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STUDY QUESTION Does follicular flushing increase the number of cumulus–oocyte complexes (COCs) retrieved compared to single aspiration? SUMMARY ANSWER Follicular flushing significantly increases the number of COCs retrieved compared to single aspiration. WHAT IS KNOWN ALREADY On the basis of published meta-analyses, follicular flushing does not seem to increase the number of oocytes retrieved, the probability of clinical pregnancy, or that of live birth and has been associated with an increase in the duration of oocyte retrieval. It should be noted, however, that all the eligible randomized controlled trials (RCTs) in these meta-analyses have randomized patients into either single aspiration or follicular flushing. This study design might not allow the detection of the true effect of follicular flushing. Despite randomization, this might still be obscured, to an extent, by heterogeneity in patients, stimulation characteristics, and differences in the oocyte retrieval procedure. STUDY DESIGN, SIZE, DURATION A prospective, single centre, RCT, including 105 patients was performed between July and December 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS Eligible patients were those undergoing oocyte retrieval for ICSI, aged <43 years, with BMI 18–35 kg/m2. Patients with all types of ovarian response (low-normal-high), as assessed on the day of triggering final oocyte maturation, were included. Random allocation of the ovaries of each patient to either single aspiration or follicular flushing was performed on the day of oocyte retrieval, using a computer-generated randomization list. Patients could enter the study only once. All follicles from ovaries allocated to either follicular flushing or single aspiration, were aspirated by the same 16G double lumen needle, with a constant aspiration pressure of 190 mmHg, resulting in flow rate of 0.42 ml/s. In the ovaries allocated to the follicular flushing group, if a COC was not recovered in the initial aspirate of each follicle, follicular flushing was performed until a COC was retrieved, up to a maximum of five times. The primary outcome measure was the number of COCs retrieved. Secondary outcomes were oocyte recovery rate, oocyte maturation rate, fertilization rate, and rate of good quality embryos on Day 2. Values are expressed as a median (inter-quartile range). MAIN RESULTS AND THE ROLE OF CHANCE Significantly more COCs were retrieved in the follicular flushing as compared to the single aspiration group in all patients [5 (7) vs 2 (3), P  < 0.001, respectively], as well as in patients with high [9 (3) vs 5 (4), P  < 0.001, respectively], normal [5 (2) vs 2 (3), P  < 0.001, respectively] and low [1 (1) vs 1 (1), P  < 0.001, respectively] ovarian response. In patients with low ovarian response, no COCs were retrieved in 5.7% of the ovaries in the flushing group vs 42.8% of the ovaries in the single aspiration group (P  < 0.001). The oocyte retrieval rate was significantly higher in the follicular flushing vs the single aspiration group, in all patients [88.9% (25.0) vs 45.5% (37.5), P  < 0.001, respectively], as well as in patients with high [81.8% (15.9) vs 45.5% (22.2), P  < 0.001, respectively], normal [85.7% (28.6) vs 40.0% (30.0), P  < 0.001, respectively], and low [100% (0) vs 50.0% (100), P  < 0.001, respectively] ovarian response. No significant difference was observed regarding maturation rate [85.2% (30.8) vs 100% (33.3), P  = 0.78], fertilization rate [76.4% (50) vs 83.3% (50) P  = 0.42], and the proportion of good quality embryos on Day 2 [83.3% (40) vs 100% (50), P  = 0.62]. Similarly, no differences in the above variables were observed in patients with different types of ovarian response. Follicular flushing as compared to single aspiration was associated with a significant increase in the duration of oocyte retrieval in all patients [248 s (332) vs 135 s (164), respectively], as well as in patients with high [464 s (225) vs 237 s (89), P  < 0.001, respectively], normal [248 s (108) vs 141 s (95), P  < 0.001, respectively], and low [64 s (59) vs 48 s (10), P  < 0.001, respectively] ovarian response. LIMITATIONS, REASONS FOR CAUTION Although the current study design allows for a more accurate evaluation of the true effect of follicular flushing on the number of COCs retrieved, it does not permit the evaluation of its role on the probability of pregnancy. WIDER IMPLICATIONS OF THE FINDINGS This is the first RCT to suggest that follicular flushing increases the number of COCs retrieved compared to single aspiration, independently of ovarian response. This implies that follicular flushing plays an important role in the optimization of oocyte retrieval. These results, however, need to be confirmed in future studies, in which an equal flow rate should be used during oocyte retrieval. STUDY FUNDING/COMPETING INTEREST(S) No external funding was obtained for this study. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER NCT05473455 TRIAL REGISTRATION DATE 15 July 2022 DATE OF FIRST PATIENT'S ENROLMENT 27 July 2022 [ABSTRACT FROM AUTHOR]

STUDY QUESTION How should recurrent implantation failure (RIF) in patients undergoing ART be defined and managed? SUMMARY ANSWER This is the first ESHRE good practice recommendations paper providing a definition for RIF together with recommendations on how to investigate causes and contributing factors, and how to improve the chances of a pregnancy. WHAT IS KNOWN ALREADY RIF is a challenge in the ART clinic, with a multitude of investigations and interventions offered and applied in clinical practice, often without biological rationale or with unequivocal evidence of benefit. STUDY DESIGN, SIZE, DURATION This document was developed according to a predefined methodology for ESHRE good practice recommendations. Recommendations are supported by data from the literature, if available, and the results of a previously published survey on clinical practice in RIF and the expertise of the working group. A literature search was performed in PubMed and Cochrane focussing on 'recurrent reproductive failure', 'recurrent implantation failure', and 'repeated implantation failure'. PARTICIPANTS/MATERIALS, SETTING, METHODS The ESHRE Working Group on Recurrent Implantation Failure included eight members representing the ESHRE Special Interest Groups for Implantation and Early Pregnancy, Reproductive Endocrinology, and Embryology, with an independent chair and an expert in statistics. The recommendations for clinical practice were formulated based on the expert opinion of the working group, while taking into consideration the published data and results of the survey on uptake in clinical practice. The draft document was then open to ESHRE members for online peer review and was revised in light of the comments received. MAIN RESULTS AND THE ROLE OF CHANCE The working group recommends considering RIF as a secondary phenomenon of ART, as it can only be observed in patients undergoing IVF, and that the following description of RIF be adopted: 'RIF describes the scenario in which the transfer of embryos considered to be viable has failed to result in a positive pregnancy test sufficiently often in a specific patient to warrant consideration of further investigations and/or interventions'. It was agreed that the recommended threshold for the cumulative predicted chance of implantation to identify RIF for the purposes of initiating further investigation is 60%. When a couple have not had a successful implantation by a certain number of embryo transfers and the cumulative predicted chance of implantation associated with that number is greater than 60%, then they should be counselled on further investigation and/or treatment options. This term defines clinical RIF for which further actions should be considered. Nineteen recommendations were formulated on investigations when RIF is suspected, and 13 on interventions. Recommendations were colour-coded based on whether the investigations/interventions were recommended (green), to be considered (orange), or not recommended, i.e. not to be offered routinely (red). LIMITATIONS, REASONS FOR CAUTION While awaiting the results of further studies and trials, the ESHRE Working Group on Recurrent Implantation Failure recommends identifying RIF based on the chance of successful implantation for the individual patient or couple and to restrict investigations and treatments to those supported by a clear rationale and data indicating their likely benefit. WIDER IMPLICATIONS OF THE FINDINGS This article provides not only good practice advice but also highlights the investigations and interventions that need further research. This research, when well-conducted, will be key to making progress in the clinical management of RIF. STUDY FUNDING/COMPETING INTEREST(S) The meetings and technical support for this project were funded by ESHRE. N.M. declared consulting fees from ArtPRED (The Netherlands) and Freya Biosciences (Denmark); Honoraria for lectures from Gedeon Richter, Merck, Abbott, and IBSA; being co-founder of Verso Biosense. He is Co-Chief Editor of Reproductive Biomedicine Online (RBMO). D.C. declared being an Associate Editor of Human Reproduction Update , and declared honoraria for lectures from Merck, Organon, IBSA, and Fairtility; support for attending meetings from Cooper Surgical, Fujifilm Irvine Scientific. G.G. declared that he or his institution received financial or non-financial support for research, lectures, workshops, advisory roles, or travelling from Ferring, Merck, Gedeon-Richter, PregLem, Abbott, Vifor, Organon, MSD, Coopersurgical, ObsEVA, and ReprodWissen. He is an Editor of the journals Archives of Obstetrics and Gynecology and Reproductive Biomedicine Online , and Editor in Chief of Journal Gynäkologische Endokrinologie. He is involved in guideline developments and quality control on national and international level. G.L. declared he or his institution received honoraria for lectures from Merck, Ferring, Vianex/Organon, and MSD. He is an Associate Editor of Human Reproduction Update , immediate past Coordinator of Special Interest Group for Reproductive Endocrinology of ESHRE and has been involved in Guideline Development Groups of ESHRE and national fertility authorities. D.J.M. declared being an Associate Editor for Human Reproduction Open and statistical Advisor for Reproductive Biomedicine Online. B.T. declared being shareholder of Reprognostics and she or her institution received financial or non-financial support for research, clinical trials, lectures, workshops, advisory roles or travelling from support for attending meetings from Ferring, MSD, Exeltis, Merck Serono, Bayer, Teva, Theramex and Novartis, Astropharm, Ferring. The other authors had nothing to disclose. DISCLAIMER This Good Practice Recommendations (GPR) document represents the views of ESHRE, which are the result of consensus between the relevant ESHRE stakeholders and are based on the scientific evidence available at the time of preparation. ESHRE GPRs should be used for information and educational purposes. They should not be interpreted as setting a standard of care or be deemed inclusive of all proper methods of care, or be exclusive of other methods of care reasonably directed to obtaining the same results. They do not replace the need for application of clinical judgement to each individual presentation, or variations based on locality and facility type. Furthermore, ESHRE GPRs do not constitute or imply the endorsement, or favouring, of any of the included technologies by ESHRE. [ABSTRACT FROM AUTHOR]

Ovarian hyperstimulation syndrome (OHSS) is a serious complication of ovarian stimulation protocols. Currently, no curative therapy exists and the main preventive option is cycle cancellation. Gonadotrophin-releasing hormone (GnRH) antagonist administration in the luteal phase was recently proposed as a new approach for the management of patients with established severe OHSS. Three polycystic ovarian syndrome patients undergoing IVF treatment developed severe OHSS, diagnosed 6 days after oocyte retrieval. On day 6, the patients underwent blastocyst transfer and received GnRH antagonist for 4 days, combined with luteal phase support using exogenous oestradiol and progesterone. Two patients had successful pregnancies that resulted in births of healthy infants, while one patient had a biochemical pregnancy. In all patients, established severe OHSS regressed to a moderate form of the syndrome, no pregnancy-induced life-threatening OHSS was observed, while a short monitoring period was required at an outpatient level, avoiding the need for patient hospitalization. This is the first report in the literature on GnRH antagonist administration in the luteal phase, combined with embryo transfer and exogenous oestradiol and progesterone supplementation. This novel treatment was effective in the regression of established severe OHSS, and resulted in the birth of healthy infants. [ABSTRACT FROM AUTHOR]

Despite the fact that many methods have been proposed for the management of severe ovarian hyperstimulation syndrome (OHSS), its prevention is mainly achieved by withholding human chorionic gonadotrophin (HCG) administration and cycle cancellation. Currently no curative therapy is available. Three women diagnosed with polycystic ovarian syndrome underwent ovarian stimulation for IVF using a long gonadotrophin-releasing hormone (GnRH) agonist protocol. Six days after oocyte retrieval, severe early OHSS was diagnosed by analysis of haematocrit, white blood cell (WBC) count, serum urea, and ultrasonographic assessment of ovarian size and ascitic fluid. On the same day, antagonist administration was administrated and continued daily for 1 week, while resulting blastocysts were cryopreserved. Progression of severe early OHSS was inhibited in all three patients. A marked decrease of haematocrit, WBC, ascitic fluid, oestradiol, progesterone and ovarian volume was observed, during 1 week of follow-up suggesting a luteolytic effect of GnRH antagonist. None of the patients required hospitalization. In conclusion, GnRH antagonist administration combined with blastocyst cryopreservation 6 days post retrieval might represent a new approach for the effective management of patients with established severe OHSS. The flexibility of the approach allows the elongation of the monitoring period up to 8 days following HCG administration. [ABSTRACT FROM AUTHOR]

Several approaches have been proposed for the management of OHSS that reduce, but do not completely eliminate the incidence of human chorionic gonadotrophin (HCG)-induced early severe OHSS. Three women diagnosed with polycystic ovarian syndrome underwent ovarian stimulation for IVF using a gonadotrophin-releasing hormone (GnRH) antagonist protocol. Three days after oocyte retrieval, severe early OHSS was diagnosed by analysis of haematocrit (Ht), white blood cell (WBC) count, serum urea, and ultrasonographic assessment of ovarian size and ascitic fluid. On the same day, antagonist administration was re-initiated and continued daily for a week, while all embryos were cryopreserved. No progression of severe early OHSS was observed in any of the patients. A marked decrease of Ht, WBC count, ovarian volume and ascitic fluid was observed during 1 week of follow-up, and none of the patients required hospitalization. GnRH antagonist re-initiation might represent a new strategy for flexible management of patients with established severe early OHSS. Based on the flexibility of the approach, if severe OHSS does not occur, patients may proceed to embryo transfer, while if severe early OHSS ensues, antagonist administration combined with embryo cryopreservation appear to be associated with prevention of life-threatening OHSS, facilitation of regression of severe OHSS to a moderate form and avoidance of patient hospitalization. [ABSTRACT FROM AUTHOR]

Purpose: To provide agreed-upon guidelines on the management of a hyper-responsive patient undergoing ovarian stimulation (OS) METHODS: A literature search was performed regarding the management of hyper-response to OS for assisted reproductive technology. A scientific committee consisting of 4 experts discussed, amended, and selected the final statements. A priori, it was decided that consensus would be reached when ≥66% of the participants agreed, and ≤3 rounds would be used to obtain this consensus. A total of 28/31 experts responded (selected for global coverage), anonymous to each other., Results: A total of 26/28 statements reached consensus. The most relevant are summarized here. The target number of oocytes to be collected in a stimulation cycle for IVF in an anticipated hyper-responder is 15-19 (89.3% consensus). For a potential hyper-responder, it is preferable to achieve a hyper-response and freeze all than aim for a fresh transfer (71.4% consensus). GnRH agonists should be avoided for pituitary suppression in anticipated hyper-responders performing IVF (96.4% consensus). The preferred starting dose in the first IVF stimulation cycle of an anticipated hyper-responder of average weight is 150 IU/day (82.1% consensus). ICoasting in order to decrease the risk of OHSS should not be used (89.7% consensus). Metformin should be added before/during ovarian stimulation to anticipated hyper-responders only if the patient has PCOS and is insulin resistant (82.1% consensus). In the case of a hyper-response, a dopaminergic agent should be used only if hCG will be used as a trigger (including dual/double trigger) with or without a fresh transfer (67.9% consensus). After using a GnRH agonist trigger due to a perceived risk of OHSS, luteal phase rescue with hCG and an attempt of a fresh transfer is discouraged regardless of the number of oocytes collected (72.4% consensus). The choice of the FET protocol is not influenced by the fact that the patient is a hyper-responder (82.8% consensus). In the cases of freeze all due to OHSS risk, a FET cycle can be performed in the immediate first menstrual cycle (92.9% consensus)., Conclusion: These guidelines for the management of hyper-response can be useful for tailoring patient care and for harmonizing future research., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Study Question: How should recurrent implantation failure (RIF) in patients undergoing ART be defined and managed?, Summary Answer: This is the first ESHRE good practice recommendations paper providing a definition for RIF together with recommendations on how to investigate causes and contributing factors, and how to improve the chances of a pregnancy., What Is Known Already: RIF is a challenge in the ART clinic, with a multitude of investigations and interventions offered and applied in clinical practice, often without biological rationale or with unequivocal evidence of benefit., Study Design Size Duration: This document was developed according to a predefined methodology for ESHRE good practice recommendations. Recommendations are supported by data from the literature, if available, and the results of a previously published survey on clinical practice in RIF and the expertise of the working group. A literature search was performed in PubMed and Cochrane focussing on 'recurrent reproductive failure', 'recurrent implantation failure', and 'repeated implantation failure'., Participants/materials Setting Methods: The ESHRE Working Group on Recurrent Implantation Failure included eight members representing the ESHRE Special Interest Groups for Implantation and Early Pregnancy, Reproductive Endocrinology, and Embryology, with an independent chair and an expert in statistics. The recommendations for clinical practice were formulated based on the expert opinion of the working group, while taking into consideration the published data and results of the survey on uptake in clinical practice. The draft document was then open to ESHRE members for online peer review and was revised in light of the comments received., Main Results and the Role of Chance: The working group recommends considering RIF as a secondary phenomenon of ART, as it can only be observed in patients undergoing IVF, and that the following description of RIF be adopted: 'RIF describes the scenario in which the transfer of embryos considered to be viable has failed to result in a positive pregnancy test sufficiently often in a specific patient to warrant consideration of further investigations and/or interventions'. It was agreed that the recommended threshold for the cumulative predicted chance of implantation to identify RIF for the purposes of initiating further investigation is 60%. When a couple have not had a successful implantation by a certain number of embryo transfers and the cumulative predicted chance of implantation associated with that number is greater than 60%, then they should be counselled on further investigation and/or treatment options. This term defines clinical RIF for which further actions should be considered. Nineteen recommendations were formulated on investigations when RIF is suspected, and 13 on interventions. Recommendations were colour-coded based on whether the investigations/interventions were recommended (green), to be considered (orange), or not recommended, i.e. not to be offered routinely (red)., Limitations Reasons for Caution: While awaiting the results of further studies and trials, the ESHRE Working Group on Recurrent Implantation Failure recommends identifying RIF based on the chance of successful implantation for the individual patient or couple and to restrict investigations and treatments to those supported by a clear rationale and data indicating their likely benefit., Wider Implications of the Findings: This article provides not only good practice advice but also highlights the investigations and interventions that need further research. This research, when well-conducted, will be key to making progress in the clinical management of RIF., Study Funding/competing Interests: The meetings and technical support for this project were funded by ESHRE. N.M. declared consulting fees from ArtPRED (The Netherlands) and Freya Biosciences (Denmark); Honoraria for lectures from Gedeon Richter, Merck, Abbott, and IBSA; being co-founder of Verso Biosense. He is Co-Chief Editor of Reproductive Biomedicine Online (RBMO). D.C. declared being an Associate Editor of Human Reproduction Update , and declared honoraria for lectures from Merck, Organon, IBSA, and Fairtility; support for attending meetings from Cooper Surgical, Fujifilm Irvine Scientific. G.G. declared that he or his institution received financial or non-financial support for research, lectures, workshops, advisory roles, or travelling from Ferring, Merck, Gedeon-Richter, PregLem, Abbott, Vifor, Organon, MSD, Coopersurgical, ObsEVA, and ReprodWissen. He is an Editor of the journals Archives of Obstetrics and Gynecology and Reproductive Biomedicine Online , and Editor in Chief of Journal Gynäkologische Endokrinologie . He is involved in guideline developments and quality control on national and international level. G.L. declared he or his institution received honoraria for lectures from Merck, Ferring, Vianex/Organon, and MSD. He is an Associate Editor of Human Reproduction Update , immediate past Coordinator of Special Interest Group for Reproductive Endocrinology of ESHRE and has been involved in Guideline Development Groups of ESHRE and national fertility authorities. D.J.M. declared being an Associate Editor for Human Reproduction Open and statistical Advisor for Reproductive Biomedicine Online . B.T. declared being shareholder of Reprognostics and she or her institution received financial or non-financial support for research, clinical trials, lectures, workshops, advisory roles or travelling from support for attending meetings from Ferring, MSD, Exeltis, Merck Serono, Bayer, Teva, Theramex and Novartis, Astropharm, Ferring. The other authors had nothing to disclose., Disclaimer: This Good Practice Recommendations (GPR) document represents the views of ESHRE, which are the result of consensus between the relevant ESHRE stakeholders and are based on the scientific evidence available at the time of preparation . ESHRE GPRs should be used for information and educational purposes. They should not be interpreted as setting a standard of care or be deemed inclusive of all proper methods of care, or be exclusive of other methods of care reasonably directed to obtaining the same results. They do not replace the need for application of clinical judgement to each individual presentation, or variations based on locality and facility type . Furthermore, ESHRE GPRs do not constitute or imply the endorsement, or favouring, of any of the included technologies by ESHRE ., Competing Interests: N.M. declared consulting fees from ArtPRED (The Netherlands) and Freya Biosciences (Denmark); honoraria for lectures from Gedeon Richter, Merck, Abbott, and IBSA; being co-founder of Verso Biosense. He is Co-Chief Editor of Reproductive Biomedicine Online (RBMO). D.C. declared being an Associate Editor of Human Reproduction Update, and declared honoraria for lectures from Merck, Organon, IBSA, and Fairtility; support for attending meetings from Cooper Surgical, Fujifilm Irvine Scientific. G.G. declared that he or his institution received financial or non-financial support for research, lectures, workshops, advisory roles or travelling from Ferring, Merck, Gedeon-Richter, PregLem, Abbott, Vifor, Organon, MSD, Coopersurgical, ObsEVA, and ReprodWissen. He is an Editor of the journals Archives of Obstetrics and Gynecology and Reproductive Biomedicine Online, and Editor in Chief of Journal Gynäkologische Endokrinologie. He is involved in guideline developments and quality control on national and international level. G.L. declared he or his institution received honoraria for lectures from Merck, Ferring, Vianex/Organon, and MSD. He is an Associate Editor of Human Reproduction Update, immediate past Co-ordinator of Special Interest Group for Reproductive Endocrinology of ESHRE and has been involved in Guideline Development Groups of ESHRE and national fertility authorities. D.J.M. declared being an Associate Editor for Human Reproduction Open and statistical Advisor for Reproductive Biomedicine Online. B.T. declared being shareholder of Reprognostics and she or her institution received financial or non-financial support for research, clinical trials, lectures, workshops, advisory roles or travelling from support for attending meetings from Ferring, MSD, Exeltis, Merck Serono, Bayer, Teva, Theramex and Novartis, Astropharm, Ferring. The other authors had nothing to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Purpose of Review: To critically evaluate the use of follicular flushing during oocyte retrieval., Recent Findings: The latest meta-analysis evaluating follicular flushing does not favour its use over single aspiration. The randomized controlled trials (RCTs) included, however, are characterized by significant heterogeneity regarding the population analysed, the needle type and lumen used, the aspiration pressure applied and the number of flushing attempts performed. More importantly, information regarding the flow rate used for aspiration is scarce. The only RCT employing a constant flow rate between single aspiration and follicular flushing in women with monofollicular development, suggests that a higher number of oocytes is retrieved after follicular flushing., Summary: In order to eliminate clinical heterogeneity that might obscure the detection of the true effect of follicular flushing, randomization to single aspiration and follicular flushing should occur within the same patient. This can be achieved by randomly allocating each patient's ovary to either single aspiration or follicular flushing, maintaining similar flow rates between the groups compared.Given the importance of maximizing the number of oocytes retrieved from a given number of follicles developed, the conduction of properly designed RCTs evaluating follicular flushing is certainly required., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Study Question: Is it possible to define a set of performance indicators (PIs) for clinical work in ART, which can create competency profiles for clinicians and for specific clinical process steps?, Summary Answer: The current paper recommends six PIs to be used for monitoring clinical work in ovarian stimulation for ART, embryo transfer, and pregnancy achievement: cycle cancellation rate (before oocyte pick-up (OPU)) (%CCR), rate of cycles with moderate/severe ovarian hyperstimulation syndrome (OHSS) (%mosOHSS), the proportion of mature (MII) oocytes at ICSI (%MII), complication rate after OPU (%CoOPU), clinical pregnancy rate (%CPR), and multiple pregnancy rate (%MPR)., What Is Known Already: PIs are objective measures for evaluating critical healthcare domains. In 2017, ART laboratory key PIs (KPIs) were defined., Study Design Size Duration: A list of possible indicators was defined by a working group. The value and limitations of each indicator were confirmed through assessing published data and acceptability was evaluated through an online survey among members of ESHRE, mostly clinicians, of the special interest group Reproductive Endocrinology., Participants/materials Setting Methods: The online survey was open for 5 weeks and 222 replies were received. Statements (indicators, indicator definitions, or general statements) were considered accepted when ≥70% of the responders agreed (agreed or strongly agreed). There was only one round to seek levels of agreement between the stakeholders.Indicators that were accepted by the survey responders were included in the final list of indicators. Statements reaching less than 70% were not included in the final list but were discussed in the paper., Main Results and the Role of Chance: Cycle cancellation rate (before OPU) and the rate of cycles with moderate/severe OHSS, calculated on the number of started cycles, were defined as relevant PIs for monitoring ovarian stimulation. For monitoring ovarian response, trigger and OPU, the proportion of MII oocytes at ICSI and complication rate after OPU were listed as PIs: the latter PI was defined as the number of complications (any) that require an (additional) medical intervention or hospital admission (apart from OHSS) over the number of OPUs performed. Finally, clinical pregnancy rate and multiple pregnancy rate were considered relevant PIs for embryo transfer and pregnancy. The defined PIs should be calculated every 6 months or per 100 cycles, whichever comes first. Clinical pregnancy rate and multiple pregnancy rate should be monitored more frequently (every 3 months or per 50 cycles). Live birth rate (LBR) is a generally accepted and an important parameter for measuring ART success. However, LBR is affected by many factors, even apart from ART, and it cannot be adequately used to monitor clinical practice. In addition to monitoring performance in general, PIs are essential for managing the performance of staff over time, and more specifically the gap between expected performance and actual performance measured. Individual clinics should determine which indicators are key to the success in their organisation based on their patient population, protocols, and procedures, and as such, which are their KPIs., Limitations Reasons for Caution: The consensus values are based on data found in the literature and suggestions of experts. When calculated and compared to the competence/benchmark limits, prudent interpretation is necessary taking into account the specific clinical practice of each individual centre., Wider Implications of the Findings: The defined PIs complement the earlier defined indicators for the ART laboratory. Together, both sets of indicators aim to enhance the overall quality of the ART practice and are an essential part of the total quality management. PIs are important for education and can be applied during clinical subspecialty., Study Funding/competing Interests: This paper was developed and funded by ESHRE, covering expenses associated with meetings, literature searches, and dissemination. The writing group members did not receive payment.Dr G.G. reports personal fees from Merck, MSD, Ferring, Theramex, Finox, Gedeon-Richter, Abbott, Biosilu, ReprodWissen, Obseva, PregLem, and Guerbet, outside the submitted work. Dr A.D. reports personal fees from Cook, outside the submitted work; Dr S.A. reports starting a new employment in May 2020 at Vitrolife. Previously, she has been part of the Nordic Embryology Academic Team, with meetings were sponsored by Gedeon Richter. The other authors have no conflicts of interest to declare., Disclaimer: This document represents the views of ESHRE, which are the result of consensus between the relevant ESHRE stakeholders and where relevant based on the scientific evidence available at the time of preparation.The recommendations should be used for informational and educational purposes. They should not be interpreted as setting a standard of care, or be deemed inclusive of all proper methods of care nor exclusive of other methods of care reasonably directed to obtaining the same results. They do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type.Furthermore, ESHREs recommendations do not constitute or imply the endorsement, recommendation, or favouring of any of the included technologies by ESHRE., (© The Author(s) 2021. Published by Oxford University Press.)

Study Question: Can the grade of ascites, haematocrit (Ht), white blood cell (WBC) count and maximal ovarian diameter (MOD) measured on Day 3 be used to construct a decision-making algorithm for performing or cancelling embryo transfer in patients at high risk for severe ovarian hyperstimulation syndrome (OHSS) after an hCG trigger?, Summary Answer: Using cut-offs of ascites grade>2, Ht>39.2%, WBC>12 900/mm 3 and MOD>85 mm on Day 3, a decision-making algorithm was constructed that could predict subsequent development of severe OHSS on Day 5 with an AUC of 0.93, a sensitivity of 88.5% and a specificity of 84.2% in high-risk patients triggered with hCG., What Is Known Already: Despite the increasing popularity of GnRH agonist trigger for final oocyte maturation as a way to prevent OHSS, ≥75% of IVF cycles still involve an hCG trigger. Numerous risk factors and predictive models of OHSS have been proposed, but the measurement of these early predictors is restricted either prior to or during the controlled ovarian stimulation. In high-risk patients triggered with hCG, the identification of luteal-phase predictors assessed post-oocyte retrieval, which reflect the pathophysiological changes leading to severe early OHSS, is currently lacking., Study Design Size Duration: A retrospective study of 321 patients at high risk for severe OHSS following hCG triggering of final oocyte maturation. High risk for OHSS was defined as the presence of at least 19 follicles ≥11 mm on the day of triggering of final oocyte maturation., Participants/materials Setting Methods: The study includes IVF/ICSI patients at high risk for developing severe OHSS, who administered hCG to trigger final oocyte maturation. Ascites grade, MOD, Ht and WBC were assessed in the luteal phase starting from the day of oocyte retrieval. Outcome measures were the optimal thresholds of ascites grade, MOD, Ht and WBC measured on Day 3 post-oocyte retrieval to predict subsequent severe OHSS development on Day 5. These criteria were used to construct a decision-making algorithm for embryo transfer, based on the estimated probability of severe OHSS development on Day 5., Main Results and the Role of Chance: The optimal Day 3 cutoffs for severe OHSS prediction on Day 5 were ascites grade>2, Ht>39.2%, WBC>12 900/mm 3 and MOD>85 mm. The probability of severe OHSS with no criteria fulfilled on Day 3 is 0% (95% CI: 0-5.5); with one criterion, 0.8% (95% CI: 0.15-4.6); with two criteria, 13.3% (95% CI: 7.4-22.8); with three criteria, 37.2% (95% CI: 24.4-52.1); and with four criteria, 88.9% (95% CI, 67.2-98.1). The predictive model of severe OHSS had an AUC of 0.93 with a sensitivity of 88.5% and a specificity of 84.2%., Limitations Reasons for Caution: This is a retrospective study, and therefore, it cannot be excluded that non-apparent sources of bias might be present. In addition, we acknowledge the lack of external validation of our model. We have created a web-based calculator (http://ohsspredict.org), for wider access and usage of our tool. By inserting the values of ascites grade, MOD, Ht and WBC of high-risk patients on Day 3 after oocyte retrieval, the clinician instantly receives the predicted probability of severe OHSS development on Day 5., Wider Implications of the Findings: The present study describes a novel decision-making algorithm for embryo transfer based on ascites, Ht, WBC and MOD measurements on Day 3. The algorithm may be useful for the management of high-risk patients triggered with hCG and for helping the clinician's decision to proceed with, or to cancel, embryo transfer. It must be emphasized that the availability of the present decision-making algorithm should in no way encourage the use of hCG trigger in patients at high risk for OHSS. In these patients, the recommended approach is the use of GnRH antagonist protocols, GnRH agonist trigger and elective embryo cryopreservation. In addition, in patients triggered with hCG, freezing all embryos and luteal-phase GnRH antagonist administration should be considered for the outpatient management of severe early OHSS and prevention of late OHSS., Study Funding/competing Interests: NHMRC Early Career Fellowship (GNT1147154) to C.A.V. No conflict of interest to declare., Trial Registration Number: N/A., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.)

Study Question: What is the recommended management of ovarian stimulation, based on the best available evidence in the literature?, Summary Answer: The guideline development group formulated 84 recommendations answering 18 key questions on ovarian stimulation., What Is Known Already: Ovarian stimulation for IVF/ICSI has been discussed briefly in the National Institute for Health and Care Excellence guideline on fertility problems, and the Royal Australian and New Zealand College of Obstetricians and Gynaecologist has published a statement on ovarian stimulation in assisted reproduction. There are, to our knowledge, no evidence-based guidelines dedicated to the process of ovarian stimulation., Study Design Size Duration: The guideline was developed according to the structured methodology for development of ESHRE guidelines. After formulation of key questions by a group of experts, literature searches and assessments were performed. Papers published up to 8 November 2018 and written in English were included. The critical outcomes for this guideline were efficacy in terms of cumulative live birth rate per started cycle or live birth rate per started cycle, as well as safety in terms of the rate of occurrence of moderate and/or severe ovarian hyperstimulation syndrome (OHSS)., Participants/materials Setting Methods: Based on the collected evidence, recommendations were formulated and discussed until consensus was reached within the guideline group. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline group and the ESHRE Executive Committee., Main Results and the Role of Chance: The guideline provides 84 recommendations: 7 recommendations on pre-stimulation management, 40 recommendations on LH suppression and gonadotrophin stimulation, 11 recommendations on monitoring during ovarian stimulation, 18 recommendations on triggering of final oocyte maturation and luteal support and 8 recommendations on the prevention of OHSS. These include 61 evidence-based recommendations-of which only 21 were formulated as strong recommendations-and 19 good practice points and 4 research-only recommendations. The guideline includes a strong recommendation for the use of either antral follicle count or anti-Müllerian hormone (instead of other ovarian reserve tests) to predict high and poor response to ovarian stimulation. The guideline also includes a strong recommendation for the use of the GnRH antagonist protocol over the GnRH agonist protocols in the general IVF/ICSI population, based on the comparable efficacy and higher safety. For predicted poor responders, GnRH antagonists and GnRH agonists are equally recommended. With regards to hormone pre-treatment and other adjuvant treatments (metformin, growth hormone (GH), testosterone, dehydroepiandrosterone, aspirin and sildenafil), the guideline group concluded that none are recommended for increasing efficacy or safety., Limitations Reason for Caution: Several newer interventions are not well studied yet. For most of these interventions, a recommendation against the intervention or a research-only recommendation was formulated based on insufficient evidence. Future studies may require these recommendations to be revised., Wider Implications of the Findings: The guideline provides clinicians with clear advice on best practice in ovarian stimulation, based on the best evidence available. In addition, a list of research recommendations is provided to promote further studies in ovarian stimulation., Study Funding/competing Interests: The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the dissemination of the guideline. The guideline group members did not receive payment. F.B. reports research grant from Ferring and consulting fees from Merck, Ferring, Gedeon Richter and speaker's fees from Merck. N.P. reports research grants from Ferring, MSD, Roche Diagnositics, Theramex and Besins Healthcare; consulting fees from MSD, Ferring and IBSA; and speaker's fees from Ferring, MSD, Merck Serono, IBSA, Theramex, Besins Healthcare, Gedeon Richter and Roche Diagnostics. A.L.M reports research grants from Ferring, MSD, IBSA, Merck Serono, Gedeon Richter and TEVA and consulting fees from Roche, Beckman-Coulter. G.G. reports consulting fees from MSD, Ferring, Merck Serono, IBSA, Finox, Theramex, Gedeon-Richter, Glycotope, Abbott, Vitrolife, Biosilu, ReprodWissen, Obseva and PregLem and speaker's fees from MSD, Ferring, Merck Serono, IBSA, Finox, TEVA, Gedeon Richter, Glycotope, Abbott, Vitrolife and Biosilu. E.B. reports research grants from Gedeon Richter; consulting and speaker's fees from MSD, Ferring, Abbot, Gedeon Richter, Merck Serono, Roche Diagnostics and IBSA; and ownership interest from IVI-RMS Valencia. P.H. reports research grants from Gedeon Richter, Merck, IBSA and Ferring and speaker's fees from MSD, IBSA, Merck and Gedeon Richter. J.U. reports speaker's fees from IBSA and Ferring. N.M. reports research grants from MSD, Merck and IBSA; consulting fees from MSD, Merck, IBSA and Ferring and speaker's fees from MSD, Merck, IBSA, Gedeon Richter and Theramex. M.G. reports speaker's fees from Merck Serono, Ferring, Gedeon Richter and MSD. S.K.S. reports speaker's fees from Merck, MSD, Ferring and Pharmasure. E.K. reports speaker's fees from Merck Serono, Angellini Pharma and MSD. M.K. reports speaker's fees from Ferring. T.T. reports speaker's fees from Merck, MSD and MLD. The other authors report no conflicts of interest., Disclaimer: This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained . Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type . ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines. ) † ESHRE Pages content is not externally peer reviewed. The manuscript has been approved by the Executive Committee of ESHRE., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.)

Objective: To investigate the kinetics of serum vascular endothelial growth factor (VEGF) following gonadotrophin-releasing hormone (GnRH) antagonist administration in the luteal phase in women with established severe early ovarian hyperstimulation syndrome (OHSS)., Design: Pilot observational cohort study., Setting: Private in vitro fertilisation (IVF) Unit., Population: Twelve IVF women diagnosed with established severe early OHSS 5 days post oocyte retrieval (POR)., Methods: Women undergoing IVF diagnosed with severe early OHSS 5 days POR were given 0.25 mg GnRH antagonist for 4 days, from day 5 until and including day 8 POR, combined with elective blastocyst cryopreservation. Serum VEGF was measured from the day of oocyte retrieval until day 11 POR. Ovarian volume, ascites, serum estradiol and progesterone, haematocrit and white blood cells were monitored during the same period., Main Outcome Measures: Kinetics of VEGF following luteal GnRH antagonist administration in women with established severe early OHSS., Results: The concentration of VEGF was highest (390.9 ± 137.4 pg/ml) 5 days POR, coinciding with the day of diagnosis of severe OHSS. There was a significant decline of VEGF on day 7 (302.8 ± 104.9 pg/ml; P = 0.026), day 9 (303.3 ± 148.3 pg/ml; P = 0.007), and day 11 (252.6 ± 182.7 pg/ml; P = 0.010) compared with day 5 POR. This decline was associated with an improvement of ultrasound and laboratory parameters, indicating regression of severe OHSS. All women were managed at an outpatient level., Conclusions: GnRH antagonist administration in the luteal phase is associated with a significant decline of VEGF and with regression of established severe early OHSS., (© 2014 Royal College of Obstetricians and Gynaecologists.)

Background: The purpose of the study was to assess ongoing pregnancy rates across groups of patients treated by IVF, which were defined according to criteria aimed at the prevention of premature LH surge and used for initiating GnRH antagonist., Methods: This is a prospective observational cohort study. During the last 3 years, in IVF-ICSI patients undergoing controlled ovarian stimulation (COS) with the antagonist protocol, the antagonist administration was initiated according to at least one of the following patient-specific criteria: (i) at least one follicle measuring >14 mm; (ii) estradiol levels >600 pg/ml; and (iii) LH levels >10 IU/l. Based upon these criteria, 208 cases of normal responders were analysed and categorized into three groups according to the starting day of the regimen: group D4 (n = 40) for day 4, group D5 (n = 98) for day 5 and group D6 (n = 70) for day 6. The main outcome measure was the ongoing pregnancy rate per started cycle., Results: The total number of patients in the D4 and D5 groups (138 out of 208), who received the antagonist earlier, was considerably larger compared with that of D6 (70 out of 208). Ongoing pregnancy rates were 37.5, 34.7 and 18.6% for groups D4, D5 and D6, respectively. Patients who initiated the GnRH antagonist on days 4 and 5 had statistically significant higher pregnancy rates compared with day 6. Rapid response, causing earlier antagonist administration initiation, according to the proposed criteria for the prevention of premature LH surges, and the absence of premature luteinization, as evidenced by normal progesterone levels on HCG day, were found to be independent positive predictive factors for favourable IVF outcome., Conclusions: The employment of an algorithm of criteria, aimed at the prevention of premature LH surges in a flexible antagonist protocol, resulted in antagonist initiation earlier than on stimulation day 6 in a significant proportion of patients. In those patients, a higher pregnancy rate was observed.

Objective: To discuss, through the experience of a case report and extensive literature review, the best practices for the diagnosis and treatment of osseous metaplasia, which is the cause of secondary infertility., Design: Case report., Setting: In vitro fertilization unit in Athens., Patient(s): A 40-year-old woman with a 10-year history of secondary infertility., Intervention(s): Hysteroscopic diagnosis and removal of the bony fragment., Main Outcome Measure(s): Elimination of secondary infertility caused by osseous metaplasia., Result(s): After treatment, the woman underwent an IVF program and a healthy neonate was born with cesarean section., Conclusion(s): Hysteroscopy remains the best practice for the diagnosis and removal of endometrial ossifications, causing secondary infertility.