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A high ovarian response to conventional ovarian stimulation (OS) is characterized by an increased number of follicles and/or oocytes compared with a normal response (10-15 oocytes retrieved). According to current definitions, a high response can be diagnosed before oocyte pick-up when >18-20 follicles ≥11-12 mm are observed on the day of ovulation triggering; high response can be diagnosed after oocyte pick-up when >18-20 oocytes have been retrieved. Women with a high response are also at high risk of early ovarian hyper-stimulation syndrome (OHSS)/or late OHSS after fresh embryo transfers. Women at risk of high response can be diagnosed before stimulation based on several indices, including ovarian reserve markers (anti-Müllerian hormone [AMH] and antral follicle count [AFC], with cutoff values indicative of a high response in patients with PCOS of >3.4 ng/mL for AMH and >24 for AFC). Owing to the high proportion of high responders who are at the risk of developing OHSS (up to 30%), this educational article provides a framework for the identification and management of patients who fall into this category. The risk of high response can be greatly reduced through appropriate management, such as individualized choice of the gonadotropin starting dose, dose adjustment based on hormonal and ultrasound monitoring during OS, the choice of down-regulation protocol and ovulation trigger, and the choice between fresh or elective frozen embryo transfer. Appropriate management strategies still need to be defined for women who are predicted to have a high response and those who have an unexpected high response after starting treatment., Competing Interests: Declaration of competing interest PD declares research grants and honoraria from Merck KGaA, Darmstadt, Germany, MSD, Ferring Pharmaceuticals; and paid consultancy work from Merck KGaA, Darmstadt, Germany. YaK received lecture fees/honoraria/grants from MSD; Merck KGaA, Darmstadt, Germany; Besins Healthcare; Gedeon Richter; Abbott; Bayer; ISBA; LD Collins; Ferring and Sun Pharma. SCE declares the receipt of unrestricted research grants from Merck and lecture fees from Merck, Event Planet, and Med.E.A. NP declares research grants and honoraria from Merck KGaA, Darmstadt, Germany; MSD; Organon; Ferring Pharmaceuticals; Besins International; Roche Diagnostics; IBSA; Theramex; Gedeon Richter. SKS has received speaker fees for non-promotional educational symposia by Merck KGaA, Darmstadt, Germany; MSD; Ferring; Pharmasure. DS has participated in Speaker's bureaus for both Merck KGaA, Darmstadt, Germany and Organon. BR has no conflicts of interest to declare. HY has no conflicts of interest to declare. MC has declared past sponsorship from Merck KGaA, Darmstadt, Germany, for scientific conference presentations. YuK received speaker fees/honoraria/grants from MSD, Merck KGaA, Darmstadt, Germany; Besins Healthcare; Gedeon Richter; Abbott; Bayer; and Sun Pharma. BS received research grants and honoraria from Merck KGaA, Darmstadt, Germany and Gedeon Richter. ML and TDH are employees of Merck Healthcare KGaA, Darmstadt, Germany. ALM declares research grants and honoraria from Merck KGaA, Darmstadt, Germany; MSD; Ferring Pharmaceuticals; Gedeon Richter; ISBA; Theramex; Organon; Roche; Beckman Coulter., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Study Question: Which success rates do female and male IVF patients expect, what determines their expectations and do patients reconsider their expectations after receiving a personal IVF prognosis at the expense of anxious reactions?, Summary Answer: Female and male IVF patients have unrealistic high expectations which are positively associated with their dispositional optimism, and which are only reconsidered by patients receiving a less than average IVF prognosis, which leads to more anxious reactions in females., What Is Known Already: Female patients undergoing IVF are known to have unrealistic expectations of the success of their own IVF cycle. The available evidence suggests women expect above average performance of their fertility clinic and (family) reproductive systems. The association of gender and personality trait dispositional optimism, with expectations of IVF success and the impact of providing couples with their IVF prognosis have not been studied previously., Study Design, Size, Duration: A total of 148 partnered individuals participated in this prospective survey at two separate points in treatment: following oocyte aspiration (T1) and embryo transfer (T2) (2019-2020, participation rate = 85%). At the time of embryo transfer, gynaecologists provided couples with their IVF prognosis, calculated with the Adapted van Loendersloot model. Women and their male partners completed questionnaires independently and immediately following oocyte aspiration and embryo transfer., Participants/materials, Setting, Methods: Dispositional optimism ('LOT-R' questionnaire) and expectations of IVF success (numerical rating scale) were assessed in eligible couples commencing a 2nd-6th IVF cycle on T1. Expectations of IVF success and anxiety ('Spielberger State-Anxiety Inventory') were (re)assessed on T2. The inter-partner correlation of expectations of IVF success was examined. Linear mixed models examined hypothesized determinants of expectations of IVF success (T1) and explored (determinants of) whether participants reconsidered their expectations after receiving their IVF prognosis (T1-T2) and whether couple's IVF prognosis was associated with anxious reactions (T2)., Main Results and the Role of Chance: The mean of the IVF success rates expected by patients immediately after oocyte aspiration was 59.1% (±20.0), irrespective of gender (P = 0.077). Partners expectations of IVF success were moderately correlated (r = 0.483; P < 0.001). Expectations of IVF success were positively associated with the participant's dispositional optimism (P < 0.001) but were not associated with their partner's dispositional optimism, women's age and their previous (un)successful IVF experiences. Gynaecologists gave couples their calculated IVF prognosis ranging from 4.8% to 69.2% (mean = 30.9%) at the time of embryo transfer. Gender did not influence whether participants reconsidered their expectations after receiving their prognosis. In contrast to the subgroup (n = 78), who received at least an average IVF prognosis and that did not reconsider their expectations of IVF success, the subgroup (n = 70) receiving a below average IVF prognosis lowered their expectations of IVF success (interaction effect: P < 0.001) from 55% to 46%. A below average IVF prognosis was associated with anxious reactions in women but not in men (interaction effect: P = 0.011)., Limitations, Reasons for Caution: The study design and sample size were more optimal for examining hypothesized determinants of patient's expectations of IVF success than for studying the impact of sharing prognoses with patients. Whether (reconsidering) expectations influences IVF discontinuation rates and achieved live birth rates has yet to be followed-up., Wider Implications of the Findings: Clinics are advised to offer patients the opportunity of receiving their IVF prognosis. Providing prognoses is in line with patient preferences and tempers the unrealistic high expectations of both partners in couples with a less than average prognosis. A sensitive communication style is indicated, as lower prognoses are associated with mild anxious reactions in women., Study Funding/competing Interest(s): E.A.F.D. holds a postdoctoral fellowship of the Research Foundation-Flanders (12H9819N) and this study was funded by the Research Council of the KU Leuven (C14/18/106; project of J.V., K.P. and E.A.F.D.) and as an investigator sponsored study of K.P. and E.A.F.D. by Merck nv/sa Belgium, an affiliate of Merck KGaA, Darmstadt, Germany. The authors declare no conflict of interest related to this study., Trial Registration Number: N/A., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Study Question: Can the Poor Responder Outcome Prediction (PROsPeR) score identify live birth outcomes in subpopulations of patients with poor ovarian response (POR) defined according to the ESHRE Bologna criteria (female age, anti-Müllerian hormone (AMH), number of oocytes retrieved during the previous cycle (PNO) after treatment with originator recombinant human follitropin alfa?, Summary Answer: The PROsPeR score discriminated the probability of live birth in patients with POR using observational data with fair discrimination (AUC ≅ 70%) and calibration, and the AUC losing less than 5% precision compared with a model developed using the observational data., What Is Known Already: Although scoring systems for the likelihood of live birth after ART have been developed, their accuracy may be insufficient, as they have generally been developed in the general population with infertility and were not validated for patients with POR. The PROsPeR score was developed using data from the follitropin alfa (GONAL-f; Merck KGaA, Darmstadt, Germany) arm of the Efficacy and Safety of Pergoveris in Assisted Reproductive Technology (ESPART) randomized controlled trial (RCT) and classifies women with POR as mild, moderate or severe, based upon three variables: female age, serum AMH level and number of oocytes retrieved during the previous cycle (PNO)., Study Design, Size, Duration: The external validation of the PROsPeR score was completed using data derived from eight different centres in France. In addition, the follitropin alfa data from the ESPART RCT, originally used to develop the PROsPeR score, were used as reference cohort. The external validation of the PROsPeR score l was assessed using AUC. A predetermined non-inferiority limit of 0.10 compared with a reference sample and calibration (Hosmer-Lemeshow test) were the two conditions required for evaluation., Participants/materials, Setting, Methods: The observational cohort included data from 8085 ART treatment cycles performed with follitropin alfa in patients with POR defined according to the ESHRE Bologna criteria (17.6% of the initial data set). The ESPART cohort included 477 ART treatment cycles with ovarian stimulation performed with follitropin alfa in patients with POR., Main Results and the Role of Chance: The external validation of the PROsPeR score to identify subpopulations of women with POR with different live birth outcomes was shown in the observational cohort (AUC = 0.688; 95% CI: 0.662, 0.714) compared with the ESPART cohort (AUC = 0.695; 95% CI: 0.623, 0.767). The AUC difference was -0.0074 (95% CI: -0.083, 0.0689). This provided evidence, with 97.5% one-sided confidence, that there was a maximum estimated loss of 8.4% in discrimination between the observational cohort and the ESPART cohort, which was below the predetermined margin of 10%. The Hosmer-Lemeshow test did not reject the calibration when comparing observed and predicted data (Hosmer-Lemeshow test = 1.266688; P = 0.260)., Limitations, Reasons for Caution: The study was based on secondary use of data that had not been collected specifically for the analysis reported here and the number of characteristics used to classify women with POR was limited to the available data. The data were from a limited number of ART centres in a single country, which may present a bias risk; however, baseline patient data were similar to other POR studies., Wider Implications of the Findings: This evaluation of the PROsPeR score using observational data supports the notion that the likelihood of live birth may be calculated with reasonable precision using three readily available pieces of data (female age, serum AMH and PNO). The PROsPeR score has potential to be used to discriminate expected probability of live birth according to the degree of POR (mild, moderate, severe) after treatment with follitropin alfa, enabling comparison of performance at one centre over time and the comparison between centres., Study Funding/competing Interest(s): This analysis was funded by Merck KGaA, Darmstadt, Germany. P.L. received grants from Merck KGaA, outside of the submitted work. N.M. reports grants, personal fees and non-financial support from Merck KGaA outside the submitted work. T.D.H. is Vice President and Head of Global Medical Affairs Fertility, Research and Development at Merck KGaA, Darmstadt, Germany. P.A. has received personal fees from Merck KGaA, Darmstadt, Germany, outside the submitted work. C.R. has received grants and personal fees from Gedeon Richter and Merck Serono S.A.S., France, an affiliate of Merck KGaA, Darmstadt, Germany, outside the submitted work. P.S. reports congress support from Merck Serono S.A.S., France (an affiliate of Merck KGaA, Darmstadt, Germany), Gedeon Richter, TEVA and MDS outside the submitted work. C.A., J.P., G.P. and R.W. declare no conflict of interest., Trial Registration Number: N/A., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: A Delphi consensus was conducted to evaluate global expert opinions on key aspects of assisted reproductive technology (ART) treatment., Methods: Ten experts plus the Scientific Coordinator discussed and amended statements plus supporting references proposed by the Scientific Coordinator. The statements were distributed via an online survey to 35 experts, who voted on their level of agreement or disagreement with each statement. Consensus was reached if the proportion of participants agreeing or disagreeing with a statement was >66%., Results: Eighteen statements were developed. All statements reached consensus and the most relevant are summarised here. (1) Follicular development and stimulation with gonadotropins (n = 9 statements): Recombinant human follicle stimulating hormone (r-hFSH) alone is sufficient for follicular development in normogonadotropic patients aged <35 years. Oocyte number and live birth rate are strongly correlated; there is a positive linear correlation with cumulative live birth rate. Different r-hFSH preparations have identical polypeptide chains but different glycosylation patterns, affecting the biospecific activity of r-hFSH. r-hFSH plus recombinant human LH (r-hFSH:r-hLH) demonstrates improved pregnancy rates and cost efficacy versus human menopausal gonadotropin (hMG) in patients with severe FSH and LH deficiency. (2) Pituitary suppression (n = 2 statements): Gonadotropin releasing hormone (GnRH) antagonists are associated with lower rates of any grade ovarian hyperstimulation syndrome (OHSS) and cycle cancellation versus GnRH agonists. (3) Final oocyte maturation triggering (n=4 statements): Human chorionic gonadotropin (hCG) represents the gold standard in fresh cycles. The efficacy of hCG triggering for frozen transfers in modified natural cycles is controversial compared with LH peak monitoring. Current evidence supports significantly higher pregnancy rates with hCG + GnRH agonist versus hCG alone, but further evidence is needed. GnRH agonist trigger, in GnRH antagonist protocol, is recommended for final oocyte maturation in women at risk of OHSS. (4) Luteal-phase support (n = 3 statements): Vaginal progesterone therapy represents the gold standard for luteal-phase support., Conclusions: This Delphi consensus provides a real-world clinical perspective on the specific approaches during the key steps of ART treatment from a diverse group of international experts. Additional guidance from clinicians on ART strategies could complement guidelines and policies, and may help to further improve treatment outcomes., Competing Interests: TD and SL are employees of Merck KGaA, Darmstadt, Germany. RO received speaker fees/honoraria from Ferring and Merck KGaA, Darmstadt, Germany. CV is supported by a NHMRC Early Career Fellowship (GNT1147154). He also has equity interests in Virtus Health and reports grants, personal fees and non-financial support from Merck KGaA, Darmstadt, Germany, personal fees and non-financial support from MSD, grants and non-financial support from Ferring, personal fees from Besins Healthcare, and grants and non-financial support from Abbott. HF received speaker fees/honoraria/grants from MSD, Ferring, Besin, Merck KGaA, Darmstadt, Germany, and Sun Pharma. RF received consulting fees and honoraria from Merck KGaA, Darmstadt, Germany. YK received speaker fees/honoraria/grants from MSD, Merck KGaA, Darmstadt, Germany, Besins Healthcare, Gedeon Richter, Abbott, Bayer, and Sun Pharma. MH declares receipt of research grants from Merck KGaA, Darmstadt, Germany, and lecture fees from Merck KGaA, Darmstadt, Germany and Ferring. MG received fees from Merck KGaA, Darmstadt, Germany, Ferring, Gedeon Richter, MSD, IBSA. SE declares receipt of unrestricted research grants from Merck KGaA, Darmstadt, Germany, and lecture fees from Merck KGaA, Darmstadt, Germany, Gedeon Richter and Medical Education Academy. SS was speaker at non-promotional educational symposia by Merck KGaA, Darmstadt, Germany and Ferring in the last 12 months. YL received speaker fees/grants from Merck KGaA, Darmstadt, Germany, MSD, and Bayer. CA received consulting fees and payment/honoraria from Merck KGaA, Darmstadt, Germany., (Copyright © 2021 Orvieto, Venetis, Fatemi, D’Hooghe, Fischer, Koloda, Horton, Grynberg, Longobardi, Esteves, Sunkara, Li and Alviggi.)

Research Question: How might time to healthy singleton delivery affect decision-making during infertility treatment?, Design: This was a Delphi consensus investigating expert opinion that comprised three steps. In Step 1, 12 experts developed statements. In Step 2, 27 experts (including 12 from Step 1) voted (online survey) on their agreement/disagreement with each statement (providing reasons). Consensus was reached if ≥66% of participants agreed/disagreed. Statements not reaching consensus were revised and the process repeated until consensus was achieved. In Step 3 details of the final agreed statements were communicated., Results: Twelve statements were developed, and consensus (agreement) was reached on all after one round of voting., Conclusions: Time to healthy singleton delivery should be taken into consideration when making decisions related to infertility treatment, and it is important that fertility treatment is provided in a timely manner, avoiding over- or under-treatment. In all subfertile women <40 years old, IVF outcomes could be optimized by performing up to six single-embryo transfers and certain procedures might reduce time to healthy singleton delivery. These procedures include preimplantation genetic testing for aneuploidies, frozen replacement cycles immediately after failed fresh cycles and use of gonadotrophin-releasing hormone antagonists. Finally, the number of oocytes retrieved should be maximized to increase cumulative live birth rate., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This monograph, written by the pioneers of IVF and reproductive medicine, celebrates the history, achievements, and medical advancements made over the last 40 years in this rapidly growing field., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Research Question: A number of live-birth predictive models are available, and despite clinical interest these are rarely used owing to poor performance. In addition, no predictive models specifically for poor ovarian responders (POR) are available. The aim of the current project was to develop a clinically applicable tool for predicting live birth for PORs receiving recombinant human FSH [r-hFSH]., Design: A model was developed to predict live birth in PORs receiving r-hFSH, using data from the ESPART trial. Initially, two models were developed separately: one for patients with data from a previous assisted reproductive technology (ART) cycle and one for ART treatment-naïve patients. Subsequently, the simplified Poor Responder Outcome Prediction (PROsPeR) concept was derived., Results: PROsPeR considers three predictors and categorizes PORs into three scores, with predicted the live-birth rate divided by three with each worsening category. When adequately calibrated, a discrimination score up to area under the receiver operating characteristic (AUC ROC ) (95% CI) of 0.84 (0.79 to 0.88) was observed, which is superior to previously published models. Lower discriminations were observed when the PROsPeR model was used to evaluate the patients who received both r-hFSH and recombinant human LH in the ESPART study (AUC ROC [95% CI] 0.66 [0.61 to 0.71]) and when all the patients included in the ESPART study were evaluated (AUC ROC [95% CI] 0.68 [0.61 to 0.72])., Conclusions: This model, specific to PORs receiving r-hFSH, constitutes the best compromise between precision and simplicity, and is suitable for routine practice., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The distress that couples experience in IVF treatment is well-documented though research exploring factors that might contribute to the distress is scarce and the role of infertility-specific versus more general psychological characteristics in predicting psychological distress remains unexplored. This exploratory study aimed to describe, explore and test a self-constructed conceptual framework designed to understand the relative impact of infertility-specific and general psychological characteristics, in predicting psychological distress., Methods: Validated self-report questionnaires that measured the concepts of the encompassing framework (personality characteristics self-criticism and dependency, attachment in the partner relationship, child wish, coping, intrusiveness, infertility-related stress and general psychological distress) were completed by 106 women and 102 men before starting the first IVF/ICSI treatment at a university hospital-based fertility centre. Data were analysed by hierarchical multivariate linear regression analysis and path analysis., Results: The overall conceptual psychological framework explained 55% of the variance in psychological distress. The strongest predictors of psychological distress were general psychological characteristics: passive and active coping, self-criticism and dependency and intrusiveness. A path analysis confirmed the framework and highlighted the mediating role of coping and intrusiveness. In the final analysis, none of the infertility-specific variables significantly predicted psychological distress., Conclusions: The current study of patients starting IVF-treatment demonstrated that general psychological characteristics, specifically active and passive coping, personality characteristics, dependency and self-criticism and intrusiveness, are more important in predicting the variability in psychological distress than infertility-specific concerns. The results raise important questions for infertility counselling. However, the cross-sectional nature of the study only allows for insight into baseline measurement (before starting the first IVF-treatment) and therefore this area of research could benefit from additional longitudinal studies.

Chromosome instability is a hallmark of tumorigenesis. This study establishes that chromosome instability is also common during early human embryogenesis. A new array-based method allowed screening of genome-wide copy number and loss of heterozygosity in single cells. This revealed not only mosaicism for whole-chromosome aneuploidies and uniparental disomies in most cleavage-stage embryos but also frequent segmental deletions, duplications and amplifications that were reciprocal in sister blastomeres, implying the occurrence of breakage-fusion-bridge cycles. This explains the low human fecundity and identifies post-zygotic chromosome instability as a leading cause of constitutional chromosomal disorders.

Background: Baboon in vitro fertilization requires capacitated sperm inappropriate media. In this study, we compared the effect of baboon serum (Bas), human serum albumin (HSA) and bovine serum albumin (BSA) on baboon sperm capacitation., Methods: Five males (n = 5) were electroejaculated and 43 oocytes retrieved from super-ovulated female baboons (n = 10). Each sperm sample was assessed for initial motility and concentration before and after swim-up. For swim-up, each sperm sample was incubated separately in Biggers-Whitten-Whittingham media containing either BaS, HSA, BSA or without protein supplementation (control). After swim-up, each sperm aliquot was incubated with two to three oocytes. The number of sperm bound to the zona was evaluated after overnight incubation., Results: Sperm motility and zona binding was significantly higher after capacitation in media supplemented with BaS than in HSA or BSA or in media without protein supplementation (P < 0.05)., Conclusion: Baboon serum is superior to HSA or BSA for baboon sperm capacitation and zona binding.

This study reports on anti-Müllerian hormone (AMH) in serum and follicular fluid (FF) in relation to inflammatory parameters in women with and without endometriosis undergoing IVF. Serum and FF samples were obtained from 72 women, with (n = 34) and without (n = 38) endometriosis, undergoing IVF. The concentrations of AMH, FSH, tumour necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF) and several interleukins were analysed. Women with endometriosis had significantly lower AMH in serum and FF (serum: 6.38 versus 12.8 pM; P < 0.01, FF: 14.0 versus 19.6 pM; P < 0.05). TNF was increased in FF (40.0 versus 30.8 pg/ml, P < 0.05) from women with endometriosis and significantly higher concentrations of IL-15 and GM-CSF were detected in FF (both P < 0.05). During IVF, women with endometriosis responded well to FSH but had lower fertilization rates. Women with endometriosis have elevated concentrations of several cytokines in FF. They respond adequately to exogenous FSH but may have impaired oocyte quality, reflected in lower fertilization rates, presumably resulting from an inflammatory process in the ovaries. Further studies are needed to elucidate the role of AMH in predicting ovarian reserve in women with endometriosis.

Background: IVF treatment involves a reassessment of issues concerning autonomy and relatedness. This study aims to extend prior studies on the psychological impact of IVF/ICSI by studying the association between the personality dimensions of Self-Criticism and Dependency with the psychological well-being and quality of the couple relationship for women starting their first IVF treatment., Methods: This is a cross-sectional study of 68 women starting their first IVF treatment at the Leuven University Fertility Centre of the University of Leuven, Belgium. All women were administered validated self-report measures assessing Self-Criticism and Dependency, negative life events, psychological well-being, relationship satisfaction, and relationship and sexual concerns. Pearson's correlation coefficients were calculated between all study variables, followed by four separate hierarchical multiple regression analyses for psychological well-being, relationship satisfaction, and relationship and sexual concerns., Results: High Self-Criticism was negatively associated with psychological well-being (r = -0.63, P < 0.001) and relationship satisfaction (r = -0.29, P < 0.05), and positively associated with relationship (r = 0.39, P < 0.01) and sexual (r = 0.37, P < 0.01) concerns. High Dependency was negatively associated with psychological well-being (r = -0.30, P < 0.05), not significantly associated with relationship satisfaction and relationship concerns, and positively related to sexual concerns (r = 0.31, P < 0.05)., Conclusions: This cross-sectional study suggests that the personality dimensions of Self-Criticism and Dependency may enhance our understanding of the psychological well-being and quality of the couple relationship of women starting their first IVF treatment. However, further prospective research on this topic is needed.

Objective: To extend existing research on the psychological impact of IVF by studying the association between the psychosocial factors of self-criticism and dependency, and romantic attachment, with the well-being and relationship satisfaction of couples across the different phases of IVF/intracytoplasmic sperm injection (ICSI) treatment., Design: Prospective, three-wave study (i.e., from start of IVF/ICSI treatment, to 3- and 6-month follow-up)., Setting: University hospital., Patient(s): Seventy couples in IVF/ICSI treatment., Intervention(s): Psychometric tests were administered at first visit of IVF/ICSI treatment, and at 3- and 6-month follow-up., Main Outcome Measure(s): Psychological well-being, relationship satisfaction., Result(s): Results demonstrated that preexisting psychosocial factors such as self-criticism, dependency, and romantic attachment are more important factors for psychological well-being and relationship satisfaction during IVF/ICSI than gender and treatment-related factors such as duration of fertility problems. In addition, multilevel analysis, a statistical method that is required for the analysis of longitudinal couple data and decomposes variation in three levels (i.e., time, individuals, and couples), showed more variation in psychological well-being and relationship satisfaction between couples, than between individuals and different time measurements., Conclusion(s): Preexisting personality factors and being embedded within a certain couple relationship are important factors for the psychological well-being and relationship satisfaction during IVF/ICSI.

Background: The objective of this study was to explore the reasons why couples discontinue fertility treatment., Methods: A retrospective exploratory study was performed at the Leuven University Fertility Centre, a university hospital-based fertility center. Women who discontinued treatment between September 2000 and December 2001 were contacted in 2004-2005 by telephone for a standardized interview which covered 9 dropout reasons. For each reason, its importance on the decision to stop treatment was measured on an 11-point Likert scale., Results: On average, psychological burden (x = 5.96) had the highest impact on the decision to stop treatment followed by physical burden (x = 4.48) and female age (x = 3.64). Perceived lack of staff expertise (x = 1.84), negative impact on social contacts (x = 2.12) and financial burden (x = 2.16) had the lowest impact on the decision to stop treatment. Longer duration of infertility was significantly positively correlated with a higher rating of physical burden as a reason to discontinue treatment (r = 0.48; p < 0.05)., Discussion: On average, psychological burden appears to be most frequently named as the number one reason to discontinue infertility treatment, whereas financial burden had the lowest impact. Longer duration of infertility is associated with more externalizing reasons to discontinue treatment.

Objective: To determine the prevalence of chromosomal abnormalities in female partners of couples undergoing IVF or intracytoplasmic sperm injection (ICSI)., Design: Prospective study., Setting: Leuven University Fertility Center., Patient(s): Female candidates for IVF or ICSI., Intervention(s): An initial cytogenetic study was performed on peripheral blood lymphocyte cultures using G- and R-banding. In all patients, > or =25 metaphases were examined. If a chromosomal aberration was detected, additional cytogenetic studies were performed for precise identification., Main Outcome Measure(s): Abnormal female karyotypes in comparison with the general female population., Result(s): Cytogenetic analysis was performed in 263 female partners of couples before entering an IVF or ICSI program. The prevalence of autosomal reciprocal balanced translocations was seven times higher in the study group (1.14%) than in the general population (0.16%). All abnormal karyotypes were found in the IVF group with male factor infertility., Conclusion(s): Chromosomal abnormalities are more frequent in the female partners of couples seeking fertility treatment. We recommend chromosomal analysis in women before starting IVF or ICSI treatment, even in the presence of male factor infertility.

Objective: To examine the influence of depression levels and coping on IVF outcome in women, taking into account the cause of infertility., Design: Prospective clinical study., Setting: A university hospital., Patient(s): Ninety-eight women undergoing IVF treatment., Intervention(s): Psychometric tests were administered at the first visit (day 3) of the investigated treatment cycle., Main Outcome Measure(s): Achievement of pregnancy., Results: The nonpregnant group reported increased expression of negative emotions. In the subgroup with a female indication for IVF, increased depressive symptomatology (correlated with increased expression of negative emotions) was associated with lower pregnancy rates (PRs), whereas in the subgroup with a male indication for IVF, increased depressive symptomatology (correlated with decreased expression of negative emotions) was associated with higher PRs., Conclusion(s): Expression of negative emotions predicts depression levels and outcome in IVF. The cause of infertility should be taken into account when investigating the relation between psychologic functioning and outcome in IVF.

Objective: To test the hypothesis that alpha-glycosidase activity in seminal plasma can predict the outcome of both IUI and IVF., Design: A retrospective cohort study., Setting: Tertiary fertility center in a university hospital., Patient(s): Eighty-three subfertile couples who underwent IUI and 125 subfertile couples who underwent IVF., Intervention: None., Main Outcome Measure(s): Determination of the alpha-glycosidase activity in seminal plasma before an IUI or IVF attempt, correlation of alpha-glycosidase activity and other semen parameters, and prediction of pregnancy using alpha-glycosidase activity in seminal plasma., Result(s): Alpha-glycosidase activity correlated with sperm count. In the IUI group, alpha-glycosidase activity of >23.9 mU/mL predicted pregnancy with a sensitivity of 100% and a specificity of 55.2%. In the IVF group, the outcome could not be predicted with use of any of the semen parameters., Conclusion(s): Alpha-glycosidase activity measured in mU/mL probably can be used as a predictor for IVF and pregnancy in an IUI program but has no predictive value with regard to pregnancy rate in an IVF program.

Study Question: Does ultra-long downregulation with a GnRH agonist (triptorelin depot) in previously operated patients with endometriosis improve the rate of clinical pregnancy with positive fetal heart beat (CPHB) in the subsequent initiated fresh ART cycle?Summary Answer: Ultra-long downregulation with a GnRH agonist prior to ART did not improve the rate of CPHB in the subsequent fresh ART cycle in previously completely operated patients but the trial was underpowered due to early termination.What Is Known Already: Administration of GnRH agonists for a period of 3-6 months prior to ART in women with endometriosis may increase the odds of clinical pregnancy. However, the quality of the studies on which this statement is based is questionable, so these findings need confirmation.Study Design, Size, Duration: A controlled, randomized, open label trial was performed between 1 June 2013 and 31 December 2016 (start and end of recruitment, respectively). Patients with prior complete laparoscopic treatment of any type or stage of endometriosis and an indication for ART were randomized (by a computer-generated allocation sequence) into two groups: the control group underwent ART stimulation in a classical long agonist protocol using preparation with oral contraceptives, the ultra-long group first underwent at least 3 months downregulation followed by a long agonist protocol for ART stimulation. The sample size was calculated to detect a superiority of the ultra-long downregulation protocol, based on the hypothesis that baseline CPHB rate in the control group of 20% would increase to 40% in the ultra-long group. For a power of 20% at a significance level of 5%, based on two-sided testing, including 5% of patients lost to follow-up, the necessary sample size was 172 patients (86 per group).Participants/materials, Setting, Methods: This trial was conducted at the Leuven University Fertility Center, a tertiary care center for endometriosis and infertility, and a total of 42 patients were randomized (21 in the control group and 21 in the ultra-long group).Main Results and the Role Of Chance: Baseline characteristics were similar in both groups. The primary outcome studied-CPHB after the initiated ART treatment-did not differ and was 25% (5/20) in the control group, and 20% (4/20) in the ultra-long group (P > 0.999; relative risk (RR) 1.25, 95% CI 0.41-3.88). Cumulative (fresh + associated frozen) CPHB rates were also similar in the control versus ultra-long group (8/20, 40% vs 6/20, 30%, P = 0.7411; RR = 1.33, 95% CI 0.57-3.19). When other secondary outcomes were compared with the ultra-long group, patients from the control group had a shorter duration of stimulation (mean 11.8 days (SD ± 2.4) versus 13.2 days (SD ± 1.5), P = 0.0373), a lower total dose of gonadotrophins used (mean 1793 IU/d (SD ± 787) vs 2329 (SD ± 680), P = 0.0154), and a higher serum estradiol concentration (ng/ml) at the end of ovarian stimulation on the day of ovulation triggering or cycle cancellation (mean1971 (SD ± 1495) vs 929 (± 548); P = 0.0326), suggesting a better ovarian response in the control group.Limitations, Reasons For Caution: Due to a strong patient preference, nearly exclusively against ultra-long downregulation (even though patients were thoroughly informed of the potential benefits), the targeted sample size could not be achieved and the trial was stopped prematurely.Wider Implications Of the Findings: Conditional power analysis revealed that the probability of confirming the study hypothesis if the study were completed would be low. We hypothesize that in patients with prior complete surgical treatment of endometriosis, the ultra-long protocol does not enhance ART-CPHB rates. Patient's concerns and preferences regarding possible side-effects, and delay of ART treatment start with the ultra-long protocol should be taken into account when considering this type of treatment in women with endometriosis.Study Funding/competing Interest(s): C.T. was during 2 years funded by a grant from the Clinical research Foundation of UZ Leuven (KOF) and during 2 years by the Research Foundation-Flanders (FWO grant number: 1700816N). C.T. reports grants from Clinical Research Foundation of the University Hospitals of Leuven (KOF), grants from Fund for Scientific Research Flanders (FWO), during the conduct of the study; grants, non-financial support and other from Merck SA, non-financial support and other from Gedeon Richter, non-financial support from Ferring Pharmaceuticals, outside the submitted work. T.D. is vice president and head of Global Medical Affairs Fertility, Research and Development, Merck KGaA, Darmstadt, Germany. He is also a professor in Reproductive Medicine and Biology at the Department of Development and Regeneration, Group Biomedical Sciences, KU Leuven (University of Leuven), Belgium and an adjunct professor at the Department of Obstetrics and Gynecology in the University of Yale, New Haven, USA. Neither his corporate role nor his academic roles represent a conflict of interest with respect to the work done by him for this study. A.C. reports personal fees from Merck S.p.A., outside the submitted work. The other co-authors have no conflict of interest.Trial Registration Number: UZ Leuven trial registry SS55300, EudraCT number 2013-000993-32, clinicaltrials.gov NCT02400801.Trial Registration Date: Registration for EudraCT on 1 March 2013.Date Of First Patient’s Enrolment: 4 September 2013. [ABSTRACT FROM AUTHOR]

Study Question: Is the microRNA (miRNA) expression pattern of cumulus oophorus cells (COCs) in women undergoing medically assisted reproduction (MAR) procedures differentially modulated according to patient age and gonadotropin treatment strategy?Summary Answer: Maternal age is an independent factor impacting miRNA expression in COCs while gonadotropin treatment may affect follicular miRNA expression and IVF efficacy.What Is Known Already: Epigenetic mechanisms in female infertility are complex and poorly studied. DNA methylation, histone modifications, miRNAs and nucleosome positioning influence cellular machinery through positive and negative feedback mechanisms either alone or interactively. miRNAs are important regulators during oogenesis, spermatogenesis and early embryogenesis, and are reported to play a role in regulating crosstalk between the oocyte and COCs. Although miRNome analysis has been performed in female human reproductive tissues (endometrium, myometrium, cervix and ovaries), epigenetic modifications in women with infertility have not been explored in detail. In addition, the impact of gonadotropin treatments during MAR on miRNA expression in COCs has not been fully investigated.Study Design, Size, Duration: This study was carried out in 53 COC samples obtained from mature metaphase II (MII) oocytes in 53 women undergoing MAR treatment. A total of 38 samples for assay development were pooled by maternal age and gonadotropin treatment into four predetermined subgroups: ≥36 years and recombinant human FSH (r-hFSH), n = 10; ≥36 years and r-hFSH+ recombinant human-luteinizing hormone (r-hLH), n = 10; ≤35 years and r-hFSH, n = 9; ≤35 years and r-hFSH+r-hLH, n = 9. miRNome profiles were determined and compared between subgroups. Expression of defined miRNAs was validated in the remaining fifteen samples, representative of each subgroup, by quantitative polymerase chain reaction (PCR).Participants/materials, Setting, Methods: COCs were processed for miRNA-enriched total RNA extraction and pooled in homogeneous subgroups to obtain a sufficient amount and quality of starting material to perform the analysis. Each pooled sample underwent miRNA profiling using PCR assay system to examine expression of 752 human miRNAs without pre-amplification. Data were analyzed using the delta-delta Ct method for relative quantitation and prediction of target genes (with at least four algorithms predicting the same miRNA-gene interaction pair (HIT)>4). The miRSystem database provided functional annotation enrichment (raw P-value <0.05) of co-expressed miRNAs.Main Results and the Role Of Chance: We found distinctive miRNA expression profiles in each subgroup correlating with age and MAR stimulation. In addition, a number of selective and co-expressed miRNAs were revealed by comparative analysis. A cluster of 37 miRNAs were commonly but differentially expressed in all four pools. Significant differences were observed in expression regulation of 37 miRNAs between age groups (≤35 or ≥36) in women receiving r-hFSH+r-hLH compared to those receiving r-hFSH alone. Higher concentrations and increased numbers of miRNAs were recorded in younger than in older patients, regardless of treatment. Functional and expression studies performed to retrieve common miRNome profiles revealed an enrichment of biological functions in oocyte growth and maturation, embryo development, steroidogenesis, ovarian hyperstimulation, apoptosis and cell survival, glucagon and lipid metabolism, and cell trafficking. The highest scored pathways of target genes of the 37 common miRNAs were associated with mitogen-activated protein kinase (MAPK) signaling pathways, G alpha signaling, transcription regulation, tight junctions, RNA polymerase I and III, and mitochondrial transcription. We identified a potential age- and MAR stimulation-dependent signature in the miRNA landscape of COCs.Limitations, Reasons For Caution: We cannot rule out the possibility that other unknown individual genetic or clinical factors may have interfered with the reported results. Since miRNA profiling was conducted with a predefined array of target probes, other miRNA molecules, potentially modulated by age and hormonal stimulation, may have been missed in this study.Wider Implications Of the Findings: miRNA expression in COCs is modulated by gonadotropin treatment and correlates strongly with age. A better understanding of the expression patterns and functions of miRNAs may lead to the development of novel therapeutics to treat ovarian dysfunction and improve fertility in older women.Study Funding/competing Interest: This study was funded by Merck KGaA, Darmstadt, Germany. All authors declared no competing interest, except SL and TD who are fully employed by Merck KGaA.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

This study aimed to demonstrate the clinical performance of an ultra-sensitive follicular fluid (FF) granulocyte colony stimulating factor (G-CSF) immunoassay to confirm previous work, indicating a correlation between FF G-CSF concentration and live birth potential of the corresponding embryo after in vitro fertilization. This study was a noninterventional, prospective, diagnostic clinical multicentric study conducted between August 2012 and January 2014 with 396 single embryo transfers (SETs) from 278 subjects. During oocyte retrieval, FF was individually collected. Embryo morphology and implantation success were evaluated. The implantation success rate in the high G-CSF group (32.3%) was higher than the overall rate (27.5%). Similarly, for embryos with optimal morphology, implantation success rates were highest among those in the high G-CSF concentration category (34.5%) compared with low (19.6%) and intermediate (29.8%) G-CSF concentration categories. Significant differences in mean G-CSF concentrations were observed between the study sites. To minimize bias, analyses were repeated using data from the center with the largest number of SETs. In alignment with the overall analysis, this center demonstrated a 43% greater probability of implantation for optimal embryos with high G-CSF compared to the general implantation rate among optimal embryos and a 327% increase compared with the implantation rate of optimal embryos with low G-CSF. [ABSTRACT FROM AUTHOR]

Study Question: The 15th European IVF-monitoring (EIM) report presents the results of treatments involving assisted reproductive technology (ART) initiated in Europe during 2011: are there any changes in the trends compared with previous years?Summary Answer: Despite some fluctuations in the number of countries reporting data, while the overall number of ART cycles has continued to increase year by year, the pregnancy rates in 2011 decreased slightly to those reported in 2010, and the number of transfers with multiple embryos (3+) and the multiple delivery rates declined.What Is Known Already: Since 1997, ART data in Europe have been collected and reported in 14 manuscripts, published in Human Reproduction.Study Design, Size, Duration: Retrospective data collection of European ART data by the EIM Consortium for the European Society of Human Reproduction and Embryology (ESHRE); cycles started between 1 January and 31 December 2011 are collected on a yearly basis. The data are collected by National Registers, when existing, or on a voluntary basis by personal information.Participants/materials Setting, Methods: From 33 countries (+2 compared with 2010), 1064 clinics reported 609 973 treatment cycles including: IVF 138 592, ICSI 298 918, frozen embryo replacement (FER) 129 693, egg donation (ED) 30 198, in vitro maturation 511, preimplantation genetic diagnosis/screening 6824 and frozen oocyte replacements 5237. European data on intrauterine insemination (IUI) using husband/partner's semen (IUI-H) and donor semen (IUI-D) were reported from 861 IUI laboratories in 24 countries. A total of 174 390 IUI-H and 41 151 IUI-D cycles were included.Main Results and the Role Of Chance: In 17 countries where all clinics reported to the ART register, a total of 361 972 ART cycles were performed in a population of 285 million inhabitants, corresponding to 1269 cycles per million inhabitants. For all IVF cycles, the clinical pregnancy rates per aspiration and per transfer were stable with 29.1 and 33.2%, respectively, and for ICSI, the corresponding rates also were stable with 27.9 and 31.8%, respectively. In FER cycles, the pregnancy rate per thawing increased to 21.3% if compared with previous years. In ED cycles, the pregnancy rate per fresh transfer decreased to 45.8% (47.4% in 2010) and increased to 33.6% (33.3% in 2010) per thawed transfer. The delivery rate after IUI-H decreased to 8.3 (8.9 in 2010), and to 12.2% (13.8% in 2010) after IUI-D. In IVF and ICSI cycles, 1, 2, 3 and 4+ embryos were transferred in 27.5, 56.7, 14.5 and 1.3% of cycles, respectively. The proportions of singleton, twin and triplet deliveries after IVF and ICSI (added together) were 80.8, 18.6 and 0.6%, respectively, resulting in a total multiple delivery rate of 19.2% compared with 20.6% in 2010, 20.2% in 2009, 21.7% in 2008, 22.3% in 2007 and 20.8% in 2006. In FER cycles, the multiple delivery rate was 13.2% (12.8% twins and 0.4% triplets). Twin and triplet delivery rates associated with IUI cycles were 9.7/0.6% and 7.3/0.3%, following IUI-H and IUI-D treatment, respectively.Limitations, Reasons For Caution: The method of reporting varies among countries, and registers from a number of countries have been unable to provide some of the relevant data such as initiated cycles and deliveries. As long as data are incomplete and generated through different methods of collection, results should be interpreted with caution.Wider Implications Of the Findings: The 15th ESHRE report on ART shows a continuing expansion of the number of treatment cycles in Europe, with more than 600 000 cycles reported in 2011. Since 2006, the proportion of IVF to ICSI cycles has reached a plateau after a small decrease in 2009. Pregnancy and delivery rates after IVF remained relatively stable compared with 2010 and 2009. The pregnancy rate per aspiration in ICSI cycles declined for the first time by 0.9%. The multiple delivery rate is lower than ever before.Study Funding/competing Interests: The study had no external funding; all costs are covered by ESHRE. There are no competing interests. [ABSTRACT FROM AUTHOR]

An abstract of the article "Using a model based on serum biochemistry at 4 and 5 weeks gestation to predict immediate viability and viability at 12 weeks in IVF pregnancies," by A. Pexsters and colleagues is presented.