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Study Question: Does intentional endometrial injury (scratching) during the follicular phase of ovarian stimulation (OS) increase the clinical pregnancy rate (CPR) in ART?Summary Answer: CPR did not vary between the endometrial injury and the control group, but the trial was underpowered due to early termination because of a higher clinical miscarriage rate observed in the endometrial injury arm after a prespecified interim analysis.What Is Known Already: Intentional endometrial injury has been put forward as an inexpensive clinical tool capable of enhancing endometrial receptivity. However, despite its widespread use, the benefit of endometrial scratching remains controversial, with several recent randomized controlled trials (RCTs) being unable to confirm its added value. So far, most research has focused on endometrial scratching during the luteal phase of the cycle preceding the one with embryo transfer (ET), while only a few studies investigated in-cycle injury during the follicular phase of OS. Also, the persistence of a scratch effect in subsequent treatment cycles remains unclear and possible harms have been insufficiently studied.Study Design, Size, Duration: This RCT was performed in a tertiary hospital setting between 3 April 2014 and 8 October 2017. A total of 200 women (100 per study arm) undergoing IVF/ICSI in a GnRH antagonist suppressed cycle followed by fresh ET were included.Participants/materials, Setting, Methods: Participants were randomized with a 1:1 allocation ratio to either undergo a pipelle endometrial biopsy between Days 6 and 8 of OS or to be in the control group.The primary outcome was CPR. Secondary outcomes included biochemical pregnancy rate, live birth rate (LBR), early pregnancy loss (biochemical pregnancy losses and clinical miscarriages), excessive procedure pain/bleeding and cumulative reproductive outcomes within 6 months of the study cycle.Main Results and the Role Of Chance: The RCT was stopped prematurely by the trial team after the second prespecified interim analysis raised safety concerns, namely a higher clinical miscarriage rate in the intervention group. The intention-to-treat CPR was similar between the biopsy and the control arm (respectively, 44 versus 40%, P = 0.61, risk difference = 3.6 with 95% confidence interval = -10.1;17.3), as was the LBR (respectively, 32 versus 36%, P = 0.52). The incidence of a biochemical pregnancy loss was comparable between both groups (10% in the intervention group versus 15% in the control, P = 0.49), but clinical miscarriages occurred significantly more frequent in the biopsy group (25% versus 8%, P = 0.032). In the intervention group, 3% of the patients experienced excessive procedure pain and 5% bleeding. The cumulative LBR taking into account all conceptions (spontaneous or following ART) within 6 months of randomization was not significantly different between the biopsy and the control group (54% versus 60%, respectively, P = 0.43).Limitations, Reasons For Caution: The trial was stopped prematurely due to safety concerns after the inclusion of 200 of the required 360 patients. Not reaching the predefined sample size implies that definite conclusions on the outcome parameters cannot be drawn. Furthermore, the pragmatic design of the study may have limited the detection of specific subgroups of women who may benefit from endometrial scratching.Wider Implications Of the Findings: Intentional endometrial injury during the follicular phase of OS warrants further attention in future research, as it may be harmful. These findings should be taken in consideration together with the growing evidence from other RCTs that scratching may not be beneficial.Study Funding/competing Interest(s): This study was supported by 'Fonds Wetenschappelijk Onderzoek' (FWO, Flanders, Belgium, 11M9415N, 1524417N). None of the authors have a conflict of interest to declare with regard to this study. [ABSTRACT FROM AUTHOR]

Study Question: Does an early proliferative phase endometrial biopsy harvested during ovarian stimulation harbour information predictive of the outcome following fresh embryo transfer (ET) in that same cycle?Summary Answer: Transcriptome analysis of the whole-tissue endometrium did not reveal significant differential gene expression (DGE) in relation to the outcome; however, the secretome profile of isolated, cultured and in vitro decidualized endometrial stromal cells (EnSCs) varied significantly between patients who had a live birth compared to those with an implantation failure following fresh ET in the same cycle as the biopsy.What Is Known Already: In the majority of endometrial receptivity research protocols, biopsies are harvested during the window of implantation (WOI). This, however, precludes ET in that same cycle, which is preferable as the endometrium has been shown to adapt over time. Endometrial biopsies taken during ovarian stimulation have been reported not to harm the chances of implantation, and in such biopsies DGE has been observed between women who achieve pregnancy versus those who do not. The impact of the endometrial proliferative phase on human embryo implantation remains unclear, but deserves further attention, especially since in luteal phase endometrial biopsies, a transcriptional signature predictive for repeated implantation failure has been associated with reduced cell proliferation, possibly indicating proliferative phase involvement. Isolation, culture and in vitro decidualization (IVD) of EnSCs is a frequently applied basic research technique to assess endometrial functioning, and a disordered EnSC secretome has previously been linked with failed implantation.Study Design, Size, Duration: This study was nested in a randomized controlled trial (RCT) investigating the effect of endometrial scratching during the early follicular phase of ovarian stimulation on clinical pregnancy rates after IVF/ICSI. Of the 96 endometrial biopsies available, after eliminating those without fresh ET and after extensive matching in order to minimize the risk of potential confounding, 18 samples were retained to study two clinical groups: nine biopsies of patients with a live birth versus nine biopsies of patients with an implantation failure, both following fresh ET performed in the same cycle as the biopsy. We studied the proliferative endometrium by analysing its transcriptome and by isolating, culturing and decidualizing EnSCs in vitro. We applied this latter technique for the first time on proliferative endometrial biopsies obtained during ovarian stimulation for in-cycle outcome prediction, in an attempt to overcome inter-cycle variability.Participants/materials, Setting, Methods: RNA-sequencing was performed for 18 individual whole-tissue endometrial biopsies on an Illumina HiSeq1500 machine. DGE was analysed three times using different approaches (DESeq2, EdgeR and the Wilcoxon rank-sum test, all in R). EnSC isolation and IVD was performed (for 2 and 4 days) for a subset of nine samples, after which media from undifferentiated and decidualized cultures were harvested, stored at -80°C and later assayed for 45 cytokines using a multiplex suspension bead immunoassay. The analysis was performed by partial least squares regression modelling.Main Results and the Role Of Chance: After correction for multiple hypothesis testing, DGE analysis revealed no significant differences between endometrial samples from patients who had a live birth and those with an implantation failure following fresh ET. However secretome analysis after EnSC isolation and culture, showed two distinct clusters that clearly corresponded to the two clinical groups. Upon IVD, the secretome profiles shifted from that of undifferentiated cells but the difference between the two clinical groups remained yet were muted, suggesting convergence of cytokine profiles after decidualization.Limitations, Reasons For Caution: Caution is warranted due to the limited sample size of the study and the in vitro nature of the EnSC experiment. Validation on a larger scale is necessary, however, hard to fulfil given the very limited availability of in-cycle proliferative endometrial biopsies outside a RCT setting.Wider Implications Of the Findings: These data support the hypothesis that the endometrium should be assessed not only during the WOI and that certain endometrial dysfunctionalities can probably be detected early in a cycle by making use of the proliferative phase. This insight opens new horizons for the development of endometrial tests, whether diagnostic or predictive of IVF/ICSI treatment outcome.Study Funding/competing Interest(s): This study was supported by Fonds Wetenschappelijk Onderzoek (FWO, Flanders, Belgium, 11M9415N, 1 524 417N), Wetenschappelijk Fonds Willy Gepts (WFWG G160, Universitair Ziekenhuis Brussel, Belgium) and the National Medicine Research Council (NMRC/CG/M003/2017, Singapore). There are no conflicts of interests.Trial Registration Number: NCT02061228. [ABSTRACT FROM AUTHOR]

Study Question: Does IVM of immature oocytes retrieved from small antral follicles in women with polycystic ovary syndrome (PCOS) have an impact on obstetric and neonatal outcomes compared to controlled ovarian stimulation (COS)?Summary Answer: Obstetric and neonatal outcomes after IVM appear to be similar to those after COS.What Is Know Already: Women with PCOS have an increased risk of adverse pregnancy outcomes and congenital malformations in their offspring. For patients with PCOS who require IVF, IVM of germinal vesicle (GV)-stage oocytes retrieved from antral follicles has been adopted as a mild approach ART, with improved pregnancy rates over the last two decades. Although reports of obstetrical and neonatal outcomes after IVM have been reassuring, the limited sample sizes in previous studies preclude firm conclusions, and further study is warranted.Study Design, Size, Duration: This is a retrospective observational study analysing obstetric and neonatal data from 1036 clinical pregnancies in unique patients with PCOS who conceived following a cycle of IVM or COS between January 2010 and December 2016 in a tertiary reproductive centre. In total, 393 singleton pregnancies with a gestational age beyond 20 weeks were included. A phenotypic approach was used for the diagnosis of PCOS. Pregnancies following oocyte donation, standard IVF (as opposed to ICSI) or preimplantation genetic testing and pregnancies requiring testicular biopsy in the male partners were excluded.Participants/materials,setting, Methods: Pregnancy outcomes were analysed in women with PCOS phenotype A, C or D, as defined by different combinations of the Rotterdam criteria. Data from 164 pregnancies beyond 20 weeks after IVM were compared with those from 229 pregnancies after COS. Pregnancies in the IVM group were obtained after minimal ovarian stimulation and IVF with ICSI of transvaginally collected GV oocytes that had reached the metaphase II stage in vitro after 28 to 40 h of culture. No hCG trigger was administered before oocyte retrieval. Outcome measures were analysed or reported in singleton pregnancies only and included adverse obstetric events and neonatal health parameters, in particular birthweight, prematurity, small-for-gestational age, large-for-gestational age, perinatal death and major/minor malformation rates. The incidence of hypertensive disorders of pregnancy (HDP) and birthweight was analysed by multiple linear and logistic regression, adjusted for relevant treatment variables and maternal characteristics.Main Results and the Role Of Chance: The IVM and the COS groups differed significantly (P < 0.001) for maternal circulating AMH levels and PCOS phenotype distribution, with more of the PCOS phenotype A in the IVM group. Pregnant women in the IVM group were younger than pregnant women in the COS group (P = 0.05). With regard to obstetric complications in singleton pregnancies, in the unadjusted analysis, mothers of infants in the IVM group more often had HDP (29/164 (17.9%) vs 22/229 (9.6%), P = 0.02) compared with mothers in the COS group. Singletons born after IVM and COS had a similar birthweight standard deviation score (SDS) (0.51 ± 0.94 after IVM vs 0.33 ± 1.05 after COS, P = 0.19). Preterm birth rate (32-36.9 weeks) and early preterm birth rate (<32 weeks) were also similar in both groups. The total malformation rate was 4.1% in singletons after IVM and 2.4% in singletons after COS. Multivariate linear regression analysis accounting for relevant confounders demonstrated that parity was the only independent predictive factor (P = 0.04) for birthweight SDS. Multivariate logistic regression analysis showed that BMI, parity and type of ART (IVM as opposed to COS) were significantly correlated with the incidence of HDP. Only patients with the PCOS phenotype A showed a tendency towards a higher risk of HDP in those who underwent IVM compared to those who had COS.Limitations, Reasons For Caution: The study is limited by its retrospective nature and loss to follow-up of a subset of children with no information regarding congenital malformations. Furthermore, the paediatricians who assessed the children after birth were not blinded for the type of ART procedure.Wider Implications Of the Findings: This study provides further evidence that, compared to COS, IVM of oocytes derived from small antral follicles does not adversely affect the neonatal health of the offspring of patients with PCOS. The observed increased risk of HDP in patients with PCOS phenotype A following IVM treatment warrants further scrutiny.Study Funding/competing Interest(s): Translational IVM research at Universitair Ziekenhuis Brussel (UZ Brussel) and Vrije Universiteit Brussel (VUB) has been supported by grants from the Institute for the Promotion of Innovation by Science and Technology in Flanders (Agentschap voor Innovatie door Wetenschap en Technologie-IWT, project 110680), the Fund for Research Flanders (Fonds Wetenschappelijk Onderzoek-Vlaanderen-FWO, project G.0343.13) and the Belgian Foundation Against Cancer (HOPE project, Dossier C69). Clinical IVM research was supported by research grants from Cook Medical and Besins Healthcare. M.D.V. reports honoraria for lectures from Cook Medical and Besins Healthcare outside the submitted work. S.S.R. reports honoraria for lectures by MSD and Besins and research grants by MSD, Ferring and Merck Serono outside of the submitted work. C.B. reports personal fees from Merck-Serono, Ferring, IBSA, Finox, MSD and Abbott outside the submitted work. H.T. reports grants from Merck, MSD, Goodlife, Cook, Roche, Besins, Ferring, Mithra (now Allergan) and the Research Fund of Flanders (FWO) and consultancy fees from Finox, Abbott, Obseva and Ovascience outside the submitted work. The other authors have nothing to disclose. [ABSTRACT FROM AUTHOR]

Study Question: Is the survival of donor oocytes with the CryotopSC device superior to the survival with the closed CBSvit device?Summary Answer: The CryotopSC device and the CBSvit device showed similar survival rates.What Is Known Already: Health authorities are cautious about possible cross contamination during liquid nitrogen storage or handling when working with open vitrification devices. At present, the use of open devices is still allowed since little information is available on the efficiency of closed devices.Study Design, Size, Duration: A prospective randomized sibling oocyte study was performed in the Centre for Reproductive Medicine (UZBrussel) between January 2014 and July 2015. The survival after warming and the embryological outcome of donor oocytes vitrified using two devices was compared: the CBSvit device (closed vitrification and closed storage) and the CryotopSC device (open vitrification and closed storage). A difference of 10% was defined to prove the superiority of the CryotopSC device. In total, 250 warmed oocytes were needed in each arm.Participants/materials, Setting, Methods: Oocytes from 48 donors were included in the study: 253 vitrified with the CBSvit device and 257 with the CryotopSC device. Equal numbers of oocytes from both devices and originated from the same donor cycle were allocated to each of 78 recipients, in order to exclude donor and recipient (male factor) effects.Main Results and the Role Of Chance: There were no differences found between the CBSvit and the CryotopSC in terms of survival after warming (93.7 versus 89.9%) or fertilization per injected oocyte (74.3 versus 81.4%). The degeneration rate after ICSI was significantly higher for the CBSvit device: 11.4 versus 6.1% (P = 0.041). A significantly higher number of zygotes in the CryotopSC group finished their first mitosis 25-27 h post-injection (34.1 versus 52.1%, P = 0.001). On Day 3, the overall embryo quality distribution did not vary between groups, but a significantly higher cell number was obtained in the CryotopSC device: 6.8 ± 2.8 versus 7.6 ± 2.8 (P = 0.01). The utilization rate per mature oocyte, per surviving oocyte or per fertilized oocyte did not differ. The embryos with the highest quality were selected for transfer on Day 3. The clinical pregnancy rate per transfer cycle was 36.5%.Limitations, Reasons For Caution: The results of this study should not be extrapolated to other female groups, since oocytes from young fertile donors were used in this study.Wider Implications Of the Findings: In many countries, the use of open devices is still allowed due to the limited reports on the efficiency of closed devices. Knowing the caution of health authorities about the use of open devices, there is an urgent need for efficiency studies with closed devices. The results obtained in the current study shows the efficiency of a safe closed vitrification device, leaving behind any concern about possible cross contamination during handling or storage.Study Funding/competing Interests: No funding was obtained. The authors have no conflict of interest to declare.Trial Registration Number: NCT01952184.Trial Registration Date: 24 September 2013.Date Of First Patient's Enrolment: 23 January 2014. [ABSTRACT FROM AUTHOR]