimental impact on ovarian physiology. Indeed, sonographic and histologic data tend to support the idea that ovarian follicles of endometriosis patients are decreased in number and more atretic. Moreover, the local intrafollicular environment of patients affected is characterized by alterations of the granulosa cell compartment including reduced P450 aromatase expression and increased intracellular reactive oxygen species generation. However, no comprehensive evaluation of the literature addressing the effect of endometriosis on oocyte quality from both a clinical and a biological perspective has so far been conducted. Based on this systematic review of the literature, oocytes retrieved from women affected by endometriosis are more likely to fail in vitro maturation and to show altered morphology and lower cytoplasmic mitochondrial content compared to women with other causes of infertility. Results from meta-analyses addressing IVF outcomes in women affected would indicate that a reduction in the number of mature oocytes retrieved is associated with endometriosis while a reduction in fertilization rates is more likely to be associated with minimal/mild rather than with moderate/severe disease. However, evidence in this field is still far to be conclusive, especially with regards to the effects of different stages of the disease and to the impact of patients’ previous medical/surgical treatment(s).

Abstract So-called mild controlled ovarian hyperstimulation (mCOH) has in recent years increased in popularity, claiming to be safer and more patient-friendly, while also improving in vitro fertilization (IVF) outcomes. We here challenge the International Society for Mild Approaches in Assisted Reproduction (ISMAAR) definition of mild stimulation, and especially address four fundamental issues, where our review found conventional COH (cCOH) advantageous over mCOH. They are: prevalence of severe ovarian hyperstimulation syndrome (OHSS), oocyte/embryo quality, pregnancy/live birth rates, and cost. We conclude that an objective review of the literature does not support the routine utilization of mCOH in assisted reproduction.

Résumé La reproduction des mammifères est l’un des phénomènes biologiques les plus complexes et fascinant; son objectif est de transférer le matériel génétique maternel et paternel à la génération suivante. A la fin de l’ovogenèse et de la spermatogenèse, les deux gamètes haploïdes contiennent un ensemble unique de chromosomes prêts à former un zygote, la première cellule du nouvel individu en développement. L’ovocyte mature et les spermatozoïdes restent dans un état quiescent au cours duquel l’ovocyte est caractérisé par un arrêt cytoplasmique et nucléaire, alors que les spermatozoïdes ont besoin d’une maturation ultérieure dans l’épididyme et le tractus génital femelle avant de pouvoir féconder l’ovocyte. Que ce soit in vivo ou in vitro, le spermatozoïde amorce une série de modifications biochimiques et physiologiques dans l’ovocyte. Le premier signal détecté après la fécondation est constitué des oscillations Ca2+ cytosoliques, une condition préalable au développement embryonnaire. Ces oscillations libèrent l’ovocyte de son arrêt en seconde méiose vers l’embryogenèse, phénomène connu sous le nom ‘d’activation de l’ovocyte’. L’isoforme phospholipase C zeta (PLCζ) est la seule protéine soluble du spermatozoïde capable d’activer dans l’ovocyte la voie de signalisation inositol triphosphate/Ca2+ qui mène aux oscillations Ca2+ et par conséquent au développement de l’embryon. Par rapport aux autres PLC, la structure spécifique de PLCζ lui confère une activité spécialisée via les domaines catalytiques préservés de X et Y, ainsi que des caractéristiques propres tels un déclenchement rapide, une grande sensibilité au Ca2+ et un arrêt des oscillations à la formation du zygote. Les découvertes récentes de PLCζ ont induit des études centrées sur les possibles applications cliniques de cette protéine dans l’évaluation et la prise en charge de l’infertilité masculine lors de FIV/ICSI. L’échec de fécondation est attribué à l’absence de reprise de la seconde méiose ovocytaire, suggérant la possibilité que l’échec de l’ICSI puisse être lié à une activité défectueuse de la PLCζ dans le spermatozoïde. La micro injection de PLCζ humaine recombinante dans des ovocytes humains après échec de fécondation en ICSI pourrait déclencher des oscillations Ca2+ et permettre une fécondation réussie, offrant de nouveaux espoirs aux couples traditionnellement orientés vers le don de spermatozoïdes. Il est toutefois nécessaire de disposer d’un plus grand nombre d’études avant toute mise en œuvre de cette approche en clinique. Des orientations pour de futures études sont discutées.

Abstract The hypothesis of preimplantation genetic diagnosis (PGS) was first proposed 20 years ago, suggesting that elimination of aneuploid embryos prior to transfer will improve implantation rates of remaining embryos during in vitro fertilization (IVF), increase pregnancy and live birth rates and reduce miscarriages. The aforementioned improved outcome was based on 5 essential assumptions: (i) Most IVF cycles fail because of aneuploid embryos. (ii) Their elimination prior to embryo transfer will improve IVF outcomes. (iii) A single trophectoderm biopsy (TEB) at blastocyst stage is representative of the whole TE. (iv) TE ploidy reliably represents the inner cell mass (ICM). (v) Ploidy does not change (i.e., self-correct) downstream from blastocyst stage. We aim to offer a review of the aforementioned assumptions and challenge the general hypothesis of PGS. We reviewed 455 publications, which as of January 20, 2017 were listed in PubMed under the search phrase . The literature review was performed by both authors who agreed on the final 55 references. Various reports over the last 18 months have raised significant questions not only about the basic clinical utility of PGS but the biological underpinnings of the hypothesis, the technical ability of a single trophectoderm (TE) biopsy to accurately assess an embryo’s ploidy, and suggested that PGS actually negatively affects IVF outcomes while not affecting miscarriage rates. Moreover, due to high rates of false positive diagnoses as a consequence of high mosaicism rates in TE, PGS leads to the discarding of large numbers of normal embryos with potential for normal euploid pregnancies if transferred rather than disposed of. We found all 5 basic assumptions underlying the hypothesis of PGS to be unsupported: (i) The association of embryo aneuploidy with IVF failure has to be reevaluated in view how much more common TE mosaicism is than has until recently been appreciated. (ii) Reliable elimination of presumed aneuploid embryos prior to embryo transfer appears unrealistic. (iii) Mathematical models demonstrate that a single TEB cannot provide reliable information about the whole TE. (iv) TE does not reliably reflect the ICM. (v) Embryos, likely, still have strong innate ability to self-correct downstream from blastocyst stage, with ICM doing so better than TE. The hypothesis of PGS, therefore, no longer appears supportable. With all 5 basic assumptions underlying the hypothesis of PGS demonstrated to have been mistaken, the hypothesis of PGS, itself, appears to be discredited. Clinical use of PGS for the purpose of IVF outcome improvements should, therefore, going forward be restricted to research studies.

Abstract In the literature, there is growing evidence that subfertile patients who conceived after infertility treatments have an increased risk of pregnancy and perinatal complications and this is particularly true for patients who conceived through use of high technology infertility treatments. Moreover, high technology infertility treatments include many concomitant clinical and biological risk factors. This review aims to summarize in a systematic fashion the current evidence regarding the relative effect of the different procedures for high technology infertility treatments on the risk of adverse pregnancy and perinatal outcome. A literature search up to August 2016 was performed in IBSS, SocINDEX, Institute for Scientific Information, PubMed, Web of Science and Google Scholar and an evidence-based hierarchy was used to determine which articles to include and analyze. Data on prepregnancy maternal factors, low technology interventions, specific procedures for male factor, ovarian tissue/ovary and uterus transplantation, and chromosomal abnormalities and malformations of the offspring were excluded. The available evidences were analyzed assessing the level and the quality of evidence according to the Oxford Centre for Evidence-Based Medicine guidelines and the Grading of Recommendations Assessment, Development, and Evaluation system, respectively. Current review highlights that every single procedure of high technology infertility treatments can play a crucial role in increasing the risk of pregnancy and perinatal complications. Due to the suboptimal level and quality of the current evidence, further well-designed studies are needed.

ObjectiveTo evaluate ovarian reserve in women after preservative cesarean delivery using uterine artery embolization due to morbidly adherent placenta.Study designA historical cohort study including all women admitted to a single tertiary care center, with morbidly adherent placenta that had preservative cesarean delivery with bilateral uterine artery embolization. Inclusion criteria included gestational age >24 weeks, singleton pregnancy and placenta increta / percreta. Exclusion criteria included maternal age > 43 years old and cesarean hysterectomy. Control group included women attending the infertility clinic due to male factor or single women conceiving via sperm donation, matched by age. Blood samples were collected on day 2-5 of menstruations for hormonal profile and Anti Mullarian Hormone (AMH) levels. Primary outcome was ovarian reserve evaluated by the levels of AMH.Results59 women underwent preservative cesarean delivery using uterine artery embolization during the study period. 21 women met inclusion criteria (33.9%) and were matched controls (n = 40). Circulating levels of E2 and FSH did not differ significantly between the two groups (p = 0.665, p = 0.396, respectively). AMH was lower in the study group (median 0.8 IQR 0.44-1.80) compared to the controls (median 2.08 IQR 1.68-3.71) (p = 0.001). This finding was consistent in linear multivariate regression analysis where the group of cesarean delivery using bilateral artery embolization due to placenta accrete was significantly predictive for the levels of AMH (B = -1.308, p = 0.012).ConclusionWomen post preservative cesarean delivery using uterine artery embolization due to placenta accrete have lower ovarian reserve compare to controls matched by age.

OBJECTIVE:To evaluate the influence of seasonal variation on in vitro fertilization (IVF) outcome in a large cohort population. METHODS & MATERIALS:A total of 5,765 IVF cycles conducted in Sheba medical center between 2013 and 2016 were retrospectively analyzed. The treatment cycles included 4214 ovarian stimulation and ovum pick up (OPU) cycles of which 3020 resulted in fresh embryo transfer and 1551 vitrified- warmed cycles of which1400 resulted in warmed embryo transfer. Cycles were assigned to seasons according to the date of OPU for fresh embryo transfer cycles or according to the date of embryo warming for vitrified warmed embryo transfer cycles. RESULTS:There were no statistically significant differences between the calendar months or seasons concerning the number of oocytes retrieved or fertilization rate in the fresh cycles. Throughout the 4 years of the study, the monthly clinical pregnancy rate fluctuated between 18.2% and 27.9% per fresh embryo transfer (mean 23.3%) and between 17.7% and 29.4% per vitrified warmed embryo transfer (mean 23%). These fluctuations did not follow any specific seasonal pattern. CONCLUSIONS:Our study did not demonstrate any significant influence of the calendar months or seasons on the clinical pregnancy rates of fresh or vitrified warmed embryo transfers. It might be speculated that the complete pharmaceutical control of the ovarian and endometrial function, as well as the homogeneous treatments, procedures and laboratory equipment used during the study period have lowered the influence of seasonal effect on IVF treatment outcome.

AimTo assess the role of mRNA accumulation in granulosa cells as the cause of low ovarian response among FMR1 premutation carriers undergoing pre-implantation genetic diagnosis (PGD).DesignCase control study in an academic IVF unit. Twenty-one consecutive FMR1 premutation carriers and 15 control women were included. After oocyte retrieval the granulosa cells mRNA levels of FMR1 was measured using RT-PCR.ResultsIn FMR1 premutation carriers, there was a significant non-linear association between the number of CGG repeats and the number of retrieved oocytes (pConclusionWe suggest that there is a no-linear association between the number of CGG repeats and ovarian function, resulting from an increased granulosa cells FMR1 mRNA accumulation in FMR1 carriers in the mid-range (80-120 repeats).

We report herein, two cases of massive delayed (2 and 4 days) intra abdominal hemorrhage following ovum pick-up (OPU), in patients at risk for thrombo-embolic events, who concomitantly used therapeutic doses of low molecular weight heparin (LMWH). We discuss the possible mechanisms involved in causing the aforementioned delayed bleeding, and call for re-evaluation of the presently accepted anticoagulant co-treatment regimen. These case reports should direct physicians' attention and keep them alert, while conducting IVF treatment to this subgroup of high risk patients.