Correlations between a deep learning-based algorithm for embryo evaluation with cleavage-stage cell numbers and fragmentation.

RESEARCH QUESTION: Do cell numbers and degree of fragmentation in cleavage-stage embryos, assessed manually, correlate with evaluations made by deep learning algorithm model iDAScore v2.0? DESIGN: Retrospective observational study (n = 5040 embryos; 1786 treatments) conducted at two Swedish assisted reproductive technology centres between 2016 and 2021. Fresh single embryo transfer was carried out on days 2 or 3 after fertilization. Embryo evaluation using iDAScore v2.0 was compared with manual assessment of numbers of cells and grade of fragmentation, analysed by video sequences. RESULTS: Data from embryos transferred on days 2 and 3 showed that having three or fewer cells compared with four or fewer cells on day 2, and six or fewer cells versus seven to eight cells on day 3, correlated significantly with a difference in iDAScore (medians 2.4 versus 4.0 and 2.6 versus 4.6 respectively; both P < 0.001). The iDAScore for 0-10% fragmentation was significantly higher compared with the groups with higher fragmentation (P < 0.001). When combining cell numbers and fragmentation, iDAScore values decreased as fragmentation increased, regardless of cell number. iDAScore discriminated between embryos that resulted in live birth or no live birth (AUC of 0.627 and 0.607), compared with the morphological model (AUC of 0.618 and 0.585) for day 2 and day 3, respectively. CONCLUSIONS: The iDAScore v2.0 values correlated significantly with cell numbers and fragmentation scored manually for cleavage-stage embryos on days 2 and 3. iDAScore had some predictive value for live birth, conditional that embryo selection was based on morphology.

A double-blind randomized controlled trial investigating a time-lapse algorithm for selecting Day 5 blastocysts for transfer.

STUDY QUESTION: Can use of a commercially available time-lapse algorithm for Day 5 blastocyst selection improve pregnancy rates compared with morphology alone? SUMMARY ANSWER: The use of a time-lapse selection model to choose blastocysts for fresh single embryo transfer on Day 5 did not improve ongoing pregnancy rate compared to morphology alone. WHAT IS KNOWN ALREADY: Evidence from time-lapse monitoring suggests correlations between timing of key developmental events and embryo viability. No good quality evidence exists to support improved pregnancy rates following time-lapse selection. STUDY DESIGN, SIZE, DURATION: A prospective multicenter randomized controlled trial including 776 randomized patients was performed between 2018 and 2021. Patients with at least two good quality blastocysts on Day 5 were allocated by a computer randomization program in a proportion of 1:1 into either the control group, whereby single blastocysts were selected for transfer by morphology alone, or the intervention group whereby final selection was decided by a commercially available time-lapse model. The embryologists at the time of blastocyst morphological scoring were blinded to which study group the patients would be randomized, and the physician and patients were blind to which group they were allocated until after the primary outcome was known. The primary outcome was number of ongoing pregnancies in the two groups. PARTICIPANTS/MATERIALS, SETTING, METHODS: From 10 Nordic IVF clinics, 776 patients with a minimum of two good quality blastocysts on Day 5 (D5) were randomized into one of the two study groups. A commercial time-lapse model decided the final selection of blastocysts for 387 patients in the intervention (time-lapse) group, and blastocysts with the highest morphological score were transferred for 389 patients in the control group. Only single embryo transfers in fresh cycles were performed. MAIN RESULTS AND THE ROLE OF CHANCE: In the full analysis set, the ongoing pregnancy rate for the time-lapse group was 47.4% (175/369) and 48.1% (181/376) in the control group. No statistically significant difference was found between the two groups: mean difference -0.7% (95% CI -8.2, 6.7, P = 0.90). Pregnancy rate (60.2% versus 59.0%, mean difference 1.1%, 95% CI -6.2, 8.4, P = 0.81) and early pregnancy loss (21.2% versus 18.5%, mean difference 2.7%, 95% CI -5.2, 10.6, P = 0.55) were the same for the time-lapse and the control group. Subgroup analyses showed that patient and treatment characteristics did not significantly affect the commercial time-lapse model D5 performance. In the time-lapse group, the choice of best blastocyst changed on 42% of occasions (154/369, 95% CI 36.9, 47.2) after the algorithm was applied, and this rate was similar for most treatment clinics. LIMITATIONS, REASONS FOR CAUTION: During 2020, the patient recruitment rate slowed down at participating clinics owing to coronavirus disease-19 restrictions, so the target sample size was not achieved as planned and it was decided to stop the trial prematurely. The study only investigated embryo selection at the blastocyst stage on D5 in fresh IVF transfer cycles. In addition, only blastocysts of good morphological quality were considered for transfer, limiting the number of embryos for selection in both groups: also, it could be argued that this manual preselection of blastocysts limits the theoretical selection power of time-lapse, as well as restricting the results mainly to a good prognosis patient group. Most patients were aimed for blastocyst stage transfer when a minimum of five zygotes were available for extended culture. Finally, the primary clinical outcome evaluated was pregnancy to only 6-8 weeks. WIDER IMPLICATIONS OF THE FINDINGS: The study suggests that time-lapse selection with a commercially available time-lapse model does not increase chance of ongoing pregnancy after single blastocyst transfer on Day 5 compared to morphology alone. STUDY FUNDING/COMPETING INTEREST(S): The study was financed by a grant from the Swedish state under the ALF-agreement between the Swedish government and the county councils (ALFGBG-723141). Vitrolife supported the study with embryo culture dishes and culture media. During the study period, T.H. changed his employment from Livio AB to Vitrolife AB. All other authors have no conflicts of interests to disclose. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov registration number NCT03445923. TRIAL REGISTRATION DATE: 26 February 2018. DATE OF FIRST PATIENT'S ENROLMENT: 11 June 2018.

Outcomes of SARS-CoV-2 infected pregancies after medically assisted reproduction.

STUDY QUESTION: What is the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the outcome of a pregnancy after medically assisted reproduction (MAR)? SUMMARY ANSWER: Our results suggest that MAR pregnancies are not differentially affected by SARS-CoV-2 infection compared to spontaneous pregnancies. WHAT IS KNOWN ALREADY: Information on the effects of coronavirus disease 2019 (COVID-19) on pregnancy after MAR is scarce when women get infected during MAR or early pregnancy, even though such information is vital for informing women seeking pregnancy. STUDY DESIGN, SIZE, DURATION: Data from SARS-CoV-2 affected MAR pregnancies were collected between May 2020 and June 2021 through a voluntary data collection, organised by the European Society of Human Reproduction and Embryology (ESHRE). PARTICIPANTS/MATERIALS, SETTING, METHODS: All ESHRE members were invited to participate to an online data collection for SARS-CoV-2-infected MAR pregnancies. MAIN RESULTS AND THE ROLE OF CHANCE: The dataset includes 80 cases from 32 countries, including 67 live births, 10 miscarriages, 2 stillbirths and 1 maternal death. An additional 25pregnancies were ongoing at the time of writing. LIMITATIONS, REASONS FOR CAUTION: An international data registry based on voluntary contribution can be subject to selective reporting with possible risks of over- or under-estimation. WIDER IMPLICATIONS OF THE FINDINGS: The current data can be used to guide clinical decisions in the care of women pregnant after MAR, in the context of the COVID-19 pandemic. STUDY FUNDING/COMPETING INTEREST(S): The authors acknowledge the support of ESHRE for the data registry and meetings. J.S.T. reports grants or contracts from Sigrid Juselius Foundation, EU and Helsinki University Hospital Funds, outside the scope of the current work. The other authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

The calm after the storm: re-starting ART treatments safely in the wake of the COVID-19 pandemic.

The coronavirus disease 2019 (COVID-19) pandemic created a significant impact on medically assisted reproduction (MAR) services. ESHRE decided to mobilize resources in order to collect, analyse, monitor, prepare and disseminate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) knowledge specifically related to ART and early pregnancy. This article presents the impact of the SARS-CoV-2 pandemic focusing on reproductive healthcare. It details the rationale behind the guidance prepared to support MAR services in organizing and managing the re-start of treatments or in case of any future wave of COVID-19 disease. The guidance includes information on patient selection and informed consent, staff and patient triage and testing, adaptation of ART services, treatment planning and code of conduct. The initiatives detailed in this article are not necessarily COVID-specific and such action plans could be applied effectively to manage similar emergency situations in different areas of medicine, in the future.

Fertility technologies and how to optimize laboratory performance to support the shortening of time to birth of a healthy singleton: a Delphi consensus.

PURPOSE: To explore how the assisted reproductive technology (ART) laboratories can be optimized and standardized to enhance embryo culture and selection, to bridge the gap between standard practice and the new concept of shortening time to healthy singleton birth. METHODS: A Delphi consensus was conducted (January to July 2018) to assess how the ART laboratory could be optimized, in conjunction with existing guidelines, to reduce the time to a healthy singleton birth. Eight experts plus the coordinator discussed and refined statements proposed by the coordinator. The statements were distributed via an online survey to 29 participants (including the eight experts from step 1), who voted on their agreement/disagreement with each statement. Consensus was reached if ≥ 66% of participants agreed/disagreed with a statement. If consensus was not achieved for any statement, that statement was revised and the process repeated until consensus was achieved. Details of statements achieving consensus were communicated to the participants. RESULTS: Consensus was achieved for all 13 statements, which underlined the need for professional guidelines and standardization of lab processes to increase laboratory competency and quality. The most important points identified were the improvement of embryo culture and embryo assessment to shorten time to live birth through the availability of more high-quality embryos, priority selection of the most viable embryos and improved cryosurvival. CONCLUSION: The efficiency of the ART laboratory can be improved through professional guidelines on standardized practices and optimized embryo culture environment, assessment, selection and cryopreservation methodologies, thereby reducing the time to a healthy singleton delivery.

Preimplantation genetic testing legislation and accessibility in the Nordic countries.

INTRODUCTION: Assisted reproduction technologies are being rapidly developed and implementation of preimplantation genetic testing (PGT) has allowed patients with genetic disorders to initiate pregnancies while minimizing or eliminating the risk of transmitting these disorders to their offspring. Testing for numeric chromosomal anomalies has been proposed as a way to increase efficacy in assisted reproduction; however, this remains disputed. Legislation is lagging behind the rapid developments in this field. MATERIAL AND METHODS: We conducted a structured online survey of legislation and accessibility to preimplantation genetic testing in the Nordic countries to compare the regulation and uptake of this technique. The survey was designed and answered by the authors. RESULTS: Key elements in the regulation of preimplantation testing for monogenic disorders and structural rearrangements are similar in the Nordic countries, although accessibility varies since only Denmark, Finland, and Sweden have national clinics offering treatment. In addition, Denmark and Finland have private clinics offering PGT. Regulation is the most stringent in Norway where a national board evaluates all couples seeking treatment. Treatment volumes vary between the Nordic countries, with Norway and Finland having lowest treatment numbers. Preimplantation genetic testing for aneuploidy in the embryo varies between the Nordic countries: Finland and Iceland allow this form of treatment, Denmark and Sweden offer it only in the form of a research protocol, and Norway does not allow it at all. Therefore the number of treatment cycles involving testing for embryo aneuploidy are lower in the Nordic countries than in other countries where this treatment option is more common. CONCLUSIONS: Science needs to inform politics regarding the rapidly evolving field of reproductive medicine and we recommend harmonization of legislation and accessibility between the Nordic countries.

Comprehensive analysis of soluble RNAs in human embryo culture media and blastocoel fluid.

PURPOSE: miRNAs have been suggested as biomarkers of embryo viability; however, findings from preliminary studies are divergent. Furthermore, the presence of other types of small RNA molecules remains to be investigated. The purpose of this study was to perform a comprehensive analysis of small non-coding RNA levels in spent and unconditioned embryo culture media, along with miRNA levels in blastocoelic fluid samples from human embryos. METHODS: miRNAs in unconditioned culture medium from 3 different manufacturers, along with miRNA from day 5 conditioned culture medium, control medium, and corresponding blastocoel fluid from 10 human blastocysts were analyzed with array-based q-PCR analysis. Subsequently, deep sequencing of total and small RNA in day 5 spent culture medium from 5 human blastocysts and corresponding controls was performed. RESULTS: In spite of using state-of-the-art sensitive detection methods, no miRNAs were found to be reliably present in the spent culture medium or the blastocoel fluid. Ct values were above the recommended limit for detection in the array-based analysis, a finding that was confirmed by deep sequencing. The majority of miRNAs identified by deep sequencing were expressed in all samples including control media and seem to originate from sources other than conditioned IVF media. CONCLUSIONS: Our findings question the use of miRNAs as a reliable biomarker and highlight the need for a critical methodological approach in miRNA studies. Interestingly, tiRNA fragments appear to be overexpressed in conditioned IVF media samples and could potentially be a novel biomarker worthy of investigation.

Adjuncts in the IVF laboratory: where is the evidence for 'add-on' interventions?

Globally, IVF patients are routinely offered and charged for a selection of adjunct treatments and tests or 'add-ons' that they are told may improve their chance of a live birth, despite there being no clinical evidence supporting the efficacy of the add-on. Any new IVF technology claiming to improve live birth rates (LBR) should, in most cases, first be tested in an appropriate animal model, then in clinical trials, to ensure safety, and finally in a randomized controlled trial (RCT) to provide high-quality evidence that the procedure is safe and effective. Only then should the technique be considered as 'routine' and only when applied to the similar patient population as those studied in the RCT. Even then, further pediatric and long-term follow-up studies will need to be undertaken to examine the long-term safety of the procedure. Alarmingly, there are currently numerous examples where adjunct treatments are used in the absence of evidence-based medicine and often at an additional fee. In some cases, when RCTs have shown the technique to be ineffective, it is eventually withdrawn from the clinic. In this paper, we discuss some of the adjunct treatments currently being offered globally in IVF laboratories, including embryo glue and adherence compounds, sperm DNA fragmentation, time-lapse imaging, preimplantation genetic screening, mitochondria DNA load measurement and assisted hatching. We examine the evidence for their safety and efficacy in increasing LBRs. We conclude that robust studies are needed to confirm the safety and efficacy of any adjunct treatment or test before they are offered routinely to IVF patients.

Time to take human embryo culture seriously.

STUDY QUESTION: Is it important that end-users know the composition of human embryo culture media? SUMMARY ANSWER: We argue that there is as strong case for full transparency concerning the composition of embryo culture media intended for human use. WHAT IS KNOWN ALREADY: Published data suggest that the composition of embryo culture media may influence the phenotype of the offspring. STUDY DESIGN, SIZE, DURATION: A review of the literature was carried out. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data concerning the potential effects on embryo development of culture media were assessed and recommendations for users made. MAIN RESULTS AND THE ROLE OF CHANCE: The safety of ART procedures, especially with respect to the health of the offspring, is of major importance. There are reports from the literature indicating a possible effect of culture conditions, including culture media, on embryo and fetal development. Since the introduction of commercially available culture media, there has been a rapid development of different formulations, often not fully documented, disclosed or justified. There is now evidence that the environment the early embryo is exposed to can cause reprogramming of embryonic growth leading to alterations in fetal growth trajectory, birthweight, childhood growth and long-term disease including Type II diabetes and cardiovascular problems. The mechanism for this is likely to be epigenetic changes during the preimplantation period of development. In the present paper the ESHRE working group on culture media summarizes the present knowledge of potential effects on embryo development related to culture media, and makes recommendations. LIMITATIONS, REASONS FOR CAUTION: There is still a need for large prospective randomized trials to further elucidate the link between the composition of embryo culture media used and the phenotype of the offspring. We do not presently know if the phenotypic changes induced by in vitro embryo culture represent a problem for long-term health of the offspring. WIDER IMPLICATIONS OF THE FINDINGS: Published data indicate that there is a strong case for demanding full transparency concerning the compositions of and the scientific rationale behind the composition of embryo culture media. STUDY FUNDING/COMPETING INTERESTS: This work was funded by The European Society for Human Reproduction and Embryology. No competing interests to declare.

Revised guidelines for good practice in IVF laboratories (2015).

STUDY QUESTION: Which recommendations can be provided by the European Society of Human Reproduction and Embryology Special Interest Group (ESHRE SIG) Embryology to support laboratory specialists in the organization and management of IVF laboratories and the optimization of IVF patient care? SUMMARY ANSWER: Structured in 13 sections, the guideline development group formulated recommendations for good practice in the organization and management of IVF laboratories, and for good practice of the specific procedures performed within the IVF laboratory. WHAT IS KNOWN ALREADY: NA. STUDY DESIGN, SIZE, DURATION: The guideline was produced by a group of 10 embryologists representing different European countries, settings and levels of expertise. The group evaluated the document of 2008, and based on this assessment, each group member rewrote one or more sections. Two 2-day meetings were organized during which each of the recommendations was discussed and rewritten until consensus within the guideline group was reached. After finalizing the draft, the members of the ESHRE SIG embryology were invited to review the guideline. PARTICIPANTS/MATERIALS, SETTING, METHODS: NA. MAIN RESULTS AND THE ROLE OF CHANCE: The guideline provides recommendations on the general organization of an IVF laboratory (staffing and direction, quality management, laboratory safety), and on the specific aspects of the procedures performed in IVF laboratories (Identification of patients and traceability of their reproductive cells, consumables, handling of biological material, oocyte retrieval, sperm preparation, insemination of oocytes, scoring for fertilization, embryo culture and transfer, and cryopreservation). A last section provides recommendations regarding an Emergency plan for IVF laboratories. LIMITATIONS, REASONS FOR CAUTION: Evidence on most of the issues described is scarce, and therefore it was decided not to perform a formal search for and assessment of scientific evidence. However, recommendations published in the EUTCD and relevant and recent documents, manuals and consensus papers were taken into account when formulating the recommendations. WIDER IMPLICATIONS OF THE FINDINGS: Despite the limitations, the guideline group is confident that this document will be helpful to directors and managers involved in the management and organization of IVF laboratories, but also to embryologists and laboratory technicians performing daily tasks. STUDY FUNDING/COMPETING INTERESTS: The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings. The guideline group members did not receive payment. Dr Coticchio reports speaker's fees from IBSA and Cook, outside the submitted work; Dr Lundin reports grants from Vitrolife, personal fees from Merck Serono, non-financial support from Unisense, outside the submitted work; Dr. Rienzi reports personal fees from Merck Serono, personal fees from MSD, grants from GFI, outside the submitted work; the other authors had nothing to disclose. TRIAL REGISTRATION NUMBER: NA.

Biological optimization, the Goldilocks principle, and how much is lagom in the preimplantation embryo.

The quiet embryo hypothesis postulates that early embryo viability is associated with a relatively low metabolism (Leese, 2002 BioEssays 24: 845-849). This proposal is re-visited here using retrospective and prospective data on the metabolic activity and kinetics of preimplantation development alongside the concept that an optimal range of such indices and of energetic efficiency influences embryogenesis. It is concluded that these considerations may be rationalized by proposing the existence of a "Goldilocks zone," or as it is known in Sweden, of lagom-meaning "just the right amount"-within which embryos with maximum developmental potential can be categorized. Mol. Reprod. Dev. 83: 748-754, 2016 © 2016 Wiley Periodicals, Inc.

Conventional morphology performs better than morphokinetics for prediction of live birth after day 2 transfer.

Numerous studies have reported on the potential value of time-lapse variables for prediction of embryo viability. However, these variables have not been evaluated in combination with conventional morphological grading and patient characteristics. The aim of this study was to assess the ability of patient characteristics and embryo morphology together with morphokinetic variables to predict live birth after day 2 transfer. This retrospective analysis included 207 transferred embryos from 199 couples cultured in a time-lapse system up to day 2 of development. Good prediction of live birth or ranking of embryos with respect to live birth potential was achieved with early cleavage combined with fragmentation grade at 43-45 h. These variables were selected as the strongest predictors of live birth, as assessed by stepwise logistic regression, and additional inclusion of morphokinetic variables did not improve the model significantly. Also, neither logistic regression models nor classification tree models with morphokinetic variables were able to achieve equally good prediction of live birth, as measured by AUC on an external data set not used for model development. In conclusion, for fresh day 2 transfers early cleavage in combination with fragmentation grade at 43-45 h should be considered when selecting between good quality embryos.

Quality control and standardization of embryo morphology scoring and viability markers.

A so-called 'good-quality embryo' may be defined as an embryo that has the potential to implant into the uterine endometrium and give rise to the birth of a healthy child. A standardized and objective scoring of embryo 'quality' is therefore crucial in the classification and selection of embryos. However, embryo scoring is still being performed mainly via ocular evaluation, which often results in different interpretations of embryo quality. The addition of viability markers, such as measuring gene expression or the uptake/release of metabolites, proteins or RNA/DNA molecules in the culture media, would increase the possibility of standardized measurements. However, no single biomarker has yet been introduced into standard clinical practice, mainly due to the complexity of the techniques and the influence of biological variations and differences in culture conditions. In this paper different methods for the scoring of embryos and the possibility of standardizing and implementing quality control systems are discussed.

Association between blastocyst morphology and outcome of single-blastocyst transfer.

The aim of this study was to assess the ability of three individual blastocyst morphology parameters - expansion and hatching (EH) stage, inner cell mass (ICM) grade and trophectoderm grade - to predict outcome of a cycle with single-blastocyst transfer. The study was a secondary analysis of data prospectively collected in a large multicentre trial. A total of 618 intracytoplasmic sperm injection patients undergoing ovarian stimulation in a gonadotrophin-releasing hormone antagonist cycle with compulsory single-blastocyst transfer on day 5 were included. In the simple logistic regression analysis, all three blastocyst morphology parameters were statistically significantly (P<0.005 for each) associated with positive human chorionic gonadotrophin, clinical and ongoing pregnancy rates and live birth rates, while only the ICM grade was significantly (P=0.033) associated with early pregnancy loss rate. Blastocyst EH stage was the only significant predictor of live birth (P=0.002) in the multiple logistic regression. In conclusion, although all three blastocyst morphology parameters were related to treatment outcome of fresh single-blastocyst cycles, selection of high-quality blastocysts for transfer should consider first the EH stage. Transfer of a blastocyst with ICM grade A may reduce the risk of early pregnancy loss. Choosing the embryo(s) with the best implantation potential is essential for securing each couple the highest chance of achieving pregnancy after assisted reproduction. The selection of embryo(s) for transfer at the blastocyst stage is based on morphology parameters of expansion and hatching stage, inner cell mass grade and trophectoderm grade. The aim of this study was to assess the relative impact of each parameter in predicting the probability of a successful outcome. The study was a secondary analysis of data prospectively collected in a large multicentre trial. A total of 618 patients who underwent single-blastocyst transfer on day 5 were included. Statistical analysis showed that all three blastocyst morphology parameters were significantly associated with positive human chorionic gonadotrophin (ßHCG), clinical and ongoing pregnancy rates and live birth rates. Only the inner cell mass grade was significantly associated with early pregnancy loss between the positive ßHCG test and confirmation of ongoing pregnancy 10-11weeks after transfer. The expansion and hatching stage was the only significant predictor of live birth in the multiple logistic regression analysis. In conclusion, although all three blastocyst morphology parameters were related to treatment outcome of fresh single-blastocyst cycles, selection of high-quality blastocysts for transfer should consider first the expansion and hatching stage. Transfer of a blastocyst with inner cell mass grade A may reduce the risk of early pregnancy loss.

SARS-CoV-2, fertility and assisted reproduction.

BACKGROUND: In 2020, SARS-CoV-2 and the COVID-19 pandemic had a huge impact on the access to and provision of ART treatments. Gradually, knowledge of the virus and its transmission has become available, allowing ART activities to resume. Still, questions on the impact of the virus on human gametes and fertility remain. OBJECTIVE AND RATIONALE: This article summarizes published data, aiming to clarify the impact of SARS-CoV-2 and the COVID-19 disease on human fertility and assisted reproduction, as well as the impact of vaccination, and from this, provide answers to questions that are relevant for people contemplating pregnancy and for health care professionals. SEARCH METHODS: PUBMED/MEDLINE and the WHO COVID-19 database were searched from inception to 5 October 2022 with search terms focusing on 'SARS-CoV-2' and gametes, embryos, reproductive function, fertility and ART. Non-English studies and papers published prior to 2020 were excluded, as well as reviews and non-peer reviewed publications. Full papers were assessed for relevance and quality, where feasible. OUTCOMES: From the 148 papers included, the following observations were made. The SARS-CoV-2-binding proteins, angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2), are expressed in the testis, but co-expression remains to be proven. There is some evidence of SARS-CoV-2 RNA in the ejaculate of COVID-19 patients with severe disease, but not in those with mild/moderate disease. SARS-CoV-2 infection can impair spermatogenesis, but this seems to resolve after one spermatogenic cycle. Testosterone levels seem to be lower during and after COVID-19, but long-term data are lacking; disease severity may be associated with testosterone levels. COVID-19 cannot be considered a sexually transmitted disease. There is no co-expression of ACE2 and TMPRSS2 in the myometrium, uterus, ovaries or fallopian tubes. Oocytes seem to have the receptors and protease machinery to be susceptible to SARS-CoV-2 infection; however, viral RNA in oocytes has not been detected so far. Women contemplating pregnancy following COVID-19 may benefit from screening for thyroid dysfunction. There is a possible (transient) impact of COVID-19 on menstrual patterns. Embryos, and particularly late blastocysts, seem to have the machinery to be susceptible to SARS-CoV-2 infection. Most studies have not reported a significant impact of COVID-19 on ovarian reserve, ovarian function or follicular fluid parameters. Previous asymptomatic or mild SARS-CoV-2 infection in females does not seem to negatively affect laboratory and clinical outcomes of ART. There are no data on the minimum required interval, if any, between COVID-19 recovery and ART. There is no evidence of a negative effect of SARS-CoV-2 vaccination on semen parameters or spermatogenesis, ovarian function, ovarian reserve or folliculogenesis. A transient effect on the menstrual cycle has been documented. Despite concerns, cross reactivity between anti-SARS-CoV-2 spike protein antibodies and Syncytin-1, an essential protein in human implantation, is absent. There is no influence of mRNA SARS-CoV-2 vaccine on patients' performance during their immediate subsequent ART cycle. Pregnancy rates post-vaccination are similar to those in unvaccinated patients. WIDER IMPLICATIONS: This review highlights existing knowledge on the impact of SARS-CoV-2 infection or COVID-19 on fertility and assisted reproduction, but also identifies gaps and offers suggestions for future research. The knowledge presented should help to provide evidence-based advice for practitioners and couples contemplating pregnancy alike, facilitating informed decision-making in an environment of significant emotional turmoil.

When and how should new technology be introduced into the IVF laboratory?

There are many examples in assisted reproduction technology, where new technology and methods have been introduced into the clinical setting without appropriate development and evidence-based medicine to show that the procedure is safe and beneficial to the patient. Examples include preimplantation genetic screening, assisted hatching, in vitro maturation, blastocyst transfer and vitrification. Changes to culture media composition, stimulation regimes and laboratory protocols are also often established internationally without adequate validation. More recently, novel equipment that needs to be validated before it enters routine clinical use is being developed for IVF. With technologies such as producing gametes from stem cells around the corner, it is vital to ensure that the necessary research and development is conducted before bringing new techniques into clinical practice. Ideally, this should include preliminary work on animal models, such as mice/rats/rabbits/larger mammals, followed by studies on human embryos donated for research and finally well-designed RCTs with a follow up of all children born from the procedure. If such preliminary studies are not performed and published, it is possible that technology bringing no clinical benefit or leading to adverse health outcomes in the children born by these practices may be introduced. All IVF clinics need to consider the safety and efficacy of new technologies before introducing them.

[Developments within the IVF laboratory]. / Labbtekniska framsteg har lett till fler lyckade födslar efter IVF.

The area of assisted reproduction is continuing to develop at a rapid pace, especially within the laboratory. So called ¼time-lapse« photography, where embryos can be kept and assessed in a closed environment, has simplified the crucial handling of gametes and embryos as well as the logistics in the laboratory. Pregnancy and live birth rates have increased considerably since the start of IVF. This is to a large extent due to the implementation of prolonged embryo culture to the blastocyst stage, and to the introduction of vitrification, a cryopreservation technique which has greatly improved the survival rates of oocytes and blastocysts. The concept of single embryo transfer (SET) is being increasingly implemented around the world and has been shown to effectively decrease multiple birth rates, without compromising live birth rates.

Good practice recommendations for information provision for those involved in reproductive donation†.

STUDY QUESTION: What information and support should be offered to donors, intended parents and donor-conceived people, in general and in consideration of the availability of direct-to-consumer genetic testing and matching services? SUMMARY ANSWER: For donors, intended parents and donor-conceived offspring, recommendations are made that cover information needs and informed consent, psychosocial implications and disclosure. WHAT IS KNOWN ALREADY: Trends indicate that the use of donor-assisted conception is growing and guidance is needed to help these recipients/intended parents, the donors and offspring, navigate the rapidly changing environment in which donor-assisted conception takes place. STUDY DESIGN SIZE DURATION: A working group (WG) collaborated on writing recommendations based, where available, on evidence collected from a literature search and expert opinion. Draft recommendations were published for stakeholder review and adapted where relevant based on the comments received. PARTICIPANTS/MATERIALS SETTING METHODS: Papers retrieved from PUBMED were included from 1 January 2014 up to 31 August 2020, focusing on studies published since direct-to-consumer genetic testing has become more widespread and accessible. The current paper is limited to reproductive donation performed in medically assisted reproduction (MAR) centres (and gamete banks): donation outside the medical context was not considered. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 32 recommendations were made for information provision and support to donors, 32 for intended parents and 27 for donor-conceived offspring requesting information/support. LIMITATIONS REASONS FOR CAUTION: The available evidence in the area of reproductive donation is limited and diverse with regards to the context and types of donation. General conclusions and recommendations are largely based on expert opinion and may need to be adapted in light of future research. WIDER IMPLICATIONS OF THE FINDINGS: These recommendations provide guidance to MAR centres and gamete banks on good practice in information provision and support but should also be considered by regulatory bodies and policymakers at a national and international level to guide regulatory and legislative efforts towards the protection of donors and donor-conceived offspring. STUDY FUNDING/COMPETING INTERESTS: The development of this good practice paper was funded by European Society of Human Reproduction and Embryology (ESHRE), covering expenses associated with the WG meetings, the literature searches and dissemination. The WG members did not receive any payment. The 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 judgement to each individual presentation, nor variations based on locality and facility type. †ESHRE pages content is not externally peer reviewed. The manuscript has been approved by the Executive Committee of ESHRE.