Natural versus artificial cycle for endometrial preparation in ovulatory women undergoing frozen-thawed embryo transfer: a randomised controlled trial

STUDY QUESTION: Does a natural cycle result in higher clinical pregnancy rates (CPR) with foetal heartbeat compared to an artificial cycle for frozen-thawed embryo transfer (FET) preparation in ovulatory women? SUMMARY ANSWER: The CPR with foetal heartbeat did not differ between natural and artificial cycles in ovulatory women undergoing FET. WHAT IS KNOWN ALREADY: Several protocols for endometrial preparation have been developed for the increasing number of FET cycles in reproductive medicine. In natural cycle FET (NC-FET), spontaneous ovulation is used to time the embryo thawing and transfer, while in artificial cycle FET (AC-FET), endometrial preparation involves sequential oestrogen and progesterone administration. Current evidence on pregnancy rates does not favour one regimen over the other in women with regular ovulatory cycles. STUDY DESIGN, SIZE, DURATION: We conducted a multicentre, open-label, randomised trial comparing NC-FET with AC-FET across five Belgian fertility centres. Between October 2018 and October 2024, 561 women were randomised (1:1) using a computer-generated allocation after written informed consent. The primary outcome was CPR with foetal heartbeat per cycle analysed on an intention-to-treat basis. Secondary outcomes included endometrial thickness, number of clinic visits for FET cycle monitoring and the rates of (biochemical) pregnancy, ongoing pregnancy, live birth, miscarriage, ectopic pregnancy, multiple pregnancy and cycle cancellation. Obstetric outcomes were recorded for all ongoing pregnancies. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged 18-45 with regular ovulatory cycles and normal uterine cavities undergoing FET after vitrification and warming of one or two day-3 embryos or blastocysts were included. In NC-FET, spontaneous ovulation was detected by serial ultrasounds and serum LH and oestradiol measurements. In AC-FET, oestradiol valerate (6 mg/day) was administered from cycle day 2 (increased to 8 mg/day after 1 week if endometrial thickness was <7 mm) and micronized progesterone (600 mg/day) was initiated once endometrial thickness reached ≥7 mm. MAIN RESULTS AND THE ROLE OF CHANCE: Clinical pregnancy rates with foetal heartbeat were similar between NC-FET and AC-FET in both intention-to-treat (33.1% [94/284] vs 28.9% [80/277]; RR 1.15, 95% CI 0.89, 1.47) and as-treated analyses (34.3% [97/283] vs 31.8% [77/242]; RR 1.08, 95% CI 0.85, 1.38). Cycle cancellations were less frequent in NC-FET (3.9% vs 9.4%; RR 0.41, 95% CI 0.21, 0.82), but NC-FET required more monitoring visits (mean 3.0 vs 2.4; P = 0.0002). Caesarean section was more common after AC-FET (42.7% vs 20.2%; P = 0.003). Other reproductive, obstetric, and perinatal outcomes did not differ significantly between groups. LIMITATIONS, REASONS FOR CAUTION: The sample size was powered to detect a difference in CPR with foetal heartbeat, not for comparing live birth rates or obstetric outcomes. The study was performed in ovulatory women undergoing FET, and therefore, results may not be applicable to other populations. WIDER IMPLICATIONS OF THE FINDINGS: This RCT demonstrates no significant difference in CPR with foetal heartbeat in NC-FET and AC-FET in ovulatory women. Given recent data suggesting higher obstetric risks with AC-FET, NC-FET may be preferred in women with normal ovulatory cycles. STUDY FUNDING/COMPETING INTEREST(S): The study was an investigator-initiated study supported by internal KU Leuven funding (Project number C14/18/106 and C14/24/152) and funding from the Research Foundation Flanders (G.084515N and G.0B1819N to J.V.). K.P. has received grants from Ferring. C.B. has received speaker fees from Gedeon Richter, paid to her institution; travel support from Gedeon Richter, Ferring Pharmaceuticals, and Intuitive; and holds a leadership role as Senior Deputy of the ESHRE SIG Endometriosis and Endometrial Disorders. C.T. has received grants from Merck SA, paid to her institution; consulting fees and speaker fees from Gedeon Richter; travel support from Ferring and Gedeon Richter; and holds leadership roles as Deputy Editor of JNIG and as a board member. A.V. has received speaker fees from Gedeon Richter, paid to his institution, and holds a leadership role as Senior Deputy of the ESHRE SIG Endometriosis and Endometrial Disorders. The other authors declare that there is no conflict of interest to disclose with respect to the content of this article. TRIAL REGISTRATION NUMBER: This trial has been registered at ClinicalTrials.gov (NCT03642665). TRIAL REGISTRATION DATE: 17 July 2018. DATE OF FIRST PATIENT’S ENROLMENT: 27 October 2018.