Ovarian and reproductive hormone characteristics and risk of cycle cancellation in immediate versus postponed modified natural cycle frozen embryo transfer (mNC-FET) cycles

STUDY QUESTION: Do ovarian and reproductive hormone characteristics and risk of cycle cancellation differ between immediate and postponed modified natural cycle (mNC) frozen embryo transfer (FET) cycles? SUMMARY ANSWER: Ovarian morphology, early follicular phase levels of progesterone and LH, and follicular phase length differed significantly between immediate and postponed mNC-FET. Cancellation rates differed numerically. WHAT IS KNOWN ALREADY: The optimal timing of mNC-FET following ovarian stimulation and oocyte retrieval is heavily debated. Concerns about suboptimal ovarian and hormonal conditions in the NC immediately following ovarian stimulation have led to the widespread practice of postponing FET for at least 1 month. However, emerging evidence suggests that reproductive outcomes in immediate programmed FET cycles are comparable, or even superior, to those achieved in postponed cycles. Studies of the NC immediately following ovarian stimulation and oocyte retrieval are lacking, leaving a limited understanding of its functionality, cycle characteristics, hormonal profiles, and ovarian morphology. STUDY DESIGN, SIZE, DURATION: This descriptive study is based on data from a recently completed Danish multicentre randomised controlled non-inferiority trial (RCT) evaluating the optimal timing of FET following ovarian stimulation and oocyte retrieval. Women were randomised 1:1 to mNC-FET in the cycle immediately following ovarian stimulation and oocyte retrieval, or after a 1-month delay. Data from 468 women, collected from March 2021 to May 2025, were included in this study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with a regular menstrual cycle, aged 18-40 years, and undergoing autologous single blastocyst mNC-FET were eligible for inclusion. The presence of cystic intraovarian structures > 10 mm and plasma levels of FSH, LH, estradiol, and progesterone from cycle initiation to blastocyst transfer were assessed, as were the length of the follicular phase and cancellation rates between groups. MAIN RESULTS AND THE ROLE OF CHANCE: The number of cystic ovarian structures was significantly higher in the immediate group than in the postponed group on Days 2-5 of the treatment cycle (median, 3 [IQR, 1-6] vs 0 [IQR, 0-1]; P < 0.001) as well as on the day of ovulation trigger (median, 1 [IQR, 0-2] vs 0 [IQR, 0-1]; P < 0.001). In the early follicular phase, plasma progesterone levels were higher (median, 1.2 [IQR, 0.7-1.7] vs 0.8 [IQR, 0.6-1.5] nmol/L; P < 0.001) in the immediate compared to postponed cycles, and plasma LH levels were lower (median, 4.1 [IQR, 2.7-6.1] vs 5.9 [IQR, 4.7-7.5] IU/L; P < 0.001), as were FSH levels (median, 6.6 [IQR, 5.0-8.2] vs 6.9 [IQR, 5.9-7.9] IU/L; P = 0.047). The time to ovulation trigger was longer in the immediate than in the postponed group (mean, 15.0 [SD, 3.9] vs 13.0 [SD, 3.0] days; P < 0.001): an effect driven by freeze-all cycles. As a natural consequence of the increased time to ovulation trigger, more follicular scans were performed in the immediate group (median, 3 [IQR, 2-3] vs 2 [IQR, 1-3]; P < 0.001). Cycle cancellation was more frequent in immediate cycles, however, the difference was not statistically significant (10.3% vs 6.2%; P = 0.078). LIMITATIONS, REASONS FOR CAUTION: The main endpoints of this study were specified in the study protocol of the RCT, but some post hoc analyses were performed to explore unexpected findings. Due to variations in clinical practice, data were subjected to multiple subdivisions. No power calculations were performed for the reported endpoints. WIDER IMPLICATIONS OF THE FINDINGS: The follicular phase of immediate cycles seems to differ from postponed cycles in terms of ovarian morphology, follicular phase length, and early follicular phase levels of progesterone and LH. The rate of cycle cancellation raises concerns about the clinical feasibility of immediate FET treatment in NCs. STUDY FUNDING/COMPETING INTEREST(S): The RCT is supported by Rigshospitalet's Research Foundation and an independent research grant from Merck A/S (MS200497_0024). Merck A/S had no role in the design of this study and will not have any role during its execution, analyses, interpretation of data, or decision to submit results. The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication reflect solely those of the authors. S.B. and C.C. benefitted from a grant from Merck A/S. S.B. is currently employed by Novo Nordisk. M.S. benefitted from a grant from Gedeon Richter and received support for meeting attendance from the same. M.S. received payment for lectures from IBSA and Gedeon Richter. J.W.B. received support from meeting attendance from Merck A/S, Ferring Pharmaceuticals, and Gedeon Richter. N.C.F. received consulting fees and honoraria for a presentation from Merck A/S and Ferring Pharmaceuticals and support for meeting attendance from Merck A/S, Ferring Pharmaceuticals, IBSA, and Gedeon Richter. N.C.F. is chair of the steering committee for the guideline groups for The Danish Fertility Society. L.P. received support for meeting attendance from Merck A/S, Ferring Pharmaceuticals, and Gedeon Richter. L.P. declare stocks in Novo Nordisk. B.O.-M. received support for meeting attendance from Gedeon Richter and Ferring Pharmaceuticals and participate on a board for Ferring Pharmaceuticals. B.N. benefitted from grants from Merck A/S and Gedeon Richter. B.N. received support for meeting attendance from Gedeon Richter and participate on a board for Ferring Pharmaceuticals. E.L. received honoraria from Pfizer and Gedeon Richter, and support for meeting attendance from Gedeon Richter, Merck A/S, and Astellas. A.P. received grants from Gedeon Richter, Ferring Pharmaceuticals, and Merck A/S as payment to the institution. A.P. received consulting fees from Ferring Pharmaceuticals, Gedeon Richter, and Merck A/S, and honoraria from Ferring Pharmaceuticals, Gedeon Richter, Abbott, and Merck A/S. K.L. received a grant from Gedeon Richter as payment to the institution. K.L. received consulting fees and honoraria from Ferring Pharmaceuticals and support for attending meetings from Ferring Pharmaceuticals, Gedeon Richter, and Merck A/S. A.S.J., T.V.D., I.B.-M., M.H., and N.S. declare no conflicts of interest. TRIAL REGISTRATION NUMBER: The study is registered at ClinicalTrials.gov: NCT04748874.