Search

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. Onjective 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 implication: 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., There was no funding for the current paper, apart from technical support from ESHRE.

RESEARCH QUESTION : Is the efficacy of imported vitrified oocytes donation affected by the cryobank of origin? DESIGN : Longitudinal cohort study including 249 completed oocyte warming cycles from 200 recipients (January 2016-July 2020). No severe male factor was included. Vitrified oocytes were provided by three Spanish cryobanks. The primary outcome was the cumulative live birth-delivery rate (cLBR) per completed oocyte warming cycle. RESULTS : After warming 1535 oocytes, 1244 survived (81.0%) and 945 fertilized (76.0%) with an embryo utilization rate of 65.3%. The overall cLBR per completed cycle was 47.0%, but it was lower in cryobank 1 (31.2%) in comparison to cryobank 2 (56.0%, p=0.0010) and 3 (50.8%, p=0.0241). The multivariate logistic regression analysis identified the survival of ≥4 oocytes as the strongest predictor for delivery (p=0.0282). Only 202 of the 249 oocyte warming cycles had ≥4 survived oocytes in a proportion that was significantly lower in cryobank 1 versus cryobank 2 (70.1% vs. 89.0%, p=0.0020), whereas the comparison with cryobank 3 (81.0%) was not significant. In the 202 oocyte warming cycles, the cLBR in cryobank 1 (37.0%) was lower in comparison to cryobank 2 (58.8%, p=0.0115) and cryobank 3 (60.8%, p=0.0019) suggesting a reduced viability also in oocytes from cryobank 1 that survived warming. CONCLUSIONS : There are differences in the efficacy of the imported vitrified oocytes in relation to the cryobank of origin. Each center needs to evaluate the results internally when starting a collaboration with an oocyte cryobank to put in place the necessary measures to maximize treatments’ efficacy.

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., NA

STUDY QUESTIONHow accurately can a targeted gene expression sequencing assay estimate endometrial receptivity corresponding to the window of implantation?DESIGNEndometrial biopsies (n=175) from healthy fertile volunteers (n=66), polycystic ovarian syndrome (PCOS) patients (n=39), and recurrent implantation failure (RIF) patients (n=44) were collected and sequenced with TAC-seq (Targeted Allele Counting by sequencing) method targeting 68 biomarker genes for endometrial receptivity. The expressional profiles were clustered, and differential expression analysis was performed on the model development group, using 63 endometrial biopsies spanning over proliferative (PE, n=18), early-secretory (ESE, n=18), mid-secretory (MSE, n=17) and late-secretory (LSE, n=10) endometrial phases. A quantitative predictor model was trained on the development group and validated on sequenced samples from healthy women, consisting of 52 paired samples taken from ESE and MSE phases and five LSE phase samples from 31 individuals. Finally, the developed test was applied to 44 MSE phase samples gathered from a study group of patients diagnosed with RIF.RESULTSThe developed assay successfully captures the unique receptivity profile of the endometrium using 68 biomarker genes. When compared to healthy women of the same cycle phase, we did not detect any significant gene expression bias caused by PCOS in PE, ESE, MSE, and LSE samples. In validation samples (n=57), we detected displaced WOI in 1.8% of the samples from fertile women. In the RIF study group, we detected a significantly higher proportion of the samples with shifted WOI than in the validation set of samples from fertile women, 15.9% and 1.8%, respectively.CONCLUSIONSThe developed beREADY screening test enables highly sensitive and dynamic detection of selected transcriptome biomarkers, providing a quantitative and accurate prediction of endometrial receptivity status for personalised embryo transfer.

STUDY QUESTION Three years after the start of the ESHRE ART Centre Certification (ARTCC) programme, what is the current state of the system, in terms of the interest expressed in it and experiences during the assessment of ART services? SUMMARY ANSWER As of 1 December 2021, 25 European ART centres have been involved in the various stages of certification and the most common recommendations from inspectors were the need for documented training, verification of competencies for all staff members, verification of laboratory and clinical performance indicators, implementation of a quality management system and avoidance of overusing ICSI and add-ons. WHAT IS KNOWN ALREADY European Union (EU) legislation has included ART activities in the EU Tissue and Cells Directives (EUTCDs). Following inspections by national EUTCD authorities, many details regarding documentation, laboratory environment, handling of reproductive cells and tissues, traceability, coding and patient testing have become standardized. However, the EUTCDs do not cover all ART-specific aspects. For this reason, the ARTCC was established to focus on peculiar areas, including relevant staff qualifications, training, continuing professional development, workload, equipment suitability, (non)-evidence-based laboratory and clinical methods used, treatment approaches according to ESHRE guidelines, recommendations and laboratory and clinical key performance indicators. STUDY DESIGN, SIZE, DURATION The article reviews the state-of-the-art of the ESHRE certification of ART centres for good clinical and laboratory practice over an initial 3-year period of operation, including the number of ART centres involved in the different stages of certification and the most common recommendations by inspectors. PARTICIPANTS/MATERIALS, SETTING, METHODS In 2016, the ARTCC working group began to establish a new ESHRE ARTCC programme. Since then, the working group has organized 4 preparatory courses and appointed 37 inspectors (19 clinicians, 17 embryologists and one paramedical). A tool to verify compliance with ESHRE recommendations for good laboratory and clinical practice was developed. The ARTCC has been open for applications since September 2018. In Step 1, the applicant enters basic information about the ART centre, staff and ART activities into the application platform. After review and approval, the applicant is given the opportunity to enter Step 2 and provide detailed online checklists on general, laboratory, clinical services and clinical outcomes. Two inspectors (one clinician and one embryologist) independently evaluate the submitted checklists. The condition to proceed to evaluation is a positive mean score (at least 66%) from each of the four checklists. In Step 3, a live site visit (or virtual owing to the coronavirus disease 2019 (COVID-19) pandemic) is organized and the inspectors prepare a final report with appropriate recommendations. The application may be rejected at any time if the criteria required to advance to the next stage are not met. The ARTCC programme is currently available for European countries listed in ESHRE internal rules, available on the ESHRE website. The certificate is valid for 3 years, after which an application for renewal can be submitted. MAIN RESULTS AND THE ROLE OF CHANCE Over a 3-year period (until 1 December 2021), 63 ART centres from 25 countries started applying through an online platform. So far, 38 applications did not progress owing to lack of completion of the initial application within a 1-year period or because applications came from non-European countries. Of the remaining 25 applications, 8 centres have been inspected and 7 centres have been certified. The most common recommendations given by inspectors to assessed centres were the need for documented training, verification of competencies, skills and continuing professional development for all staff members, verification of laboratory and clinical performance indicators and implementation of a quality management system. The inspectors identified some recurring areas of medically assisted reproduction that deviate from good practice: the overuse of ICSI, preimplantation genetic testing for aneuploidies, freeze-all and other add-ons. They often reported that the clinical outcomes could not be objectively assessed because of non-inclusion of the started cycles or the frequent use of freeze-all cycles. LIMITATIONS, REASONS FOR CAUTION No major modifications have been made to the application platform and checklists since the early stages of the certification programme. However, in this short time, quite a few changes in clinical practice have occurred, especially concerning the more frequent use of the ‘freeze-all’ strategy. As a result, problems arose in the evaluation of clinical outcomes. In addition, because of the COVID-19 pandemic, site visits were substituted by the implementation of virtual visits. While this enabled the certification programme to continue, it is possible that certain critical details that would have been noticed during a traditional site visit may have been overlooked. WIDER IMPLICATIONS OF THE FINDINGS Regular monitoring of the observations of ARTCC inspectors and analysis of their reports is certainly useful to harmonize inspectors’ criteria in the assessment process and to identify chronic deficiencies in clinical and laboratory practice. Non-conformities can be addressed by ESHRE through guidelines and recommendations, as well as through discussion with EU institutions and competent authorities. STUDY FUNDING/COMPETING INTEREST(S) The ARTCC programme was developed and funded by ESHRE, covering expenses associated with the meetings. The Steering Committee members who are the authors of this article did not receive payments for the completion of this study. The inspectors were remunerated for their work with an honorarium. The authors have no conflicts of interest to declare.

Study question Do RIF patients have the preimplantation genetic testing for aneuploidy (PGT-A) overcome their infertility condition? Summary answer PGT-A positively impact on implantation rate in RIF patients What is known already The most common definition of RIF is failure to achieve a pregnancy after three consecutive transfers of good quality embryos. This term possibly represents a heterogeneous category of infertile couples as the causes of repeated failures can be diverse. Especially intriguing is the case of patients with an age lower than 39 years for which the oocyte quality is expected not to be compromised by the well known age effect on female fertility. The chromosome analysis of the resulting embryos has been proposed as a valid method to improve implantation in the great majority of RIF patients Study design, size, duration This retrospective study included 49 patients with at least three previous consecutive implantation failures, which underwent PGT-A from January 2016 to April 2020. Both partners had a normal karyotype. Only patients with a female age below 39 years were included, who presented with a normal uterine cavity. Couples with a severe male factor were excluded. Single frozen blastocysts were transferred according to chromosomal results Participants/materials, setting, methods Maternal age was 35.5 ± 3.1 years. All blastocysts were vitrified after trophectoderm biopsy. Whole genome amplification and array comparative genomic hybridization were performed on biopsies. Only euploid embryos were transferred. The primary outcome was the live-birth delivery rate after the first transfer Main results and the role of chance Before starting a PGT-A cycle, these patients underwent 213 embryo transfers with 251 embryos replaced. A total of 264 blastocysts were analyzed, 140 of which were aneuploid (53%). Monosomy or trisomy was reported in 67 of the diagnosed samples (67/140, 48%) whereas the remaining 73 carried complex aneuploidies (73/140, 52%). The remaining 124 blastocysts (47%) were diagnosed as euploid. All patients performed an embryo transfer resulting in 28 clinical pregnancies (57%). There were 5 spontaneous abortions and the live-birth delivery rate per patient was 47% Limitations, reasons for caution This study suffers from the weakness related to retrospectivity. In addition, as euploid embryos are still cryopreserved, the delivery rate could change at completion of the cycles Wider implications of the findings: A RIF condition can be attributed, at least in a good proportion of cases, to the generation of high percentages of aneuploid embryos. In this case, the transfer of euploid blastocysts has high chances to classify this category of RIF patients has having an embryonic cause of infertilit. Trial registration number Not applicable

Study question Does sperm DNA integrity evaluated by DNA fragmentation index (DFI) and big halo pattern correlate with sperm decondensation index (SDI) and semen sample parameters? Summary answer DFI correlates with SDI and semen sample parameters in a stronger way than the big halo pattern What is known already The sperm chromatin dispersion test evaluates DNA integrity by measuring the susceptibility of sperm DNA containing breaks to denature when treated by an acid solution. Spermatozoa with intact DNA produce big or medium size halos of dispersed DNA loops, whereas small halos or no halos indicate fragmented DNA. The DFI calculates the proportion of spermatozoa with fragmented DNA. Data have been published documenting the negative effect of sperm DFI on embryo viability, suggesting that its evaluation could contribute to the prediction of the male reproductive potential Study design, size, duration A prospective study between 2011 to 2019 included 300 patients attending our clinic for fertility treatment. All sperm samples were analyzed according to WHO criteria, and the results from the DNA integrity analysis were related to the semen sample indices Participants/materials, setting, methods Of the 300 males included in the study, 118 were normozoospermic, 16 were oligozoospermic (O), 63 were asthenozoospermic (A), 9 were teratozoospermic, 7 were AT, 51 were OA, 5 were OT, and 31 OAT. The DNA integrity was assessed by the Halosperm test, and DNA decondensation by the aniline blue assay. A big halo was defined as a dispersion greater or equal to the length of the minor diameter of the core Main results and the role of chance DFI showed negative correlations with progressive motility (r= –0.532, p = 2.816 E–23), total motility (r= –0.598, p = 1.688 E–30) and morphology (r= –0.338, p = 2.954 E–9). Accordingly, when compared with normozoospermic, DFI was significantly higher in A and T samples (29.5 ±12.0 and 36.5±4.8 respectively, p Limitations, reasons for caution The study did not evaluate the lifestyle and reproductive history of the patients Wider implications of the findings: Although the effects of sperm DNA damage on reproductive outcomes are still unclear, the correlation between sperm DNA fragmentation, semen parameters and reproductive potential is emerging. DFI, big halo and SDI could contribute to the diagnosis of male infertility especially in categories of patients with poor prognosis of pregnancy. Trial registration number Not applicable

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 INTEREST(S) 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.

What is the proportion of chromosomally abnormal spermatozoa in men with a history of reproductive failure, including patients with normal karyotype and carriers of translocations? Should this analysis be included in a clinical setting to define the best treatment options for infertile couples?Aneuploidy for chromosomes XY, 13, 15, 16, 17, 18, 21, 22 was tested by fluorescent in-situ hybridization (FISH) in 1665 samples from couples with normal karyotype having had at least three previous IVF failures, miscarriages, or both (group-A). A FISH test was also carried out in 76 samples from carriers of translocations (group B) to detect the proportion of spermatozoa with unbalanced rearrangement.In group A, the lowest incidence of aneuploid sperm cells was found in men with normozoospermia (1.3%, range 0.09-6.31%) compared with men with moderate oligoasthenoteratozoospermia (2.1%, range 0.41-16.6%, P0.001), severe oligoasthenoteratozoospermia (4.7%, range 0.53-30.77, P0.001), microepididymal sperm aspiration (3.1%, range 1.19-24.24, P0.001) and testicular sperm extraction samples (5.8%, range 1.54-33.3, P0.001). In group B, the proportion of spermatozoa with unbalanced rearrangement was significantly higher in reciprocal (63%, range 10.0-87.6%) than in Robertsonian translocations (16%, range 4.3-51.0%, P0.001).Patients with poor prognosis of term pregnancy tend to generate high proportions of chromosomally abnormal spermatozoa, especially in severe male factor cases. Corresponding frequencies occur at wide ranges; therefore, the FISH test is needed to assess the proportion of spermatozoa with altered chromosome condition. A flowchart, which included the FISH test, was designed to assist clinicians guide couples with poor prognosis of pregnancy, on the most indicated treatment options.

We report on the first PGD performed for the m.14487 T>C mitochondrial DNA (mtDNA) mutation in the MT-ND6 gene, associated with Leigh syndrome. The female carrier gave birth to a healthy baby boy at age 42. This case adds to the successes of PGD for mtDNA mutations.

This is a pilot study performed in a private IVF unit. The objective of the study was to investigate whether luteal support is required in IVF cycles after mild stimulation with clomiphene citrate and low FSH doses. The study included 15 patients with good prognosis (defined as ≤38 years old with normal ovarian reserve and normovulatory cycles, body mass index

STUDY QUESTION Is de novo segmental aneuploidy (SA) a biological event or an artifact that is erroneously interpreted as partial chromosome imbalance? SUMMARY ANSWER The detection of de novo SA in sequential biopsies of preimplantation embryos supports the biological nature of SA. WHAT IS KNOWN ALREADY Although some SAs are detected in oocytes and in blastocysts, the highest incidence is observed in cleavage-stage embryos. Based on these findings, we can postulate that the majority of cells affected by SAs are eliminated by apoptosis or that affected embryos mainly undergo developmental arrest. STUDY DESIGN, SIZE, DURATION This retrospective study includes 342 preimplantation genetic testing for aneuploidy (PGT-A) cycles performed between January 2014 and December 2018. Chromosome analysis was performed on 331 oocytes, 886 cleavage-stage embryos and 570 blastocysts (n = 1787). From 268 expanded blastocysts, the blastocoelic fluid (BF) was also analyzed (resulting in 2025 samples in total). In cases of SAs involving loss or gain in excess of 15 Mb, embryos were not considered for transfer and sequential biopsies were performed at following stages. This resulted in 66 sets where the initial diagnosis of SAs (4 made in polar bodies, 25 in blastomeres and 37 in trophectoderm (TE) cells) was followed up. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 2082 samples (2025 + 27 whole embryos) were processed by whole genome amplification followed by array comparative genomic hybridization. MAIN RESULTS AND THE ROLE OF CHANCE The incidence of SAs was 6.3% in oocytes, increased to 16.6% in cleavage-stage embryos (P LIMITATIONS, REASONS FOR CAUTION Chromosome analyses were performed on biopsies that might not be representative of the true constitution of the embryo itself due to the occurrence of mosaicism. WIDER IMPLICATIONS OF THE FINDINGS The permanence of SAs throughout the following stages of embryo development in more than half of the analyzed sets suggests for this dataset a very early origin of this type of chromosome imbalance, either at meiosis or at the first mitotic divisions. Since SAs remained in full concordance with the initial diagnosis until the blastocyst stage, a corrective mechanism seems not to be in place. In the remaining cases, it is likely that, as for full chromosome aneuploidy, mosaicism derived from mitotic errors could have occurred. In following cell divisions, euploid cell lines could prevail preserving the embryo chances of implantation. Due to the scarcity of data available, the transfer of embryos with SAs should be strictly followed up to establish possible clinical consequences related to this condition. STUDY FUNDING/COMPETING INTEREST(S) No specific funding was obtained. There are no conflicts of interest.

BackgroundThe success rate of in-vitro fertilisation (IVF) remains low and many women undergo multiple treatment cycles. A previous meta-analysis suggested hysteroscopy could improve outcomes in women who have had recurrent implantation failure; however, studies were of poor quality and a definitive randomised trial was needed. In the TROPHY trial we aimed to assess whether hysteroscopy improves the livebirth rate following IVF treatment in women with recurrent failure of implantation.MethodsWe did a multicentre, randomised controlled trial in eight hospitals in the UK, Belgium, Italy, and the Czech Republic. We recruited women younger than 38 years who had normal ultrasound of the uterine cavity and history of two to four unsuccessful IVF cycles. We used an independent web-based trial management system to randomly assign (1:1) women to receive outpatient hysteroscopy (hysteroscopy group) or no hysteroscopy (control group) in the month before starting a treatment cycle of IVF (with or without intracytoplasmic sperm injection). A computer-based algorithm minimised for key prognostic variables: age, body-mass index, basal follicle-stimulating hormone concentration, and the number of previous failed IVF cycles. The order of group assignment was masked to the researchers at the time of recruitment and randomisation. Embryologists involved in the embryo transfer were masked to group allocation, but physicians doing the procedure knew of group assignment and had hysteroscopy findings accessible. Participants were not masked to their group assignment. The primary outcome was the livebirth rate (proportion of women who had a live baby beyond 24 weeks of gestation) in the intention-to-treat population. The trial was registered with the ISRCTN Registry, ISRCTN35859078.FindingsBetween Jan 1, 2010, and Dec 31, 2013, we randomly assigned 350 women to the hysteroscopy group and 352 women to the control group. 102 (29%) of women in the hysteroscopy group had a livebirth after IVF compared with 102 (29%) women in the control group (risk ratio 1·0, 95% CI 0·79–1·25; p=0·96). No hysteroscopy-related adverse events were reported.InterpretationOutpatient hysteroscopy before IVF in women with a normal ultrasound of the uterine cavity and a history of unsuccessful IVF treatment cycles does not improve the livebirth rate. Further research into the effectiveness of surgical correction of specific uterine cavity abnormalities before IVF is warranted.FundingEuropean Society of Human Reproduction and Embryology, European Society for Gynaecological Endoscopy.

COVID-19 pandemic caused a huge overload of healthcare systems worldwide For such reason, in a preventive manner, governments and scientific societies recommended to stop any elective medical or surgical treatment in order to reduce the eventual burden on hospitals Fertility treatments have since then been reserved only to urgent cases as oncologic patients asking for fertility preservation However, the relevance of such policy on natality rate and on ovarian aging has soon induced the main scientific societies to ask for a fast return to action, considering that infertility should be treated as an urgent condition In this regard, phase 2 recommendations have been issued to ensure working requirements to be settled in the safest way possible Therefore, the Special Interest Group on Sterility (GISS) of the Italian Society of Gynecology and Obstetrics (SIGO) and its federates released their guidelines as Italy has been one of the first Western countries to face the phase 2 restart of treatments

Infertility is a condition affecting an increasing number of individuals all over the world. In recent years, this phenomenon has spread across both western countries and developing countries, thus developing the features of a pandemic. For this reason, the World Health Organization (WHO) acknowledged that infertility should be considered a disease to all intents and purposes, as it diminishes the health and wellbeing of the individuals who suffers from it. At present, the most effective means to contain the spread of infertility are essentially prevention and Assisted Reproductive Technologies (ART). With reference to the latter, although most of these techniques are routinely used in the majority of countries, they are still subject to medical, ethical and political debates. There are huge variations noted when the regulatory legislation adopted by different countries to govern infertility treatment in various countries all over the world are reviewed. In fact, it has to be recognized that ART legislation depends on a variety of factors, such as social structure, political choices, ethical issues and religious beliefs. This makes it apparently impossible to create a standard regulation for different countries, especially in case of controversial issues like gamete and embryo donation, embryo cryopreservation or surrogacy.

Objective To investigate blastocysts, defined as euploid and aneuploid by trophectoderm (TE) cell analysis, for the presence of DNA in the blastocoelic fluid (BF) detected by whole-genomic amplification (WGA); and to correlate the presence of DNA in BF with the clinical outcome after the transfer of TE-euploid blastocysts. Design Retrospective study. Setting In vitro fertilization unit. Patient(s) This study included 91 patients performing preimplantation genetic testing for aneuploidy on TE cells from January 2015 to December 2017. In the case of ET, only single blastocyst transfers were performed. Intervention(s) Blastocoelic fluids and TE cells were retrieved from 256 blastocysts before vitrification. All blastocysts were diagnosed by array-comparative genomic hybridization (a-CGH) on TE cells. Amplification and a-CGH of DNA from BFs was performed at a later time after TE biopsy and ET. Main Outcome Measure(s) Whole-genomic amplification of BFs, evaluation of the chromosome condition in BFs and TE cells, and correlation of BF results with the clinical outcome of TE-euploid transferred blastocysts. Result(s) The incidence of amplification after WGA was significantly lower in BFs from TE-euploid blastocysts (n = 32, 45%) when compared with the aneuploid ones (n = 150, 81%), resulting in 182 BFs with successful DNA amplification. When submitted to a-CGH, informative results were obtained from 172 BFs. Comparison of these results with those from the corresponding TE cells gave a ploidy concordance of 93.6% and a mean number of aneuploid events per sample that was higher in BFs than in TE cells (2.0 vs. 1.4, respectively). After the transfer of 53 TE-euploid blastocysts, the clinical pregnancy rate was 77% in the group with BF-failed amplification, and 37% after BF-successful amplification. The same trend was found for the ongoing pregnancy rate (68% vs. 31.5%, respectively). Conclusion(s) The presence of DNA in BFs detected by WGA is correlated with the blastocyst ploidy condition defined by TE cell biopsy and with the implantation potential of TE-euploid blastocysts. These findings could have a clinical implication for the selection of the most viable embryo for transfer because, after submitting BFs to WGA, priority would be given to TE-euploid blastocysts with BF-failed amplification. Similarly, BF-failed amplification could be an additional selection criterion to prioritize embryos for transfer even in conventional IVF cycles with blastocysts that were vitrified after BF aspiration.

STUDY QUESTION: Does preimplantation genetic testing for aneuploidy (PGT-A) by comprehensive chromosome screening (CCS) of the first and second polar body to select embryos for transfer increase the likelihood of a live birth within 1 year in advanced maternal age women aged 36-40 years planning an ICSI cycle, compared to ICSI without chromosome analysis? SUMMARY ANSWER: PGT-A by CCS in the first and second polar body to select euploid embryos for transfer does not substantially increase the live birth rate in women aged 36-40 years. WHAT IS KNOWN ALREADY: PGT-A has been used widely to select embryos for transfer in ICSI treatment, with the aim of improving treatment effectiveness. Whether PGT-A improves ICSI outcomes and is beneficial to the patients has remained controversial. STUDY DESIGN, SIZE, DURATION: This is a multinational, multicentre, pragmatic, randomized clinical trial with intention-to-treat analysis. Of 396 women enroled between June 2012 and December 2016, 205 were allocated to CCS of the first and second polar body (study group) as part of their ICSI treatment cycle and 191 were allocated to ICSI treatment without chromosome screening (control group). Block randomization was performed stratified for centre and age group. Participants and clinicians were blinded at the time of enrolment until the day after intervention. PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertile couples in which the female partner was 36-40 years old and who were scheduled to undergo ICSI treatment were eligible. In those assigned to PGT-A, array comparative genomic hybridization (aCGH) analysis of the first and second polar bodies of the fertilized oocytes was performed using the 24sure array of Illumina. If in the first treatment cycle all oocytes were aneuploid, a second treatment with PB array CGH was offered. Participants in the control arm were planned for ICSI without PGT-A. Main exclusion criteria were three or more previous unsuccessful IVF or ICSI cycles, three or more clinical miscarriages, poor response or low ovarian reserve. The primary outcome was the cumulative live birth rate after fresh or frozen embryo transfer recorded over 1 year after the start of the intervention. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 205 participants in the chromosome screening group, 50 (24%) had a live birth with intervention within 1 year, compared to 45 of the 191 in the group without intervention (24%), a difference of 0.83% (95% CI: -7.60 to 9.18%). There were significantly fewer participants in the chromosome screening group with a transfer (relative risk (RR) = 0.81; 95% CI: 0.74-0.89) and fewer with a miscarriage (RR = 0.48; 95% CI: 0.26-0.90). LIMITATIONS, REASONS FOR CAUTION: The targeted sample size was not reached because of suboptimal recruitment; however, the included sample allowed a 90% power to detect the targeted increase. Cumulative outcome data were limited to 1 year. Only 11 patients out of 32 with exclusively aneuploid results underwent a second treatment cycle in the chromosome screening group. WIDER IMPLICATIONS OF THE FINDINGS: The observation that the similarity in birth rates was achieved with fewer transfers, less cryopreservation and fewer miscarriages points to a clinical benefit of PGT-A, and this form of embryo selection may, therefore, be considered to minimize the number of interventions while producing comparable outcomes. Whether these benefits outweigh drawbacks such as the cost for the patient, the higher workload for the IVF lab and the potential effect on the children born after prolonged culture and/or cryopreservation remains to be shown. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the European Society of Human Reproduction and Embryology. Illumina provided microarrays and other consumables necessary for aCGH testing of polar bodies. M.B.'s institution (UZBrussel) has received educational grants from IBSA, Ferring, Organon, Schering-Plough, Merck and Merck Belgium. M.B. has received consultancy and speakers' fees from Organon, Serono Symposia and Merck. G.G. has received personal fees and non-financial support from MSD, Ferring, Merck-Serono, Finox, TEVA, IBSA, Glycotope, Abbott and Gedeon-Richter as well as personal fees from VitroLife, NMC Healthcare, ReprodWissen, BioSilu and ZIVA. W.V., C.S., P.M.B., V.G., G.A., M.D.,T.E.G., L.G., G.Ka., G.Ko., J. L., M.C.M., M.P., A. S., M. T., K.V., J.G. and K.S. declare no conflict of interest. TRIAL REGISTRATION NUMBER: NCT01532284. TRIAL REGISTRATION DATE: 7 February 2012. DATE OF FIRST PATIENT'S ENROLMENT: 25 June 2012.

Introduction Preimplantation genetic testing for monogenic diseases (PGT-M) is a clinical method developed to prevent the transmission of monogenic inherited disorders to the future offspring. The reproductive risk of carriers of single gene disorders depends on the typology of the disorder, with the probability of affected conceptions ranging from 25% in recessive or X-linked diseases to 50% in dominant diseases. Therefore, the possibility of having embryos suitable for transfer and the consequent chances of ongoing pregnancy are strictly related to the number of embryos available for the genetic analysis. The aim of this study was to evaluate how many embryos need to be analyzed for having one or more genetically transferrable embryos. Material and Methods 86 carriers of genetic disorders performed 99 cycles of genetic analysis between January 2010 and September 2018. They were divided into two groups according to the typology of the disorder transmission. Group 1 included recessive and X-linked diseases (58 patients, 70 cycles of analysis), while with dominant disorders were in Group 2 (28 patients, 29 cycles of analysis). Maternal age was comparable in the two groups. Following blastocyst biopsy, embryos were vitrified to complete the genetic analysis. Results Clinical results were the following. For both groups, the mean number of analyzed embryos to have genetically transferrable embryos are reported in the following table: Conclusions Based on the reported data, we define for each case the minimum number of analyzable embryos needed to have one or more transferrable embryo depending on the typology of genetic disorder. Therefore, we eventually advise patients to undergo further oocyte retrievals for the best clinical outcome.

Introduction The pivotal role of mitochondria in ATP production, as well as the high mutation rate of their genome (mtDNA) are well known. Although variants fixation within the population depends to the phenotype functionality, some recurrent variants with deleterious effect survive to natural selection.We already described a relation between mitochondrial haplogroups and aneuploidy susceptibility. Since the segregation process is strictly dependent on adequate ATP provision, the mutation load analysis of mtDNA in blastocysts may be informative of embryo viability. The aim of this study was to verify whether mtDNA analysis could be conducted on the fluid extracted from the blastocoelic cavity through a procedure that is moderately invasive compared with the conventional forms of biopsy. Material and Methods In the first part of the study, the blastocoelic fluid (BF) retrieved from 10 expanded blastocysts previously inferred as aneuploid by a-CGH was amplified for the mitochondrial D-loop region and sequenced by Sanger. Maternal age of the 10 patients ranged between 37 and 41 years. In the second part of the study, D-loop sequencing was carried out in five additional sets of sequential biopsies including both polar bodies (PB I; PB II), BF, trophectoderm (TE) and the corresponding whole embryo (EM), accounting for a total of 25 samples. Also in this case, the 5 sets had been diagnosed as aneuploid by chromosome analysis on PBs. All sequences were aligned to mtDNA reference sequence prior to haplogroup inference. Results In the first part of the study, the complete D-loop amplification and sequencing was successful for all the BF samples. Haplogroups were inferred with 60% of lineages belonging to Macro-haplogroup H, while the remaining 40% was represented by the lineages I, W and K. These haplogroups are characteristic of the European population.In the second part of the study, D-loop amplification and sequencing was possible in all samples except for the PBs from one sample set. The intra-group sequence comparison highlighted full correspondence in 4 sets, while the remaining set showed a heteroplasmic position in one PB I. Conclusions The feasibility to amplify and sequence mtDNA from the BF may offer a reliable alternative to other forms of conventional biopsy. In this context, it would be interesting to validate the method also to the complete mitochondrial genome (16Kb), testing in this way also its integrity.

Objective To validate the use of clomiphene citrate in IVF when mild stimulation approaches are chosen to reduce patient discomfort, risk, and cost. Design Prospective cohort study. Setting Private IVF clinic. Patient(s) A total of 163 patients undergoing IVF and with a good prognosis (defined as ≤38 years old with normal ovarian reserve and normovulatory cycles, body mass index 2 , no previous assisted reproductive technology cycles, no severe endometriosis, no history of recurrent miscarriage, no endocrine/autoimmune diseases, and no surgical semen extraction). Intervention(s) Mild stimulation using a fixed protocol of clomiphene citrate (100 mg/d from cycle days 3 to 7) in combination with low doses of gonadotropins (150 IU of recombinant FSH on cycle days 5, 7, and 9) and GnRH antagonist. Main Outcome Measure(s) The cumulative delivery rate per patient after three fresh and/or frozen embryo transfers and time to pregnancy. Result(s) No dropouts were observed. The cumulative delivery rate was 70%, and the mean time to pregnancy was 2.4 months. Conclusion(s) Mild stimulation using clomiphene citrate in combination with low doses of gonadotropins can be considered a realistic option for good-prognosis patients undergoing IVF.

Infertility care has improved remarkably over the last few decades and has received growing attention from health care providers. Several treatments, including expensive options such as Assisted Reproductive Techniques, are now widely available for routine clinical use. In most cases, adoption of these treatments has occurred without robust cost-effective analyses. IVF for unexplained infertility and ICSI in the absence of semen abnormalities are two examples of this gradual technology creep. More in-depth economic analyses in the field of infertility are undoubtedly warranted. However, performing these analyses is challenging because infertility care poses a number of unique challenges. Studies of cost-effectiveness are open to criticism because there is a lack of consensus about the outcomes of choice and the appropriate perspective. The use of quality adjusted life years (QALYs) to allow comparisons with other clinical conditions is also controversial because the value associated with infertility care cannot be easily captured in QALYs. Moreover, their use triggers the crucial question of whose QALYs merit consideration—an individual's, a couple's or a child's. In conclusion, economic analysis in infertility represents a peculiar but crucial challenge. If management of infertility is to become an integral part of publicly or privately funded health care systems worldwide, better quality data and a shared vision about the costs and benefits of infertility treatments are needed.

Study Question Does selection for mtDNA mutations occur in human oocytes? Summary Answer We provide statistical evidence in favor of the existence of purifying selection for mtDNA mutations in human oocytes acting between the expulsion of the first and second polar bodies (PBs). What is Known Already Several lines of evidence in Metazoa, including humans, indicate that variation within the germline of mitochondrial genomes is under purifying selection. The presence of this internal selection filter in the germline has important consequences for the evolutionary trajectory of mtDNA. However, the nature and localization of this internal filter are still unclear while several hypotheses are proposed in the literature. Study Design, Size, Duration In this study, 60 mitochondrial genomes were sequenced from 17 sets of oocytes, first and second PBs, and peripheral blood taken from nine women between 38 and 43 years of age. Participants/Materials, Setting, Methods Whole genome amplification was performed only on the single cell samples and Sanger sequencing was performed on amplicons. The comparison of variant profiles between first and second PB sequences showed no difference in substitution rates but displayed instead a sharp difference in pathogenicity scores of protein-coding sequences using three different metrics (MutPred, Polyphen and SNPs&GO). Main Results and the Role of Chance Unlike the first, second PBs showed no significant differences in pathogenic scores with blood and oocyte sequences. This suggests that a filtering mechanism for disadvantageous variants operates during oocyte development between the expulsion of the first and second PB. Large Scale Data N/A. Limitations, Reasons for Caution The sample size is small and further studies are needed before this approach can be used in clinical practice. Studies on a model organism would allow the sample size to be increased. Wider Implications of the Findings This work opens the way to the study of the correlation between mtDNA mutations, mitochondrial capacity and viability of oocytes. Study Funding/Competing Interest(s) This work was supported by a SISMER grant. Laboratory facilities and skills were freely provided by SISMER, and by the Alma Mater Studiorum, University of Bologna. The authors have no conflict of interest to disclose.

Massive parallel sequencing (MPS) can accurately quantify mitochondrial DNA (mtDNA) single nucleotide variants (SNVs), but no MPS methods are currently validated to simultaneously and accurately establish the breakpoints and frequency of large deletions at low heteroplasmic loads. Here we present the thorough validation of an MPS protocol to quantify the load of very low frequency, large mtDNA deletions in bulk DNA and single cells, along with SNV calling by standard methods. We used a set of well-characterized DNA samples, DNA mixes and single cells to thoroughly control the study. We developed a custom script for the detection of mtDNA rearrangements that proved to be more accurate in detecting and quantifying deletions than pre-existing tools. We also show that PCR conditions and primersets must be carefully chosen to avoid biases in the retrieved variants and an increase in background noise, and established a lower detection limit of 0.5% heteroplasmic load for large deletions, and 1.5 and 2% for SNVs, for bulk DNA and single cells, respectively. Finally, the analysis of different single cells provided novel insights into mtDNA cellular mosaicism.European Journal of Human Genetics advance online publication, 23 August 2017; doi:10.1038/ejhg.2017.129.

We respond to the comments made in the BBC commissioned article by Heneghan and colleagues and the Panorama programme by Deborah Cohen about pre-implantation genetic screening (PGS), which was among the three “add on” treatments highlighted in the programme and the 41 listed in the article.12 Currently an extensive evidence base supports the efficacy of PGS: more than 20 retrospective studies and four randomised controlled trials suggest that, if performed to a high standard, PGS can, and does, improve IVF success for some patient groups.34567 We accept, however, that all studies are open to criticism and thus support further investigations, randomised and retrospective. However, the programme, …

The Bologna criteria were published by the European Society of Human Reproduction and Embryology (ESHRE) in 2011 to help address the lack of a clear definition of poor ovarian responders. Since its publication, aspects of the criteria have been cited several times, whilst others have been criticized. In this debate, we re-examine the criteria (which address age, the number of oocytes retrieved and the results of ovarian reserve tests) following new evidence produced and we analyse the criticism received in an attempt to determine if revisions are needed.

Introduction. Poor response to ovarian stimulation is still a major problem in IVF. The study presents a new stimulation protocol evaluated in a suppopulation of very difficult young poor ovarian responders.Material and Methods. The study consists in two sections. The first includes data from a randomized controlled study involving forty-three young patients with a poor ovarian response in at least two previous cycles (intended as cycle cancellation or with ≤3 collected oocytes). Patients were randomized in two groups: group A (control) received FSH (400 IU/day), while group B received the new stimulation protocol consisting in a sequential association of 150 IU r-LH for 4 days followed by 400 IU r-FSH/after downregulation with daily GnRh agonist. The second includes data from the overall results in 65 patients treated with the new protocol compared to their previous performance with conventional cycles (historical control).Results. Both in the RCT and in the historical control study, LH pretreatment was able to decrease the cancellation rate, to improve thein vitroperformance, and to significantly increase the live birth rates.Conclusions. LH pretreatment improved oocyte quantity and quality in young repeated poor responders selected in accordance with the Bologna criteria.

Unintended pregnancy and sexually transmitted infections (STIs) are the major negative consequences of unsafe sex. Both are common and have long-term social and health consequences. Barrier methods of contraception can prevent both, but unfortunately they are much less effective than the more modern methods at pregnancy prevention. Modern effective contraceptives, however, do not protect against STIs and some may increase the risk of acquisition of infection. This comprehensive review discusses the magnitude of burden of reproductive ill-health, focussing on data from the European region, and explores the relationship between contraceptive use and STIs. Searches were performed by using Medline, Popline, EMBASE, Cochrane Library and the Social Sciences Citation Index databases for relevant English language publications from 1995 to 2012. Summaries were discussed by the European Society of Human Reproduction and Embryology (ESHRE) Workshop Group. An understanding of patterns of sexual behaviour helps to understand the epidemiology of unintended pregnancy and STIs and gives pointers towards their prevention, but survey methodologies differ and results are hard to compare. Contraceptive prevalence and method mix vary widely between countries, and the use of the dual method of protection is very infrequent. Abortion rates have fallen in many European countries, particularly Eastern Europe, and contraceptive prevalence increased but unsafe abortion still accounts for 11% of maternal mortality in Eastern Europe. STIs are common but reporting systems are often rudimentary or non-existent and robust data are scarce. Providers still worry about the effect of intrauterine contraception on reproductive tract infections despite reassuring evidence to the contrary. New data on HIV acquisition and hormonal contraception are causing concern in settings where HIV infection is common. New developments in multipurpose technologies aimed at producing a single device/drug, which prevents infection and pregnancy simultaneously, are in early stages. While the benefits of national screening programmes for STIs remain uncertain, human papilloma virus (HPV) vaccination is clearly reducing HPV infection rates and gives hope for the public health benefits of other STI vaccines. The consequences of unsafe sex-unintended pregnancy and STI-continue to present major public health problems worldwide even in countries where the prevalence of use of modern contraception is high. Robust systems for routine data collection are sorely needed in most countries and systematic attempts to compare patterns of sexual behaviour across men and women of all ages would be welcome.

We present a Bayesian network model for predicting the outcome of in vitro fertilization (IVF). The problem is characterized by a particular missingness process; we propose a simple but effective averaging approach which improves parameter estimates compared to the traditional MAP estimation. We present results with generated data and the analysis of a real data set. Moreover, we assess by means of a simulation study the effectiveness of the model in supporting the selection of the embryos to be transferred.

In 2004, The Italian Constitutional Court prohibited treatments involving gamate donation, embryo donation, embryo cryopreservation (except under exceptional circumstances), and the transfer of more than three embryos. Basically three statements were made by the Court: the ban violates a couple's fundamental right to health, to self-determination and to have a child. Here, the consequences of such a decision and the legal challenges that ensued are discussed.

STUDY QUESTION What classification system is more suitable for the accurate, clear, simple and related to the clinical management categorization of female genital anomalies? SUMMARY ANSWER The new ESHRE/ESGE classification system of female genital anomalies is presented. WHAT IS KNOWN ALREADY Congenital malformations of the female genital tract are common miscellaneous deviations from normal anatomy with health and reproductive consequences. Until now, three systems have been proposed for their categorization but all of them are associated with serious limitations. STUDY DESIGN, SIZE AND DURATION The European Society of Human Reproduction and Embryology (ESHRE) and the European Society for Gynaecological Endoscopy (ESGE) have established a common Working Group, under the name CONUTA (CONgenital UTerine Anomalies), with the goal of developing a new updated classification system. A scientific committee (SC) has been appointed to run the project, looking also for consensus within the scientists working in the field. PARTICIPANTS/MATERIALS, SETTING, METHODS The new system is designed and developed based on (i) scientific research through critical review of current proposals and preparation of an initial proposal for discussion between the experts, (ii) consensus measurement among the experts through the use of the DELPHI procedure and (iii) consensus development by the SC, taking into account the results of the DELPHI procedure and the comments of the experts. Almost 90 participants took part in the process of development of the ESHRE/ESGE classification system, contributing with their structured answers and comments. MAIN RESULTS AND THE ROLE OF CHANCE The ESHRE/ESGE classification system is based on anatomy. Anomalies are classified into the following main classes, expressing uterine anatomical deviations deriving from the same embryological origin: U0, normal uterus; U1, dysmorphic uterus; U2, septate uterus; U3, bicorporeal uterus; U4, hemi-uterus; U5, aplastic uterus; U6, for still unclassified cases. Main classes have been divided into sub-classes expressing anatomical varieties with clinical significance. Cervical and vaginal anomalies are classified independently into sub-classes having clinical significance. LIMITATIONS, REASONS FOR CAUTION The ESHRE/ESGE classification of female genital anomalies seems to fulfill the expectations and the needs of the experts in the field, but its clinical value needs to be proved in everyday practice. WIDER IMPLICATIONS OF THE FINDINGS The ESHRE/ESGE classification system of female genital anomalies could be used as a starting point for the development of guidelines for their diagnosis and treatment. STUDY FUNDING/COMPETING INTEREST(S) None.

In March 2005, a group of experts from the European Society of Human Genetics and European Society of Human Reproduction and Embryology met to discuss the interface between genetics and assisted reproductive technology (ART), and published an extended background paper, recommendations and two Editorials. Seven years later, in March 2012, a follow-up interdisciplinary workshop was held, involving representatives of both professional societies, including experts from the European Union Eurogentest2 Coordination Action Project. The main goal of this meeting was to discuss developments at the interface between clinical genetics and ARTs. As more genetic causes of reproductive failure are now recognised and an increasing number of patients undergo testing of their genome before conception, either in regular health care or in the context of direct-to-consumer testing, the need for genetic counselling and preimplantation genetic diagnosis (PGD) may increase. Preimplantation genetic screening (PGS) thus far does not have evidence from randomised clinical trials to substantiate that the technique is both effective and efficient. Whole-genome sequencing may create greater challenges both in the technological and interpretational domains, and requires further reflection about the ethics of genetic testing in ART and PGD/PGS. Diagnostic laboratories should be reporting their results according to internationally accepted accreditation standards (International Standards Organisation - ISO 15189). Further studies are needed in order to address issues related to the impact of ART on epigenetic reprogramming of the early embryo. The legal landscape regarding assisted reproduction is evolving but still remains very heterogeneous and often contradictory. The lack of legal harmonisation and uneven access to infertility treatment and PGD/PGS fosters considerable cross-border reproductive care in Europe and beyond. The aim of this paper is to complement previous publications and provide an update of selected topics that have evolved since 2005. ispartof: European Journal of Human Genetics vol:21 issue:Suppl 2 pages:S1-S21 ispartof: location:England status: published

Although the possibilities for the treatment of infertility have been improved tremendously, not every couple will be treated successfully.Crude overall pregnancy rates of 50-65% per patient can be achieved nowadays, irrespective of the type of profertility treatment applied first.IVF only accounts for about 20% of the pregnancies achieved. Dropout is an important reason for not reaching the estimated pregnancy rate. Even after failed IVF, spontaneous pregnancies do occur. Sperm and oocyte donation (OD) offer additional chances to subfertile couples. Severity of the male factor (in sperm donation) and young donor age (in OD) are important determinants of success.Analysis of assisted reproduction technology outcomes would benefit from more universally accepted definitions and deserves better statistical analysis. Long-term cumulative live birth rates of 80% may be expected if dropout can be limited. Milder stimulation, a patient-friendlier approach and better counseling may help to keep more patients in the program.