Not applicable.

This is the largest multicenter study evaluating for the first time the impact of ovarian response on cumulative live birth rate. The significant progressive increase of cumulative live birth rate with the number of oocytes in our study suggests that ovarian stimulation may not have a detrimental effect on oocyte/embryo quality in good-prognosis women less than 40 year old. Nevertheless, although very high ovarian response may further increase cumulative live birth rates, ovarian stimulation should be rational and avoid extreme response in terms of oocytes retrieved to preserve patients' convenience and safety and avoid ovarian hyperstimulation syndrome or other iatrogenic complications.

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STUDY QUESTIONIs oral dydrogesterone 30 mg daily (10 mg three times daily [TID]) non-inferior to micronized vaginal progesterone (MVP) 600 mg daily (200 mg TID) for luteal support in in vitro fertilization (IVF), assessed by the presence of fetal heartbeats determined by transvaginal ultrasound at 12 weeks of gestation?SUMMARY ANSWERNon-inferiority of oral dydrogesterone versus MVP was demonstrated at 12 weeks of gestation, with a difference in pregnancy rate and an associated confidence interval (CI) that were both within the non-inferiority margin.WHAT IS KNOWN ALREADYMVP is routinely used in most clinics for luteal support in IVF, but it is associated with side effects, such as vaginal irritation and discharge, as well as poor patient acceptance. Dydrogesterone may be an alternative treatment due to its patient-friendly oral administration.STUDY DESIGN, SIZE, DURATIONLotus I was an international Phase III randomized controlled trial, performed across 38 sites, from August 2013 to March 2016. Subjects were premenopausal women (>18 to <42 years of age; body mass index (BMI) ≥18 to ≤30 kg/m2) with a documented history of infertility who were planning to undergo IVF. A centralized electronic system was used for randomization, and the study investigators, sponsor's study team, and subjects remained blinded throughout the study.PARTICIPANTS/MATERIALS, SETTING, METHODSIn total, 1031 subjects were randomized to receive either oral dydrogesterone (n = 520) or MVP (n = 511). Luteal support was started on the day of oocyte retrieval and continued until 12 weeks of gestation (Week 10), if a positive pregnancy test was obtained at 2 weeks after embryo transfer.MAIN RESULTS AND THE ROLE OF CHANCEIn the full analysis set (FAS), 497 and 477 subjects in the oral dydrogesterone and MVP groups, respectively, had an embryo transfer. Non-inferiority of oral dydrogesterone was demonstrated, with pregnancy rates at 12 weeks of gestation of 37.6% and 33.1% in the oral dydrogesterone and MVP treatment groups, respectively (difference 4.7%; 95% CI: −1.2–10.6%). Live birth rates of 34.6% (172 mothers with 213 newborns) and 29.8% (142 mothers with 158 newborns) were obtained in the dydrogesterone and MVP groups, respectively (difference 4.9%; 95% CI: −0.8–10.7%). Oral dydrogesterone was well tolerated and had a similar safety profile to MVP.LIMITATIONS, REASONS FOR CAUTIONThe analysis of the results was powered to consider the clinical pregnancy rate, but the live birth rate may be of greater clinical interest. Conclusions relating to the differences between treatments in live birth rate, observed in this study, should therefore be made with caution.WIDER IMPLICATIONS OF THE FINDINGSOral dydrogesterone may replace MVP as the standard of care for luteal phase support in IVF, owing to the oral route being more patient-friendly than intravaginal administration, as well as it being a well tolerated and efficacious treatment.STUDY FUNDING/COMPETING INTEREST(S)Sponsored and supported by Abbott Established Pharmaceuticals Division. H.T....

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.

The purpose of this study was to find out whether endometrial scratching could improve live birth rate in women with previous IVF failure undergoing fresh IVF cycle. In a randomized controlled trial, 387 women with previous IVF failure were divided into two groups. Group A (193 women) was subjected to endometrial biopsy procedure twice. Group B (194 women) was subjected to a placebo procedure. Our results showed no difference in live birth rate between the two groups of women (47.2% versus 38.1%, p = 0.08). However, regression analysis revealed that endometrial scratching was an independent predictor of live birth in the subgroup of women with two or more previous failure after control of other independent predictors (odds ratio (OR) 3.4, p = 0.005). We conclude that endometrial scratching does not improve live birth rate in women undergoing IVF treatment with previous one IVF failure. Nevertheless, it may improve live birth in women with two or more previous IVF failures.

This study was supported by Methusalem grants and by grants from Wetenschappelijk Fonds Willy Gepts, all issued by the Vrije Universiteit Brussel (VUB). All co-authors except M.B. and H.T. declared no conflict of interest. M.B. has received consultancy fees from MSD, Serono Symposia and Merck. The Universitair Ziekenhuis Brussel (UZ Brussel) and the Centre for Medical Genetics have received several educational grants from IBSA, Ferring, Organon, Shering-Plough and Merck for establishing the database for follow-up research and organizing the data collection. The institution of H.T. has received research grants from the Research Fund of Flanders (FWO), an unconditional grant from Ferring for research on testicular stem cells and research grants from Ferring, Merck, MSD, Roche, Besins, Goodlife and Cook for several research projects in female infertility. H.T. has received consultancy fees from Finox, Abbott and ObsEva for research projects in female infertility.

No funding was obtained for this study, and there are no conflicts of interest to declare.