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In IVF/ICSI treatment, the FSH starting dose is often increased in predicted low responders from the belief that it improves the chance of having a baby by maximizing the number of retrieved oocytes. This intervention has been evaluated in several randomized controlled trials, and despite a slight increase in the number of oocytes—on average one to two more oocytes in the high versus standard dose group—no beneficial impact on the probability of a live birth has been demonstrated (risk difference, −0.02; 95% CI, −0.11 to 0.06). Still, many clinicians and researchers maintain a highly ingrained belief in ‘the more oocytes, the better’. This is mainly based on cross-sectional studies, where the positive correlation between the number of retrieved oocytes and the probability of a live birth is interpreted as a direct causal relation. If the latter would be present, indeed, maximizing the oocyte number would benefit our patients. The current paper argues that the use of high FSH doses may not actually improve the probability of a live birth for predicted low responders undergoing IVF/ICSI treatment and exemplifies the flaws of directly using cross-sectional data to guide FSH dosing in clinical practice. Also, difficulties in the de-implementation of the increased FSH dosing strategy are discussed, which include the prioritization of intermediate outcomes (such as cycle cancellations) and the potential biases in the interpretation of study findings (such as confirmation or rescue bias).

Study question After one failed IVF/ICSI cycle, does the endometrial microbiota composition differ between women who will or will not reach a live birth within 12 months? Summary answer The endometrial microbiota composition did not significantly differ in women with one failed IVF/ICSI cycle with or without live birth, but statistical power was low. What is known already Evidence for the presence of an indigenous endometrial microbiome is mounting, and its composition may be associated with implantation success. However, a ‘core’ endometrial microbiome has not yet been defined, and its role in embryo implantation is still poorly understood. Further investigation of this topic may allow improvement and personalisation of clinical care for infertile couples. Endometrial microbiome analysis in infertile women has not yet been performed using transcervically obtained endometrial tissue. Using endometrial tissue instead of swabs or fluid may increase the bacterial DNA yield and therefore the precision of microbiome analyses. Study design, size, duration Endometrial tissue was obtained from a cohort of 141 infertile women undergoing endometrial scratching within a randomised controlled trial (RCT) (SCRaTCH trial, NL5193/NTR5342). Briefly, women aged 18-44 years with failed implantation after one full IVF/ICSI cycle and planning a subsequent IVF/ICSI cycle, were eligible. Participants were followed-up until 12 months after randomisation, with the primary outcome being live birth, defined as the delivery of at least one live foetus after 24 weeks of gestation. Participants/materials, setting, methods Endometrial tissue was obtained with an endometrial biopsy catheter in the midluteal phase of a natural cycle preceding subsequent IVF/ICSI, snap-frozen and stored at -80 °C until use. Total DNA was isolated from these biopsies, followed by 16S rRNA sequencing (V3-V4 region) to determine the endometrial microbiota composition. Positive (mock communities) and negative controls (DNA extraction and PCRs) were included. QIIME2 and DADA2 were used for the data analysis, followed by statistical analysis in R studio. Main results and the role of chance During the 12-month follow-up, 61/141 women (43.3%) reached a live birth. While endometrial microbiota profiles of all 141 women were analysed, only samples with ≥100 reads were included in the analysis, resulting in a total of 46 samples (32.6%) that were included in the analysis, which consisted of samples from 25 women who did not have and 21 women who did have a live birth within 12 months. The median number of reads per sample was not significantly different between the two groups (respectively 2,317 (IQR 651-19,031) and 1,335 (IQR 296-3,180), p = 0.29 by Mann-Whitney test). The endometrial microbiota detected, were bacterial genera frequently reported within the vaginal microbiota (e.g. Lactobacillus, Atopobium and Gardnerella). A clear dominance of Lactobacillus (relative abundance 55-100%, n = 22) or an unclassified bacterium genus (relative abundance 52-76%, n = 18) was observed in the majority of the samples; however, this dominance was not associated with the outcome of live birth. In addition, the samples dominated by Lactobacillus genera were mostly dominated by one species of Lactobacillus each (L. crispatus, L. iners, L. gasseri or L. jensenii). Limitations, reasons for caution The low biomass and the low ratio of bacterial versus human DNA in endometrial tissue were limiting factors in endometrial microbiota analysis. Furthermore, tissue was obtained transcervically, and contamination with vaginal/cervical microbiota could therefore have occurred. In the SCRaTCH trial no vaginal swabs were taken to serve as internal controls. Wider implications of the findings Future endometrial microbiota studies should consider the use of samples with a lower proportion of human DNA to maximize bacterial DNA yield. Furthermore, for endometrial microbiota research, sampling devices avoiding cervicovaginal contamination are desirable and may be developed in the future. Trial registration number SCRaTCH trial, NL5193/NTR5342

Study question Does the endometrial synthesis and inactivation of 17β- estradiol differ between receptive and non-receptive endometrium in women undergoing IVF/ICSI? Summary answer The synthesis and inactivation of 17β-estradiol is similar in the endometrium of women who did and did not achieve a clinical pregnancy through IVF/ICSI. What is known already Implantation failure of high-quality embryos is a main concern in IVF/ICSI treatment. Blood sex-steroid concentrations do not reflect their corresponding concentrations in endometrial tissue. This is in line with the concept that blood steroids (and precursors) are locally converted to bioactive metabolites and vice versa, by expressing steroid-metabolising enzymes, such as 17β-hydroxy steroid dehydrogenase (17β-HSD). Studies indicate that alterations in intracrinology might modulate endometrial receptivity. We hypothesize that the local 17β-HSD activity during the window of implantation (WOI) differs between pregnant and non-pregnant IVF/ICSI patients. Study design, size, duration Case-control study of 40 patients that were recruited in the SCRaTCH study (NL5193/NTR5342), a randomised trial exploring whether ‘endometrial scratching’ in patients with a previous IVF/ICSI cycle failure affects pregnancy outcome in a subsequent IVF/ICSI cycle. For the present investigation, 20 endometrial biopsies from women who achieved clinical pregnancy after fresh embryo transfer (ET) were compared with 20 endometrial biopsies of women that did not conceive after fresh ET. Participants/materials, setting, methods Endometrial biopsies and serum were obtained at LH + 5-8 days (urinary test) in a natural cycle, prior to the fresh ET cycle. Cases (negative pregnancy test, n = 20) and controls (clinically pregnant, n = 20) were matched for primary vs. secondary infertility, embryo quality and age. Reduction of estrone to 17β-estradiol (synthesizing 17β-HSDs) and oxidation of 17β-estradiol to estrone (inactivating 17β-HSDs) were determined by high-performance liquid chromatography (HPLC). Results were compared with the Wilcoxon-Mann-Whitney Rank Sum Test. Main results and the role of chance Activity of 17β-HSDs responsible for the reduction of estrone to 17β-estradiol (mainly 17β-HSD type 1) was detected in all samples and ranged from 55 to 1864 pmol 17β-estradiol formed/mg protein/24 h. The values obtained from pregnant women (median: 1054) were not significantly different to those obtained from non-pregnant women (median: 997), p = 0.97. The activity of enzymes responsible for the oxidation of 17β-­ estradiol (mainly 17β-HSD type 2) into the less active estrone ranged from 32 to 1731 estrone formed/mg protein/24 h. The values obtained from pregnant women (median: 737) were not significantly different to those obtained from non-pregnant women (median: 624), p = 0.90. The ratio of 17β-HSD type 1:17β-HSD type 2 had a median of 1.63 in the pregnant woman compared to 1.95 in the group of non-pregnant woman (p = 0.57). Limitations, reasons for caution The study is pilot in nature and study population is small. Primary and secondary infertility patients were analysed together. A chance phenomenon could have occurred as included women were included after their first IVF/ICSI cycle, hence not every included study person met the criteria for repeated implantation failure (RIF). Wider implications of the findings 17β-estradiol metabolism takes place during the WOI, controlling the final 17β-estradiol level. Although the present investigation did not show differences between pregnant and non-pregnant women, it remains important to explore if estrogen balance deviations, e.g. in other cycle phases plays a role in clinical conditions such as primary infertility/RIF. Trial registration number NL5193/NTR5342

What is the recommended management of ovarian stimulation, based on the best available evidence in the literature?The guideline development group formulated 84 recommendations answering 18 key questions on ovarian stimulation.Ovarian stimulation for IVF/ICSI has been discussed briefly in the National Institute for Health and Care Excellence guideline on fertility problems, and the Royal Australian and New Zealand College of Obstetricians and Gynaecologist has published a statement on ovarian stimulation in assisted reproduction. There are, to our knowledge, no evidence-based guidelines dedicated to the process of ovarian stimulation.The guideline was developed according to the structured methodology for development of ESHRE guidelines. After formulation of key questions by a group of experts, literature searches and assessments were performed. Papers published up to 8 November 2018 and written in English were included. The critical outcomes for this guideline were efficacy in terms of cumulative live birth rate per started cycle or live birth rate per started cycle, as well as safety in terms of the rate of occurrence of moderate and/or severe ovarian hyperstimulation syndrome (OHSS).Based on the collected evidence, recommendations were formulated and discussed until consensus was reached within the guideline group. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline group and the ESHRE Executive Committee.The guideline provides 84 recommendations: 7 recommendations on pre-stimulation management, 40 recommendations on LH suppression and gonadotrophin stimulation, 11 recommendations on monitoring during ovarian stimulation, 18 recommendations on triggering of final oocyte maturation and luteal support and 8 recommendations on the prevention of OHSS. These include 61 evidence-based recommendations-of which only 21 were formulated as strong recommendations-and 19 good practice points and 4 research-only recommendations. The guideline includes a strong recommendation for the use of either antral follicle count or anti-Müllerian hormone (instead of other ovarian reserve tests) to predict high and poor response to ovarian stimulation. The guideline also includes a strong recommendation for the use of the GnRH antagonist protocol over the GnRH agonist protocols in the general IVF/ICSI population, based on the comparable efficacy and higher safety. For predicted poor responders, GnRH antagonists and GnRH agonists are equally recommended. With regards to hormone pre-treatment and other adjuvant treatments (metformin, growth hormone (GH), testosterone, dehydroepiandrosterone, aspirin and sildenafil), the guideline group concluded that none are recommended for increasing efficacy or safety.Several newer interventions are not well studied yet. For most of these interventions, a recommendation against the intervention or a research-only recommendation was formulated based on insufficient evidence. Future studies may require these recommendations to be revised.The guideline provides clinicians with clear advice on best practice in ovarian stimulation, based on the best evidence available. In addition, a list of research recommendations is provided to promote further studies in ovarian stimulation.The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the dissemination of the guideline. The guideline group members did not receive payment. F.B. reports research grant from Ferring and consulting fees from Merck, Ferring, Gedeon Richter and speaker's fees from Merck. N.P. reports research grants from Ferring, MSD, Roche Diagnositics, Theramex and Besins Healthcare; consulting fees from MSD, Ferring and IBSA; and speaker's fees from Ferring, MSD, Merck Serono, IBSA, Theramex, Besins Healthcare, Gedeon Richter and Roche Diagnostics. A.L.M reports research grants from Ferring, MSD, IBSA, Merck Serono, Gedeon Richter and TEVA and consulting fees from Roche, Beckman-Coulter. G.G. reports consulting fees from MSD, Ferring, Merck Serono, IBSA, Finox, Theramex, Gedeon-Richter, Glycotope, Abbott, Vitrolife, Biosilu, ReprodWissen, Obseva and PregLem and speaker's fees from MSD, Ferring, Merck Serono, IBSA, Finox, TEVA, Gedeon Richter, Glycotope, Abbott, Vitrolife and Biosilu. E.B. reports research grants from Gedeon Richter; consulting and speaker's fees from MSD, Ferring, Abbot, Gedeon Richter, Merck Serono, Roche Diagnostics and IBSA; and ownership interest from IVI-RMS Valencia. P.H. reports research grants from Gedeon Richter, Merck, IBSA and Ferring and speaker's fees from MSD, IBSA, Merck and Gedeon Richter. J.U. reports speaker's fees from IBSA and Ferring. N.M. reports research grants from MSD, Merck and IBSA; consulting fees from MSD, Merck, IBSA and Ferring and speaker's fees from MSD, Merck, IBSA, Gedeon Richter and Theramex. M.G. reports speaker's fees from Merck Serono, Ferring, Gedeon Richter and MSD. S.K.S. reports speaker's fees from Merck, MSD, Ferring and Pharmasure. E.K. reports speaker's fees from Merck Serono, Angellini Pharma and MSD. M.K. reports speaker's fees from Ferring. T.T. reports speaker's fees from Merck, MSD and MLD. The other authors report no conflicts of interest.

STUDY QUESTION: Is there a difference in live birth rate and/or cost-effectiveness between antral follicle count (AFC)-based individualized FSH dosing or standard FSH dosing in women starting IVF or ICSI treatment?SUMMARY ANSWER: In women initiating IVF/ICSI, AFC-based individualized FSH dosing does not improve live birth rates or reduce costs as compared to a standard FSH dose.WHAT IS KNOWN ALREADY: In IVF or ICSI, ovarian reserve testing is often used to adjust the FSH dose in order to normalize ovarian response and optimize live birth rates. However, no robust evidence for the (cost-)effectiveness of this practice exists.STUDY DESIGN, SIZE, DURATION: Between May 2011 and May 2014 we performed a multicentre prospective cohort study with two embedded RCTs in women scheduled for IVF/ICSI. Based on the AFC, women entered into one of the two RCTs (RCT1: AFC < 11; RCT2: AFC > 15) or the cohort (AFC 11-15). The primary outcome was ongoing pregnancy achieved within 18 months after randomization resulting in a live birth (delivery of at least one live foetus after 24 weeks of gestation). Data from the cohort with weight 0.5 were combined with both RCTs in order to conduct a strategy analysis. Potential half-integer numbers were rounded up. Differences in costs and effects between the two treatment strategies were compared by bootstrapping.PARTICIPANTS/MATERIALS, SETTING, METHODS: In both RCTs women were randomized to an individualized (RCT1:450/225 IU, RCT2:100 IU) or standard FSH dose (150 IU). Women in the cohort all received the standard dose (150 IU). Anti-Müllerian hormone (AMH) was measured to assess AMH post-hoc as a biomarker to individualize treatment. For RCT1 dose adjustment was allowed in subsequent cycles based on pre-specified criteria in the standard group only. For RCT2 dose adjustment was allowed in subsequent cycles in both groups. Both effectiveness and cost-effectiveness of the strategies were evaluated from an intention-to-treat perspective.MAIN RESULTS AND THE ROLE OF CHANCE: We included 1515 women, of whom 483 (31.9%) entered the cohort, 511 (33.7%) RCT1 and 521 (34.4%) RCT2. Live births occurred in 420/747 (56.3%) women in the individualized strategy and 447/769 (58.2%) women in the standard strategy (risk difference -0.019 (95% CI, -0.06 to 0.02), P = 0.39; a total of 1516 women due to rounding up the half integer numbers). The individualized strategy was more expensive (delta costs/woman = €275 (95% CI, 40 to 499)). Individualized dosing reduced the occurrence of mild and moderate ovarian hyperstimulation syndrome (OHSS) and subsequently the costs for management of these OHSS categories (costs saved/woman were €35). The analysis based on AMH as a tool for dose individualization suggested comparable results.LIMITATIONS, REASONS FOR CAUTION: Despite a training programme, the AFC might have suffered from inter-observer variation. In addition, although strict cancel criteria were provided, selective cancelling in the individualized dose group (for poor response in particular) cannot be excluded as observers were not blinded for the FSH dose and small dose adjustments were allowed in subsequent cycles. However, as both first cycle live birth rates and cumulative live birth rates show no difference between strategies, the open design probably did not mask a potential benefit for the individualized group. Despite increasing consensus on using GnRH antagonist co-treatment in women predicted for a hyper response in particular, GnRH agonists were used in almost 80% of the women in this study. Hence, in those women, the AFC and bloodsampling for the post-hoc AMH analysis were performed during pituitary suppression. As the correlation between AFC and ovarian response is not compromised during GnRH agonist use, this will probably not have influenced classification of response.WIDER IMPLICATIONS OF THE FINDINGS: Individualized FSH dosing for the IVF/ICSI population as a whole should not be pursued as it does not improve live birth rates and it increases costs. Women scheduled for IVF/ICSI with a regular menstrual cycle are therefore recommended a standard FSH starting dose of 150 IU per day. Still, safety management by individualized dosing in predicted hyper responders is open for further research.STUDY FUNDING/COMPETING INTEREST(S): This study was funded by The Netherlands Organisation for Health Research and Development (ZonMW number 171102020). AMH measurements were performed free of charge by Roche Diagnostics. TCT, HLT and SCO received an unrestricted personal grant from Merck BV. AH declares that the department of Obstetrics and Gynecology, University Medical Centre Groningen receives an unrestricted research grant from Ferring pharmaceutics BV, The Netherlands. CBL receives grants from Merck, Ferring and Guerbet. BWJM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. FJMB receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV (the Netherlands) and Merck Serono (the Netherlands) for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development (Switzerland) and for a research cooperation with Ansh Labs (USA). All other autors have nothing to declare.TRIAL REGISTRATION NUMBER: Registered at the ICMJE-recognized Dutch Trial Registry (www.trialregister.nl). Registration number: NTR2657.

STUDY QUESTION: What is the effect of endometrial scratching in patients with or without prior failed ART cycles on live birth (LBR) and clinical pregnancy rates (CPR)? SUMMARY ANSWER: It remains unclear if endometrial scratching improves the chance of pregnancy and, if so, for whom. WHAT IS KNOWN ALREADY: Endometrial scratching is hypothesized to improve embryo implantation in ART. Multiple studies have been published, but it remains unclear if endometrial scratching actually improves pregnancy rates and, if so, for which patients. STUDY DESIGN SIZE DURATION: For this review, a systematic search for published articles on endometrial scratching and ART was performed on 12 February 2018, in Pubmed, Embase and the Cochrane Library. PARTICIPANTS/MATERIALS SETTING METHODS: Randomized controlled trials (RCTs) that evaluated endometrial scratching in the cycle prior to the stimulation cycle and reported CPR or LBR were included. RCTs investigating the effect of scratching during the stimulation cycle, or prior to cryo-thaw cycles were excluded. Studies were assessed using the Cochrane Risk of Bias tool. The effect of scratching was assessed for three different patient groups: patients with no prior IVF/ICSI treatment (Group 0), patients with one failed full IVF/ICSI cycle, including cryo-thaw cycles (Group 1) and patients with two or more failed full IVF/ICSI cycles (Group 2). A meta-analysis was performed when statistical heterogeneity was low; otherwise, a descriptive analysis was performed. MAIN RESULTS AND THE ROLE OF CHANCE: Fourteen RCTs involving 2537 participants were included. Most RCTs contained a high or unclear risk of bias on one or more items. Substantial clinical and statistical heterogeneity was present; therefore meta-analysis for LBR and CPR could only be performed on Group 1. For this group, no differences between scratch and control were found for both LBR (risk ratio (RR) 1.01 [95%CI 0.68-1.51]) and CPR (RR 1.04 [95%CI 0.74-1.45]). For Groups 0 and 2, pooled analysis could not be performed, and for both groups the results of the individual RCTs were negative, neutral and positive. Miscarriage and multiple pregnancy rates were evaluated for the three groups (0, 1 and 2) together. Both outcomes were not significantly different between scratch and control (miscarriage rate RR 0.82 [95%CI 0.57-1.17] and multiple pregnancy rate RR 1.06 [95%CI 0.84-1.35]). Subgroup analysis, excluding trials with a risk of unintentional endometrial injury in the control group, was performed for Group 0 and 2 for LBR and CPR, and for the overall groups for miscarriage rate and multiple pregnancy rate. This reduced the heterogeneity and allowed for pooled analysis in these subgroups. Results of pooled analysis for the subgroups of Group 0 and 2 showed no significant difference for LBR, but CPR was significantly improved after endometrial scratching (Group 0 RR 1.28 [95%CI 1.02-1.62] and Group 2 RR 2.03 [95%CI 1.20-3.43]). Subgroup analysis of the overall groups showed no significant difference for miscarriage and multiple pregnancy rate. LIMITATIONS REASONS FOR CAUTION: The main limitations were that many RCTs had a high or unclear risk of bias on one or several items, clinical heterogeneity was still present despite categorizing into three populations, and that not all RCTs could be included in the analyses because separate data for our three groups could not be provided. WIDER IMPLICATIONS OF THE FINDINGS: It remains unclear if endometrial scratching improves the chance of pregnancy for women undergoing ART and, if so, for whom. This means endometrial scratching should not be offered in daily practice until results from large and well-designed RCTs and an individual patient data analysis become available. STUDY FUNDING/COMPETING INTERESTS: No specific funding was sought for the study. The Department of Reproductive Medicine and Gynaecology funds of the University Medical Center of Utrecht were used to support the authors throughout the study period and preparation of the manuscript. None of the authors has a conflict of interest to declare. REGISTRATION NUMBER: Not applicable. ispartof: HUMAN REPRODUCTION OPEN vol:2019 issue:1 ispartof: location:England status: published

background: Chronic endometritis is associated with abnormal uterine bleeding, recurrent abortion and infertility. It is a subtle condition, and therefore is difficult to diagnose. The diagnosis is ultimately based on the presence of plasma cells in the endometrial stroma on histopathological examination. Literature on the reproducibility of the diagnosis of chronic endometritis is lacking. Therefore, the aim of the current study was to assess the interobserver agreement of two pathologists in diagnosing chronic endometritis in asymptomatic, infertile patients. methods: In the context of a randomized controlled trial, an endometrial biopsy was taken during a screening hysteroscopy prior to IVF. All endometrial samples were independently examined by two pathologist. The slides diagnosed with chronic endometritis were replenished with a random sample of the remaining slides up to a total of 100, then exchanged between the two pathologists and reassessed. results: Of the 678 patients who underwent hysteroscopy, 19 patients were diagnosed with at least possible chronic endometritis (2.8%). Perfect agreement between the pathologists, before and after inclusion of 13 slides with additional immunohistochemistry staining, was found in 88 and 86% of reviews, respectively. The interobserver agreement was substantial, with kappa-values of 0.55 and 0.66, respectively. conclusions: The interobserver agreement in diagnosing chronic endometritis in asymptomatic infertile patients was found to be substantial. Although the diagnostic reliability is sufficient with the methods in the present study, the low prevalence and unknown clinical significance of endometritis warrants further study.

The optimal ovarian stimulation dose to obtain the best balance between the probability of pregnancy and the risk of complications, while maximizing cost-effectiveness of in vitro fertilization (IVF) treatment, is yet to be established.A systematic search of the electronic databases PubMed, EMBASE and Cochrane library, from 1984 until October 2009 for randomized controlled trials comparing different doses of recombinant FSH in IVF, was performed.Ten studies (totaling 1952 IVF cycles) were included in the present meta-analysis, comprising patients younger than 39 years with regular menstrual cycle, normal basal FSH levels and two normal ovaries. Comparison was made between studies using a daily dose of 100 versus 200 IU recFSH, and between 150 versus 200 IU recFSH or higher. Although oocyte yield was greater in the200 IU/day dose group, pregnancy rates were similar compared with lower dose groups. The risk of insufficient response to ovarian stimulation was greatest in the 100 IU/day dose group. The risk of developing ovarian hyperstimulation syndrome was greater in the200 IU/day dose group. The number of embryos available for cryopreservation was lowest in the 100 IU/day group, but similar comparing the 150 IU/day and the200 IU/day dose groups.This meta-analysis suggests that the optimal daily recFSH stimulation dose is 150 IU/day in presumed normal responders younger than 39 years undergoing IVF. Compared with higher doses, this dose is associated with a slightly lower oocyte yield, but similar pregnancy and embryo cryopreservation rates. Furthermore, the wide spread adherence to this optimal dose will allow for a considerable reduction in IVF costs and complications.

BACKGROUND: To review the accuracy of multivariate models for the prediction of ovarian reserve and pregnancy in women undergoing IVF compared with the antral follicle count ( AFC) as single test. METHODS: We performed a computerized MEDLINE and EMBASE search to identify articles published on multivariate models for ovarian reserve testing in patients undergoing IVF. In order to be selected, articles had to contain data on the outcome of IVF in terms of either pregnancy and/or poor response and on the prediction of these events based on a multivariate model. For the selected studies, sensitivity and specificity of the test in the prediction of poor ovarian response and non-pregnancy were calculated. Overall performance was assessed by estimating a summary receiver operating characteristic ( ROC) curve, which was compared with the ROC curve for the AFC as the current best single test. RESULTS: We identified 11 studies reporting on the predictive capacity of multivariate models in ovarian reserve testing. All studies reported on the prediction of poor ovarian response, whereas none reported on the occurrence of pregnancy. The sensitivity for prediction of poor ovarian response varied between 39% and 97% and the specificity between 50% and 96%. Logistic regression analysis indicated that cohort studies provided a significantly better discriminative performance than case-control studies. As cohort studies are superior to case-control studies, further analysis was limited to the cohort studies. For the cohort studies, a summary ROC curve could be estimated, which had a shape similar to that previously made for the AFC. CONCLUSIONS: The accuracy of multivariate models for the prediction of ovarian response in women undergoing IVF is similar to the accuracy of AFC. No data are available on the capacity of these models to predict pregnancy, let alone live birth. On the basis of these findings, the use of more than one single test for the assessment of ovarian reserve cannot currently be supported

textabstractBackground: Prediction models for spontaneous pregnancy may be useful tools to select subfertile couples that have good fertility prospects and should therefore be counselled for expectant management. We assessed the accuracy of a recently published prediction model for spontaneous pregnancy in a large prospective validation study. Methods: In 38 centres, we studied a consecutive cohort of subfertile couples, referred for an infertility work-up. Patients had a regular menstrual cycle, patent tubes and a total motile sperm count (TMC) >3 × 106. After the infertility work-up had been completed, we used a prediction model to calculate the chance of a spontaneous ongoing pregnancy (www.freya.nl/probability.php). The primary end-point was time until the occurrence of a spontaneous ongoing pregnancy within 1 year. The performance of the pregnancy prediction model was assessed with calibration, which is the comparison of predicted and observed ongoing pregnancy rates for groups of patients and discrimination. Results: We included 3021 couples of whom 543 (18%) had a spontaneous ongoing pregnancy, 57 (2%) a non-successful pregnancy, 1316 (44%) started treatment, 825 (27%) neither started treatment nor became pregnant and 280 (9%) were lost to follow-up. Calibration of the prediction model was almost perfect. In the 977 couples (32%) with a calculated probability between 30 and 40%, the observed cumulative pregnancy rate at 12 months was 30%, and in 611 couples (20%) with a probability of ≥40%, this was 46%. The discriminative capacity was similar to the one in which the model was developed (c-statistic 0.59). Conclusions: As the chance of a spontaneous ongoing pregnancy among subfertile couples can be accurately calculated, this prediction model can be used as an essential tool for clinical decision-making and in counselling patients. The use of the prediction model may help to prevent unnecessary treatment.

BACKGROUND: To assess the value of testing for ovarian reserve prior to a first cycle IVF incorporating patient and doctor valuation of mismatches between test results and treatment outcome. METHODS: A decision model was developed for couples who were considering participation in an IVF programme. Three strategies were evaluated: (I) withholding IVF without prior testing, (II) testing for ovarian reserve, and then deciding on IVF treatment if ovarian reserve was estimated to be sufficient, and (III) treatment with IVF without prior ovarian reserve testing. The outcome considered was the birth of a child. The valuation of the combination of the strategy conducted and the outcome accomplished was expressed on a distress scale in units of 'IVF cycles that were performed in vain'. Correct treatment with IVF and correct withholding of IVF were considered to bring no distress. The distress of withholding IVF in case pregnancy occurred is consequently specified by the ratio of the expected distress after incorrect withholding IVF to the expected distress after incorrect performing IVF (distress ratio). We interviewed both patients and doctors to determine realistic estimates for this distress ratio. RESULTS: The value of testing for ovarian reserve depends strongly on the expected pregnancy rate after IVF as well as on the valuation of the incorrect decisions from testing. For realistic ranges of the success rate after IVF and for distress ranges as were measured, treatment of all couples without testing was found to generate less distress than testing for ovarian reserve. The sensitivity and specificity of testing for ovarian reserve has to improve to 50 and 96% respectively, to make testing a valuable strategy. CONCLUSION: Based on the decision analysis, where current test accuracy and preference inventory among patients and physicians were used, testing for ovarian reserve seems not useful for current IVF programmes.

BACKGROUND: It is suggested that the skill of the physician performing the embryo transfer may influence the outcome of the procedure. In this study we investigated the effects of a change in embryo transfer technique on the variability in success rates among physicians. METHODS: Retrospectively 4439 transfer cycles in which two different embryo transfer techniques were applied by seven physicians were studied. In the first 2210 cycles, transfers were performed using the ‘clinical touch’ method. In the following 2229 cycles, the so-called fixed distance technique was used. RESULTS: With the clinical touch method pregnancy rates differed greatly among providers, whereas after the introduction of the fixed distance technique these differences disappeared. Furthermore, the overall clinical pregnancy rate increased from 33.6 to 40.4% per transfer. Using smoothing spline curves we failed to detect a sudden rise in pregnancy rates at the time the transfer method was changed. CONCLUSIONS: The introduction of the fixed distance technique greatly reduced the variation in pregnancy rates among physicians. The overall increase in pregnancy rates after the introduction is likely to be related to the change in technique although definite proof is difficult. Both observations are suggested to be attributable to the atraumatic character of the fixed distance technique.

GnRH agonists or antagonists can be used to prevent LH surges duringovarian stimulation for assisted reproduction. GnRH agonists down-regulate GnRH pituitary receptors. GnRH antagonists directly andrapidly inhibit gonadotrophin release. In a 2006 systematic review invol-ving 29 trials, the average clinical pregnancy rate was 4.7% lower withGnRH antagonist treatment and the incidence of ovarian hyperstimula-tion syndrome (OHSS) was 2% lower compared with GnRH agonisttreatment (Al-Inany et al.,2006). The current update includes 45trials which addressed live birth or ongoing pregnancy rate (OPR) inGnRH antagonist and GnRH agonist protocols among women under-going assisted reproduction treatment (Youssef et al.,2011).