Evidence and consensus on technical aspects of embryo transfer.

BACKGROUND: Ultrasound-guided embryo transfer (US-GET) is a widely performed procedure, but standards for the best practice are not available. OBJECTIVE AND RATIONALE: This document aims to provide an overview of technical aspects of US-GET after considering the published data and including the preparation for the embryo transfer (ET) procedure, the actual procedure, the post-procedure care, associated pathologies, complications and risks, quality assurance and practitioners' performance. SEARCH METHODS: A literature search for evidence on key aspects of the ET procedure was carried out from database inception to November 2021. Selected papers (n = 359) relevant to the topic were analysed by the authors. The following key points were considered in the papers: whether ultrasound (US) practice standards were explained, to what extent the ET technique was described and whether complications or incidents and how to prevent such events were reported. In the end, 89 papers could be used to support the recommendations in this document, which focused on transabdominal US-GET. OUTCOMES: The relevant papers found in the literature search were included in the current document and described according to the topic in three main sections: requirements and preparations prior to ET, the ET procedure and training and competence for ET. Recommendations are provided on preparations prior to ET, equipment and materials, ET technique, possible risks and complications, training and competence. Specific aspects of the laboratory procedures are covered, in particular the different loading techniques and their potential impact on the final outcomes. Potential future developments and research priorities regarding the ET technique are also outlined. LIMITATIONS REASONS FOR CAUTION: Many topics were not covered in the literature review and some recommendations were based on expert opinions and are not necessarily evidence based. WIDER IMPLICATIONS: ET is the last procedural step in an ART treatment and is a crucial step towards achieving a pregnancy and live birth. The current paper set out to bring together the recent developments considering all aspects of ET, especially emphasizing US quality imaging. There are still many questions needing answers, and these can be subject of future research. STUDY FUNDING/COMPETING INTERESTS: No funding. A.D.A. has received royalties from CRC Press and personal honorarium from Cook, Ferring and Cooper Surgical. The other co-authors have no conflicts of interest to declare that are relevant to the content of this article.

The Maribor consensus: report of an expert meeting on the development of performance indicators for clinical practice in ART.

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.

ESHRE guideline: female fertility preservation.

STUDY QUESTION: What is the recommended management for women and transgender men with regards to fertility preservation (FP), based on the best available evidence in the literature? SUMMARY ANSWER: The ESHRE Guideline on Female Fertility Preservation makes 78 recommendations on organization of care, information provision and support, pre-FP assessment, FP interventions and after treatment care. Ongoing developments in FP are also discussed. WHAT IS KNOWN ALREADY: The field of FP has grown hugely in the last two decades, driven by the increasing recognition of the importance of potential loss of fertility as a significant effect of the treatment of cancer and other serious diseases, and the development of the enabling technologies of oocyte vitrification and ovarian tissue cryopreservation (OTC) for subsequent autografting. This has led to the widespread, though uneven, provision of FP for young women. 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 1 November 2019 and written in English were included in the review. 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: This guideline aims to help providers meet a growing demand for FP options by diverse groups of patients, including those diagnosed with cancer undergoing gonadotoxic treatments, with benign diseases undergoing gonadotoxic treatments or those with a genetic condition predisposing to premature ovarian insufficiency, transgender men (assigned female at birth), and women requesting oocyte cryopreservation for age-related fertility loss.The guideline makes 78 recommendations on information provision and support, pre-FP assessment, FP interventions and after treatment care, including 50 evidence-based recommendations-of which 31 were formulated as strong recommendations and 19 as weak-25 good practice points and 3 research only recommendations. Of the evidence-based recommendations, 1 was supported by high-quality evidence, 3 by moderate-quality evidence, 17 by low-quality evidence and 29 by very low-quality evidence. To support future research in the field of female FP, a list of research recommendations is provided. LIMITATIONS REASONS FOR CAUTION: Most interventions included are not well studied in FP patients. As some interventions, e.g. oocyte and embryo cryopreservation, are well established for treatment of infertility, technical aspects, feasibility and outcomes can be extrapolated. For other interventions, such as OTC and IVM, more evidence is required, specifically pregnancy outcomes after applying these techniques for FP patients. Such future studies may require the current recommendations to be revised. WIDER IMPLICATIONS OF THE FINDINGS: The guideline provides clinicians with clear advice on best practice in female FP, based on the best evidence currently available. In addition, a list of research recommendations is provided to stimulate further studies in FP. 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. R.A.A. reports personal fees and non-financial support from Roche Diagnostics, personal fees from Ferring Pharmaceuticals, IBSA and Merck Serono, outside the submitted work; D.B. reports grants from Merck Serono and Goodlife, outside the submitted work; I.D. reports consulting fees from Roche and speaker's fees from Novartis; M.L. reports personal fees from Roche, Novartis, Pfizer, Lilly, Takeda, and Theramex, outside the submitted work. The other authors have no conflicts of interest to declare. 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.

Standardizing definitions and reporting guidelines for the infertility core outcome set: an international consensus development study† ‡.

STUDY QUESTION: Can consensus definitions for the core outcome set for infertility be identified in order to recommend a standardized approach to reporting? SUMMARY ANSWER: Consensus definitions for individual core outcomes, contextual statements and a standardized reporting table have been developed. WHAT IS KNOWN ALREADY: Different definitions exist for individual core outcomes for infertility. This variation increases the opportunities for researchers to engage with selective outcome reporting, which undermines secondary research and compromises clinical practice guideline development. STUDY DESIGN, SIZE, DURATION: Potential definitions were identified by a systematic review of definition development initiatives and clinical practice guidelines and by reviewing Cochrane Gynaecology and Fertility Group guidelines. These definitions were discussed in a face-to-face consensus development meeting, which agreed consensus definitions. A standardized approach to reporting was also developed as part of the process. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, researchers and people with fertility problems were brought together in an open and transparent process using formal consensus development methods. MAIN RESULTS AND THE ROLE OF CHANCE: Forty-four potential definitions were inventoried across four definition development initiatives, including the Harbin Consensus Conference Workshop Group and International Committee for Monitoring Assisted Reproductive Technologies, 12 clinical practice guidelines and Cochrane Gynaecology and Fertility Group guidelines. Twenty-seven participants, from 11 countries, contributed to the consensus development meeting. Consensus definitions were successfully developed for all core outcomes. Specific recommendations were made to improve reporting. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods, which have inherent limitations. There was limited representation from low- and middle-income countries. WIDER IMPLICATIONS OF THE FINDINGS: A minimum data set should assist researchers in populating protocols, case report forms and other data collection tools. The generic reporting table should provide clear guidance to researchers and improve the reporting of their results within journal publications and conference presentations. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials statement, and over 80 specialty journals have committed to implementing this core outcome set. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund and Maurice and Phyllis Paykel Trust. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility Group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. R.S.L. reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. C.N. reports being the Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and a financial interest in NexHand. E.H.Y.N. reports research sponsorship from Merck. A.S. reports consultancy fees from Guerbet. J.W. reports being a statistical editor for the Cochrane Gynaecology and Fertility Group. A.V. reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and of the journal Reproduction. His employing institution has received payment from Human Fertilisation and Embryology Authority for his advice on review of research evidence to inform their 'traffic light' system for infertility treatment 'add-ons'. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the work presented. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER: Core Outcome Measures in Effectiveness Trials Initiative: 1023.

Coding in medically assisted reproduction: the status of the implementation of the Single European Code for reproductive cells and tissues.

STUDY QUESTION: To evaluate the implementation of the coding systems in medically assisted reproduction (MAR) centres in the European Union (EU). SUMMARY ANSWER: Our data show that a significant number of MAR centres use the Single European Code (SEC), but it also shows certain limitations to the coding. WHAT IS KNOWN ALREADY: Traceability and identification of tissue and cells used for clinical application are extremely important as it is one of the key aspects of quality and safety both for the donors and the recipients. Patients as well as tissues and cells move across the European continent and far beyond, hence a uniform coding system was very much needed. The coding of tissues and cells from human origin was already embedded in the EU directives 2004/23/EC. The use of the Single European Code (SEC) on tissues and cells was enforced in 2017 for tissues and cells distributed within the EU or exported from the EU. The SEC ensures standardization within the EU, allowing the integration of the two existing codes (ISBT-128 and Eurocode) within the SEC structure. Likewise, in the MAR field, the SEC was launched in order to ensure the traceability of reproductive tissues and cells. Gametes and embryos from partner donation as well as reproductive cells and tissues of allogeneic donation were excluded from the SEC as long as they remain in the centre of origin. STUDY DESIGN SIZE DURATION: A cross-sectional survey aimed to gain insight into the use of SEC by MAR centres was conducted between 5 November and 15 December 2018. PARTICIPANTS/MATERIALS SETTING METHODS: The online survey was distributed among the ESHRE members. MAIN RESULTS AND THE ROLE OF CHANCE: The survey results highlight the strengths and weaknesses in the practical use of the SEC. The data from the survey showed that the SEC code is something that is known in the MAR field. Our data showed that over half of the respondents were using the SEC in their centre. On the other hand, there is also criticism about the use of SEC in MAR, especially that the added value for traceability and identification in ART is found to be rather limited. LIMITATIONS REASONS FOR CAUTION: The survey response rate was rather low (4.84%). The view of the use of SEC discussed in this paper still provides insight into the use of the SEC in several MAR centres. WIDER IMPLICATIONS OF THE FINDINGS: The survey highlights some knowledge gaps concerning coding. This information can be used to develop tools to increase knowledge of the SEC. STUDY FUNDING/COMPETING INTERESTS: There was no external funding for this study. The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Recommendations for good practice in ultrasound: oocyte pick up†.

STUDY QUESTION: What is good practice in ultrasound (US), and more specifically during the different stages of transvaginal oocyte retrieval, based on evidence in the literature and expert opinion on US practice in ART? SUMMARY ANSWER: This document provides good practice recommendations covering technical aspects of US-guided transvaginal oocyte retrieval (oocyte pick up: OPU) formulated by a group of experts after considering the published data, and including the preparatory stage of OPU, the actual procedure and post-procedure care. WHAT IS KNOWN ALREADY: US-guided transvaginal OPU is a widely performed procedure, but standards for best practice are not available. STUDY DESIGN SIZE DURATION: A working group (WG) collaborated on writing recommendations on the practical aspects of transvaginal OPU. A literature search for evidence of the key aspects of the procedure was carried out. Selected papers (n = 190) relevant to the topic were analyzed by the WG. PARTICIPANTS/MATERIALS SETTING METHODS: The WG members considered the following key points in the papers: whether US practice standards were explained; to what extent the OPU technique was described and whether complications or incidents and how to prevent such events were reported. In the end, only 108 papers could be used to support the recommendations in this document, which focused on transvaginal OPU. Laparoscopic OPU, transabdominal OPU and OPU for IVM were outside the scope of the study. MAIN RESULTS AND THE ROLE OF CHANCE: There was a scarcity of studies on the actual procedural OPU technique. The document presents general recommendations for transvaginal OPU, and specific recommendations for its different stages, including prior to, during and after the procedure. Most evidence focussed on comparing different equipment (needles) and on complications and risks, including the risk of infection. For these topics, the recommendations were largely based on the results of the studies. Recommendations are provided on equipment and materials, possible risks and complications, audit and training. One of the major research gaps was training and competence. This paper has also outlined a list of research priorities (including clarification on the value or full blood count, antibiotic prophylaxis and flushing, and the need for training and proficiency). LIMITATIONS REASONS FOR CAUTION: The recommendations of this paper were mostly based on clinical expertise, as at present, only a few clinical trials have focused on the oocyte retrieval techniques, and almost all available data are observational. In addition, studies focusing on OPU were heterogeneous with significant difference in techniques used, which made drafting conclusions and recommendations based on these studies even more challenging. WIDER IMPLICATIONS OF THE FINDINGS: These recommendations complement previous guidelines on the management of good laboratory practice in ART. Some useful troubleshooting/checklist recommendations are given for easy implementation in clinical practice. These recommendations aim to contribute to the standardization of a rather common procedure that is still performed with great heterogeneity. STUDY FUNDING/COMPETING INTERESTS: The meetings of the WG were funded by ESHRE. The other authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: NA.ESHRE Pages content is not externally peer reviewed. The manuscript has been approved by the Executive Committee of ESHRE.

A Pilot Study on Oocyte Retrieval Simulator: A New Tool for Training?

This prospective study was aimed at assessing the usefulness of a box simulator in oocyte pick-up and at establishing whether it could be an appropriate training tool for egg retrieval. Forty-four clinicians, divided in two groups on the grounds of the previous experience (Novices and Experts), participated to two training sessions with a pick-up simulator. Data concerning the mean number of follicles correctly aspired (%OK med), the average time needed to correctly aspirate one follicle (t foll med) and the ratio between the two afore-mentioned parameters (%OK med/t foll med) were collected. At the end of the two sessions all participants completed a questionnaire aimed at assessing the performance of the simulator in terms of realism and acceptability for use. A significant improvement in efficiency (mean number of follicles correctly aspired, 82% versus 75%), speed (mean time needed to aspirate one follicle, 21 versus 28 s) and accuracy (mean percentage of follicles correctly aspirated in one minute, 2.53% versus 1.86%) was noted in the total sample. The performance accuracy was significantly increased in both groups (2.34% versus 1.83% for Novices and 2.50% versus 2.06%, for Experts). Speed was significantly improved in the Novices' group. Simulator-based training has been shown to be effective and useful and it should be considered in training programs.

Elective egg freezing without medical indications.

The aim of this review is to provide current knowledge on fertility preservation for non-medical reasons in women willing to postpone childbearing. The topic is highly debatable, starting from disagreement about its terminology, the number of eggs necessary to predict chances of success, and the safety and socio/ethical point of view. Cost analysis and discrepancies among countries' recommendations and regulations are described to confirm the controversies and unsolved issues around this very interesting topic. Finally, an overview on the returning rate of women among "egg bankers" and reasons behind their decisions are illustrated.

European Recommendations for good practice in addition to an evidence-based guidelines programme: rationale and method of development.

The evidence-based approach is considered the gold standard of medical guidance. However, for some topics, it may be inappropriate to address them in an evidence-based guideline, as evidence for most of their aspects is absent or limited. Other topics may require only technical recommendations on how to perform a procedure, which are generally not covered in the published literature.In addition to an existing guideline programme, the European Society of Human Reproduction and Embryology has recently developed a manual for the development of (consensus-based) recommendations for good practice. The manual sets out a standardised methodology based on universal guideline principles with the aim of framing and improving the methodological quality of recommendations for good practice documents. The current paper outlines the relevance of recommendations for good practice, the methodology for developing these documents, and the differences and similarities with evidence-based guidelines.

Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome.

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic and potentially life threatening condition resulting from excessive ovarian stimulation. Reported incidence of moderate to severe OHSS ranges from 0.6% to 5% of in vitro fertilization (IVF) cycles. The factors contributing to OHSS have not been completely explained. The release of vasoactive substances secreted by the ovaries under human chorionic gonadotrophin (hCG) stimulation may play a key role in triggering this syndrome. This condition is characterised by a massive shift of fluid from the intravascular compartment to the third space, resulting in profound intravascular depletion and haemoconcentration. OBJECTIVES: To assess the effect of withholding gonadotrophins (coasting) on the prevention of ovarian hyperstimulation syndrome in assisted reproduction cycles. SEARCH METHODS: For the update of this review, we searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE (PubMed), CINHAL, PsycINFO, Embase, Google, and clinicaltrials.gov to 6 July 2016. SELECTION CRITERIA: We included only randomized controlled trials (RCTs) in which coasting was used to prevent OHSS. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials and extracted data. They resolved disagreements by discussion. They contacted study authors to request additional information or missing data. The intervention comparisons were coasting versus no coasting, coasting versus early unilateral follicular aspiration (EUFA), coasting versus gonadotrophin releasing hormone antagonist (antagonist), coasting versus follicle stimulating hormone administration at the time of hCG trigger (FSH co-trigger), and coasting versus cabergoline. We performed statistical analysis in accordance with Cochrane guidelines. Our primary outcomes were moderate or severe OHSS and live birth. MAIN RESULTS: We included eight RCTs (702 women at high risk of developing OHSS). The quality of evidence was low or very low. The main limitations were failure to report live birth, risk of bias due to lack of information about study methods, and imprecision due to low event rates and lack of data. Four of the studies were published only as abstracts, and provided limited data. Coasting versus no coastingRates of OHSS were lower in the coasting group (OR 0.11, 95% CI 0.05 to 0.24; I² = 0%, two RCTs; 207 women; low-quality evidence), suggesting that if 45% of women developed moderate or severe OHSS without coasting, between 4% and 17% of women would develop it with coasting. There were too few data to determine whether there was a difference between the groups in rates of live birth (OR 0.48, 95% CI 0.14 to 1.62; one RCT; 68 women; very low-quality evidence), clinical pregnancy (OR 0.82, 95% CI 0.46 to 1.44; I² = 0%; two RCTs; 207 women; low-quality evidence), multiple pregnancy (OR 0.31, 95% CI 0.12 to 0.81; one RCT; 139 women; low-quality evidence), or miscarriage (OR 0.85, 95% CI 0.25 to 2.86; I² = 0%; two RCTs; 207 women; very low-quality evidence). Coasting versus EUFAThere were too few data to determine whether there was a difference between the groups in rates of OHSS (OR 0.98, 95% CI 0.34 to 2.85; I² = 0%; 2 RCTs; 83 women; very low-quality evidence), or clinical pregnancy (OR 0.67, 95% CI 0.25 to 1.79; I² = 0%; 2 RCTs; 83 women; very low-quality evidence); no studies reported live birth, multiple pregnancy, or miscarriage. Coasting versus antagonistOne RCT (190 women) reported this comparison, and no events of OHSS occurred in either arm. There were too few data to determine whether there was a difference between the groups in clinical pregnancy rates (OR 0.74, 95% CI 0.42 to 1.31; one RCT; 190 women; low-quality evidence), or multiple pregnancy rates (OR 1.00, 95% CI 0.43 to 2.32; one RCT; 98 women; very low-quality evidence); the study did not report live birth or miscarriage. Coasting versus FSH co-triggerRates of OHSS were higher in the coasting group (OR 43.74, 95% CI 2.54 to 754.58; one RCT; 102 women; very low-quality evidence), with 15 events in the coasting arm and none in the FSH co-trigger arm. There were too few data to determine whether there was a difference between the groups in clinical pregnancy rates (OR 0.92, 95% CI 0.43 to 2.10; one RCT; 102 women; low-quality evidence). This study did not report data suitable for analysis on live birth, multiple pregnancy, or miscarriage, but stated that there was no significant difference between the groups. Coasting versus cabergolineThere were too few data to determine whether there was a difference between the groups in rates of OHSS (OR 1.98, 95% CI 0.09 to 5.68; P = 0.20; I² = 72%; two RCTs; 120 women; very low-quality evidence), with 11 events in the coasting arm and six in the cabergoline arm. The evidence suggested that coasting was associated with lower rates of clinical pregnancy (OR 0.38, 95% CI 0.16 to 0.88; P = 0.02; I² =0%; two RCTs; 120 women; very low-quality evidence), but there were only 33 events altogether. These studies did not report data suitable for analysis on live birth, multiple pregnancy, or miscarriage. AUTHORS' CONCLUSIONS: There was low-quality evidence to suggest that coasting reduced rates of moderate or severe OHSS more than no coasting. There was no evidence to suggest that coasting was more beneficial than other interventions, except that there was very low-quality evidence from a single small study to suggest that using FSH co-trigger at the time of HCG administration may be better at reducing the risk of OHSS than coasting. There were too few data to determine clearly whether there was a difference between the groups for any other outcomes.

Post-embryo transfer interventions for assisted reproduction technology cycles.

BACKGROUND: In women undergoing in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI), embryos transferred into the uterine cavity can be expelled due to many factors including uterine peristalsis and contractions, low site of deposition and negative pressure generated when removing the transfer catheter. Techniques to reduce the risk of embryo loss following embryo transfer (ET) have been described but are not standard in all centres conducting ET. OBJECTIVES: To evaluate the efficacy of interventions used to prevent post-transfer embryo expulsion in women undergoing IVF and ICSI. SEARCH METHODS: We searched the Menstrual Disorders and Subfertility Group Specialised Register of controlled trials to June 2014 and PubMed, MEDLINE, EMBASE, CENTRAL, PsycINFO, CINAHL, World Health Organization ICTRP, and trial registers from inception to June 2014, with no language restrictions. Additionally, we handsearched reference lists of relevant articles, and ESHRE and ASRM conference abstracts. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of interventions used to prevent post-transfer embryo expulsion in women undergoing IVF and ICSI. Two review authors independently screened titles and abstracts and reviewed the full-texts of all potentially eligible citations to determine whether they met our inclusion criteria. Disagreements were resolved by consensus. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the risk of bias of included trials using standardised, piloted data extraction forms. Data were extracted to allow intention-to-treat analyses. Disagreements were resolved by consensus. The overall quality of the evidence was rated using GRADE methods. MAIN RESULTS: We included four RCTs (n = 1392 women) which administered the following interventions: bed rest (two trials), fibrin sealant (one trial), and mechanical closure of the cervix (one trial). Our primary outcome, live birth rate, was not reported in any of the included trials; nor were the data available from the corresponding authors. For the ongoing pregnancy rate, two trials comparing more bed rest with less bed rest showed no evidence of a difference between groups (odds ratio (OR) 0.88; 95% confidence interval (CI) 0.60 to 1.31, 542 women, I(2) = 0%, low quality evidence). Secondary outcomes were sporadically reported with the exception of the clinical pregnancy rate, which was reported in all of the included trials. There was no evidence of a difference in clinical pregnancy rate between more bed rest and less bed rest (OR 0.88; 95% CI 0.60 to 1.31, 542 women, I(2) = 0%, low quality evidence) or between fibrin sealant and usual care (OR 0.98; 95% CI 0.54 to 1.78, 211 women, very low quality evidence). However, mechanical closure of the cervix was associated with a higher clinical pregnancy rate than usual care (OR 1.92; 95% CI 1.40 to 2.63, very low quality evidence). The quality of the evidence was rated as low or very low for all outcomes. The main limitations were failure to report live births, imprecision and risk of bias. Overall, the risk of bias of the included trials was high. The use of a proper method of randomisation and allocation concealment was fairly well reported, while only one trial clearly reported blinding. There was no evidence that any of the interventions had an effect on adverse event rates but data were too few to reach any conclusions. AUTHORS' CONCLUSIONS: There is insufficient evidence to support any specific length of time for women to remain recumbent, if at all, following embryo transfer, nor is there sufficient evidence to recommend the use of fibrin sealants added to the embryo transfer fluid. There is very limited evidence to support the use of mechanical pressure to close the cervical canal following embryo transfer. Further well-designed and powered studies are required to determine the true effectiveness and safety of these interventions.

Beyond the dichotomy: a tool for distinguishing between experimental, innovative and established treatment.

STUDY QUESTION: The precise delineation of the research phase is a recurrent subject of debate: When is the evidence base firm enough to decide that a new technology or treatment no longer needs to be regarded as 'experimental'? SUMMARY ANSWER: We propose a framework that distinguishes between three instead of two types of treatment and describes a continuum from experimental over innovative to established treatment, offering a tool meant to facilitate decision-making about the introduction of new technologies in the clinic. WHAT IS KNOWN ALREADY: Traditionally, guidelines from medical societies on the notion of 'experimental treatment' depart from a dichotomy between experimental and established treatment. However, in the field of reproductive medicine, there are several problems with a dichotomous framework. First, it does not offer an adequate account of the reality in the clinic. Secondly, this view may bring about several negative effects for the patient, such as techniques being considered established too early, holding risks unknown to patients. A further drawback of the dichotomy is that if a technique is no longer considered experimental, centres offering the technique may no longer consider it useful gathering and critically examining (follow-up) data. STUDY DESIGN, SIZE, DURATION: The framework and scoring tool were developed over several phases during which the authors operated as a consensus group of experts. PARTICIPANTS/MATERIALS, SETTING, METHODS: The scoring tool reflects the continuous progression of a new procedure from experimental through innovative to established. For this evolution, four criteria were considered relevant. The first (efficacy) is a categorical criterion (pass/fail). The other three criteria (safety, procedural reliability and transparency and effectiveness) are ordinal in nature. Thresholds have been introduced for all four criteria to avoid that a technology scoring high on procedure and effectiveness but extremely low on safety could move to the next level because of a sufficiently high overall score. MAIN RESULTS AND THE ROLE OF CHANCE: Only treatments that are rated above the thresholds for all four criteria could be considered at least innovative treatments. When they score 4 or higher on the last three criteria, they are considered established treatments. LIMITATIONS, REASONS FOR CAUTION: Knowledge about the procedures or techniques under discussion is essential in order to use the tool. WIDER IMPLICATIONS OF THE FINDINGS: The tool is designed to be used on a macro-level (e.g. by professional societies) although it could also be valuable in the local setting. Both the framework and the tool can bring more clarity on the notion of 'experimental treatment', especially with regard to how to decide when a specific technology or treatment falls in this category and when it can move into one of the other categories. STUDY FUNDING/COMPETING INTEREST(S): none. TRIAL REGISTRATION NUMBER: none.

Imatinib mesylate therapy induces reduction in neutrophil gelatinase-associated lipocalin serum levels and increase in leptin concentrations in chronic myeloid leukemia patients in molecular remission.

The aim of the present study was to determine serum levels of neutrophil gelatinase-associated lipocalin (NGAL) and leptin in patients with chronic myeloid leukemia (CML) at diagnosis and after imatinib therapy when patients achieved a complete molecular remission. The study was conducted on 22 patients with CML in the chronic phase and 10 healthy subjects. The median serum NGAL levels in CML patients at diagnosis were significantly higher compared to age-matched controls. After imatinib therapy, all patients achieved complete molecular remission and NGAL levels decreased and were found significantly lower with respect to the baseline. No significant correlations were found between NGAL levels and other disease parameters. Before imatinib therapy, the median blood leptin levels were not significantly different from those of controls. After therapy with imatinib, all patients in molecular remission presented an increase in leptin levels. Future research is eagerly awaited as it may demonstrate the real role of NGAL and leptin in the onset and progression of CML.

Stevens-Johnson syndrome after lenalidomide therapy for multiple myeloma: a case report and a review of treatment options.

Stevens- Johnson syndrome (SJS) is a severe and life-threatening condition. Although allopurinol, an antihyperuricemia drug, is the drug most commonly associated with SJS, more than 100 different causative drugs have been reported. Among hematologic drugs recently introduced into the market, drugs such as rituximab, imatinib, and bortezomib are reported. Here, we describe a patient with SJS while receiving lenalidomide in combination with prednisolone for treatment-naïve multiple myeloma. Although SJS has been reported rarely as an adverse reaction to Lenalidomide, this drug should be considered in the etiology of SJS, and the increased number of prescriptions of Lenalidomide for the therapy of multiple myeloma has to stress the awareness of its potentially serious side-effects.

Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome.

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic and potentially life threatening condition resulting from excessive ovarian stimulation. Reported incidence varies from 1% to 10% of in vitro fertilization (IVF) cycles. The factors contributing to OHSS have not been completely explained. The release of vasoactive substances secreted by the ovaries under human chorionic gonadotrophin (hCG) stimulation may play a key role in triggering this syndrome. This condition is characterised by a massive shift of fluid from the intra-vascular compartment to the third space resulting in profound intra-vascular depletion and haemoconcentration. OBJECTIVES: To assess the effect of withholding gonadotrophins (coasting) on the prevention of ovarian hyperstimulation syndrome in assisted reproduction cycles. SEARCH STRATEGY: For the update of this review we searched the Cochrane Menstrual Disorders and Subfertility Review Group Trials Register (July 2010), CENTRAL (inception to July 2010), MEDLINE (PubMed) (inception to July 2010), and EMBASE (inception to July 2010) for randomised controlled trials (RCTs) in which coasting was used to prevent OHSS. SELECTION CRITERIA: Only randomised controlled trials (RCTs) in which coasting was used to prevent OHSS were included. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials and extracted data. Disagreements were resolved by discussion. Study authors were contacted to request additional information or missing data. The intervention comparisons were coasting versus early unilateral follicular aspiration (EUFA), no coasting or other interventions. Statistical analysis was performed in accordance with the Cochrane Menstrual Disorders and Subfertility Group guidelines. MAIN RESULTS: This updated review identified 16 studies of which four met the inclusion criteria. There was no evidence of a difference in the incidence of moderate and severe OHSS (odds ratio (OR) 0.53, 95% CI 0.23 to 1.23), live birth (OR 0.48, 95% CI 0.14 to 1.62; P = 0.24) or in the clinical pregnancy rate (OR 0.69, 95% CI 0.44 to 1.08) between the groups. Significantly fewer oocytes were retrieved in coasting groups compared with GnRHa (OR -2.44, 95% CI -4.30 to -0.58; P = 0.01) or no coasting (OR -3.92, 95% CI -4.47 to -3.37; P < 0.0001). Data for coasting versus EUFA were not pooled for number of oocytes retrieved due to heterogeneity (I(2) = 87%). AUTHORS' CONCLUSIONS: There was no evidence to suggest a benefit of using coasting to prevent OHSS compared with no coasting or other interventions.

Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome.

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic and potentially life threatening condition resulting from excessive ovarian stimulation. Reported incidence varies from 1% to 10% of in vitro fertilization (IVF) cycles. The factors contributing to OHSS have not been completely explained. The release of vasoactive substances secreted by the ovaries under human chorionic gonadotrophin (hCG) stimulation may play a key role in triggering this syndrome. This condition is characterised by a massive shift of fluid from the intra-vascular compartment to the third space resulting in profound intra-vascular depletion and haemoconcentration. OBJECTIVES: To assess the effect of withholding gonadotrophins (coasting) on the prevention of ovarian hyperstimulation syndrome in assisted reproduction cycles. SEARCH STRATEGY: For the update of this review we searched the Cochrane Menstrual Disorders and Subfertility Review Group Trials Register (July 2010), CENTRAL (inception to July 2010), MEDLINE (PubMed) (inception to July 2010), and EMBASE (inception to July 2010) for randomised controlled trials (RCTs) in which coasting was used to prevent OHSS. SELECTION CRITERIA: Only randomised controlled trials (RCTs) in which coasting was used to prevent OHSS were included. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials and extracted data. Disagreements were resolved by discussion. Study authors were contacted to request additional information or missing data. The intervention comparisons were coasting versus early unilateral follicular aspiration (EUFA), no coasting or other interventions. Statistical analysis was performed in accordance with the Cochrane Menstrual Disorders and Subfertility Group guidelines. MAIN RESULTS: This updated review identified 16 studies of which four met the inclusion criteria. There was no evidence of a difference in the incidence of moderate and severe OHSS (odds ratio (OR) 0.53, 95% CI 0.23 to 1.23), live birth (OR 0.48, 95% CI 0.14 to 1.62; P = 0.24) or in the clinical pregnancy rate (OR 0.69, 95% CI 0.44 to 1.08) between the groups. Significantly fewer oocytes were retrieved in coasting groups compared with GnRHa (OR -2.44, 95% CI -4.30 to -0.58; P = 0.01) or no coasting (OR -3.92, 95% CI -4.47 to -3.37; P < 0.0001). Data for coasting versus EUFA were not pooled for number of oocytes retrieved due to heterogeneity (I(2) = 87%). AUTHORS' CONCLUSIONS: There was no evidence to suggest a benefit of using coasting to prevent OHSS compared with no coasting or other interventions.

Novel therapeutic strategies in multiple myeloma: role of the heat shock protein inhibitors.

Despite advances in understanding the molecular pathogenesis of multiple myeloma and promising new therapies, almost all patients eventually relapse with resistant disease. There is therefore a strong rationale for combining novel therapies that target intrinsic molecular pathways mediating multiple myeloma cell resistance. One such protein family is the heat shock proteins (HSP), especially the HSP90 family. Heat shock protein inhibitors have been identified as promising cancer treatments as, while they only inhibit a single biologic function, the chaperone-protein association, their effect is widespread as it results in the destruction of numerous client proteins. This article reviews the preclinical and clinical data, which support the testing of HSP90 inhibitors as cancer drugs and update the reader on the current status of the ongoing clinical trials of HSP90 inhibitors in multiple myeloma.