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STUDY QUESTIONCan risks associated with novelties in assisted reproduction technologies (ARTs) be assessed in a systematic and structured way?SUMMARY ANSWERAn ART-specific risk assessment tool has been developed to assess the risks associated with the development of novelties in ART (EuroGTP II-ART).WHAT IS KNOWN ALREADYHow to implement new technologies in ART is well-described in the literature. The successive steps should include testing in animal models, executing pre-clinical studies using supernumerary gametes or embryos, prospective clinical trials and finally, short- and long-term follow-up studies on the health of the offspring. A framework categorizing treatments from experimental through innovative to established according to the extent of the studies conducted has been devised. However, a systematic and standardized methodology to facilitate risk evaluation before innovations are performed in a clinical setting is lacking.STUDY DESIGN, SIZE, DURATIONThe EuroGTP II-ART risk assessment tool was developed on the basis of a generic risk assessment algorithm developed for tissue and cell therapies and products (TCTPs) in the context of the project ‘Good Practices for demonstrating safety and quality through recipient follow-up European Good Tissue and cells Practices II (EuroGTP II)’. For this purpose, a series of four meetings was held in which eight ART experts participated. In addition, several tests and simulations were undertaken to fine-tune the final tool.PARTICIPANTS/MATERIALS, SETTING, METHODSThe three steps comprising the EuroGTP II methodology were evaluated against its usefulness and applicability in ART. Ways to improve and adapt the methodology into ART risk assessment were agreed and implemented.MAIN RESULTS AND THE ROLE OF CHANCEAssessment of the novelty (Step 1), consisting of seven questions, is the same as for other TCTPs. Practical examples were included for better understanding. Identification of potential risks and consequences (Step 2), consisting of a series of risks and risk consequences to consider during risk assessment, was adapted from the generic methodology, adding more potential risks for processes involving gonadic tissues. The algorithm to score risks was also adapted, giving a specific range of highest possible risk scores. A list of strategies for risk reduction and definition of extended studies required to ensure effectiveness and safety (Step 3) was also produced by the ART experts, based on generic EuroGTP II methodology. Several explanations and examples were provided for each of the steps for better understanding within this field.LIMITATIONS, REASONS FOR CAUTIONA multidisciplinary team is needed to perform risk assessment, to interpret results and to determine risk mitigation strategies and/or next steps required to ensure the safety in the clinical use of novelties.WIDER IMPLICATIONS OF THE FINDINGSThis is a dynamic tool whose value goes beyond assessment of risk before implementing a novel ART in clinical practice, to re-evaluate risks based on information collected during the process.STUDY FUNDING / COMPETING INTEREST(S)This study was called EUROGTP II and was funded by the European Commission (Grant agreement number 709567). The authors declare no competing interests concerning the results of this study.

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 INTEREST(S) 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 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.

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 INTEREST(S) There was no external funding for this study. The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER N/A.

STUDY QUESTIONWhat 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 ANSWERThis 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 ALREADYUS-guided transvaginal OPU is a widely performed procedure, but standards for best practice are not available.STUDY DESIGN, SIZE, DURATIONA 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, METHODSThe 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 CHANCEThere 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 CAUTIONThe 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 FINDINGSThese 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 INTEREST(S)The meetings of the WG were funded by ESHRE. The other authors declare that they have no conflict of interest.TRIAL REGISTRATION NUMBERNA.ESHRE Pages content is not externally peer reviewed. The manuscript has been approved by the Executive Committee of ESHRE.

Objective: The study was aimed to evaluate which factors affect the cumulative live birth rate after elective single embryo transfer in women younger than 36 years. Additionally, number of children in women with more than one delivery per ovum pick-up after fresh elective single embryo transfer and subsequent frozen embryo transfers was assessed. Study design: Retrospective cohort study analysing data of a university hospital's infertility clinic in 2001-2010. A total of 739 IVF/ICSI cycles with elective single embryo transfer were included. Analyses were made per ovum pick-up including fresh and subsequent frozen embryo transfers. Factors affecting cumulative live birth rates were examined in uni- and multivariate analyses. A secondary endpoint was the number of children born after all treatments. Results: In the fresh cycles, the live birth rate was 29.2% and the cumulative live birth rate was 51.3%, with a twin rate of 3.4%. In the multivariate analysis, having two (odds ratio (OR) 1.73; 95% confidence interval (CI) 1.12-2.67) or >= 3 top embryos (OR 2.66; 95% CI 1.79-3.95) was associated with higher odds for live birth after fresh and frozen embryo cycles. Age, body mass index, duration of infertility, diagnosis or total gonadotropin dose were not associated with the cumulative live birth rate. In cycles with one top embryo, the cumulative live birth rate was 40.2%, whereas it was 64.1% in those with at least three top embryos. Of women who had a live birth in the fresh cycle, 20.4% had more than one child after all frozen embryo transfers. Among women with three or more top embryos after ovum pick-up, 16.1% gave birth to more than one child. Conclusion: The cumulative live birth rate in this age group varies from 40% to 64% and is dependent on the quality of embryos. Women with three or more top embryos have good chance of having more than one child per ovum pick-up without elevated risk of multiple pregnancies. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Which clinical and laboratory factors affect live birth rate (LBR) after frozen-thawed embryo transfer (FET)?Top quality embryo characteristics, endometrial preparation protocol, number of embryos transferred and BMI affected independently the LBR in FET.FET is an important part of present-day IVF/ICSI treatment. There is limited understanding of the factors affecting success rates after FET.This is a two-centre retrospective cohort study. Analysis was carried out on 1972 consecutive FET cycles in 1998-2007, with embryos frozen on Day 2. The primary outcome was LBR per cycle.We assessed the independent effect on LBR of the following variables: female age, female age at embryo freezing, BMI, diagnosis, primary versus secondary infertility, fertilization by IVF versus ICSI, pregnancy in the fresh cycle, type (spontaneous, spontaneous with luteal progesterone and estrogen/progesterone substitution) and rank of the FET cycle, as well as number and presence (yes versus no) of top quality embryo(s) at freezing, thawing and transfer, damaged thawed embryos and overnight culture.In 78% of the cycles with top quality embryos frozen (n = 1319), at least one embryo still had high-quality morphology after thawing. Top quality embryo morphology observed at any stage of culture improved the outcome even if high-quality characteristics disappeared before transfer. LBRs after the transfer of a top quality embryo were similar in the FET (24.9%) and fresh cycles of the same period (21.9%). The chance of live birth increased significantly if ≥1 top quality embryo was present at freezing (odds ratio (OR) 1.85, 95% confidence interval (CI) 1.10-3.14), at thawing (OR 1.93, CI 1.20-3.11) or at transfer (OR 3.41, CI 2.12-5.48). Compared with spontaneous cycles with luteal support, purely spontaneous cycles (OR 0.58, CI 0.40-0.84) and hormonally substituted FET (OR 0.47, CI 0.32-0.69) diminished the odds of pregnancy. BMI (OR 0.96, CI 0.92-0.99) and transfer of two embryos versus one (OR 1.45, CI 1.08-1.94) were other factors that improved LBR after FET.The sample sizes available in some subanalyses were small, limiting the power of the study.The presence of ≥1 top quality embryo at any step of the freezing and thawing process increases the chance of pregnancy. The data do not support the freezing of all embryos for transfer in order to improve the outcome. A top quality embryo transferred in FET may even have the same potential as in a fresh cycle. On the contrary, LBR in the group with no top quality embryos frozen was quite low (10.4%), raising the question of whether a re-evaluation of freezing criteria is necessary to avoid costly treatments with a low success rate.

BACKGROUND: Although elective single embryo transfer (eSET) minimizes the multiple birth rate after in vitro fertilization (IVF)/intra cytoplasmic sperm injection (ICSI), there remain concerns in many countries that it is less effective and more expensive than conventional double embryo transfer (DET). METHODS: We compared the clinical outcome achieved in the years 1995-1999, in which eSET was rarely used (4.2% of women, DET period) with that of the years 2000-2004, in which eSET was more widely used (46.2%, eSET period). In the DET period, 826 women had 1359 fresh embryo cycles followed by 589 frozen-thawed embryo transfer (FET) cycles. In the eSET period, 684 women had 1027 fresh and 683 FET cycles. The cumulative term live birth rate/woman was the primary clinical outcome measure. An incremental cost-effectiveness ratio of a term live birth was also calculated based on hospital charges and medication prices of IVF/ICSI treatment. RESULTS: The cumulative pregnancy rate/oocytes pickup (38.2 versus 33.1%, P = 0.01), cumulative live birth rate/oocytes pickup (28.0 versus 22.5%, P = 0.002) and cumulative live birth rate/woman (41.7 versus 36.6%, P = 0.04) were all higher in the eSET period than in the DET period. The cumulative multiple birth rate was significantly lower in the eSET period than in the DET period (8.9 versus 19.6%, P < 0.0001). A term live birth in the eSET period was 19 889 euros less expensive than in the DET period. CONCLUSIONS: This study shows that eSET with cryopreservation is more effective and less expensive than DET and should be adopted as a treatment of choice.

BACKGROUND: The extremes of BMI are associated with an increased risk of miscarriage both in spontaneously conceived pregnancies and after fertility treatment. The aim of the present study was to study the effect of BMI on miscarriage rate (MR) in fresh IVF/ICSI, and in spontaneous and hormonally substituted frozen-thawed embryo (FET) cycles. METHODS: Analysis was carried out on 3330 first pregnancy cycles, performed during the years 1999–2004, of which 2198 were fresh, 666 were spontaneous and 466 were hormonally substituted FET cycles. A categorical, a linear and a quadratic models of the effect of BMI on miscarriage were studied by logistic regression. Factors related to patient characteristics, protocol and embryo parameters were also examined. RESULTS: MR was higher in hormonally substituted FET (23.0%), compared with the fresh cycles (13.8%) and spontaneous FET (11.4%, P< 0.0001). Multivariate logistic regression revealed that the relationship between BMI and the risk of miscarriage is not linear but quadratic (U-shaped) (P 5 0.01), indicating a higher risk of miscarriage in underweight and obese women. Hormonal substitution for FET was also associated with a 1.7-fold higher MR, compared with the fresh cycles (P 5 0.002, 95% confidence interval 1.2–2.3). CONCLUSIONS: Obese and underweight women have an increased risk of miscarriage, and hormonally substituted FET is associated with an even higher MR.

BACKGROUND: The elective single embryo transfer policy is the only effective strategy known to minimize the risk of multiple pregnancy. However, little is known about its applicability to women older than 35 years. METHODS: Analysis was carried out on 1224 fresh IVF/ICSI cycles with embryo transfer and 828 frozen embryo transfer (FET) cycles of women aged 36-39 years. In the fresh cycles, 335 elective single top quality embryo (eSET), 110 elective single non top quality embryo (nt-eSET), 194 compulsory single embryo (cSET) and 585 double embryo transfers (DET) were carried out. RESULTS: Pregnancy rate/embryo transfer (33.1 versus 29.9%) and live birth rate (26.0 versus 21.9%) in fresh cycles did not differ significantly between the eSET and the DET groups. However, women in the eSET group had a higher cumulative pregnancy rate (54.0% versus 35.0%) and a higher cumulative live birth rate (41.8% versus 26.7%, P < 0.0001) compared with those in the DET group. The cumulative multiple birth rate in the eSET group was 1.7%, whereas in the DET group it was 16.6% (P < 0.0001). CONCLUSIONS: The eSET policy can be applied also to patients aged 36-39 years, reducing the risk of multiple birth and increasing the safety of assisted reproduction technique (ART) in this age group.

Objective To study the predictive value of initial low response (LR) in IVF/intracytoplasmic sperm injection (ICSI). Design Retrospective analysis. Setting Two Finnish fertility centers. Patient(s) A total of 3,846 IVF/ICSI cycles performed from 1994 to 2002. Intervention(s) Consecutive cycles in the same subject were identified. The study groups consisted of subjects who had three treatment cycles and at least one LR cycle (n = 80). Main Outcome Measure(s) Pregnancy rate (PR), total gonadotropin dose, and embryo quality. Result(s) Only 2.5% (2/80) of subjects had a LR in all three consecutive cycles. In 43 women an initial LR was followed by ≥1 normal response (NR) cycle, and in 35 women an initial NR was followed by ≥1 LR cycle. The PR/cycle was similarly low in women with an initial LR and an initial NR (10.1% vs. 16.2%). An increase in gonadotropin dose resulted in a higher number of oocytes in women with an initial LR (from 2.1 ± 0.9 to 6.7 ± 2.7) but the PR/cycle remained low, compared to the overall mean PR (27.2%). In cycles in which top quality embryos were transferred, subjects with an initial LR had a lower PR than women with an initial NR (17.8% vs. 41.2%). Conclusion(s) An initial LR is a predictor of poor outcome in subsequent cycles, even if ovarian response is improved by increasing the gonadotropin dose or a top quality embryo is replaced.