STUDY QUESTION: Does progesterone-based embryo transfer timing achieve live birth rates comparable to LH-surge-based timing in true natural cycle frozen embryo transfer (NC-FET)? SUMMARY ANSWER: Progesterone-based embryo transfer timing was associated with live birth rates comparable to those achieved with LH surge-based timing in true NC-FET, with no evidence of an independent association between ovulation timing strategy and live birth after adjustment for potential confounders. WHAT IS KNOWN ALREADY: In true NC-FET, embryo transfer timing is commonly scheduled according to the LH surge. However, identification of the LH surge may be challenging. Serum progesterone rise may reflect ovulation timing, yet its use as an alternative approach for scheduling embryo transfer in NC-FET cycles remains insufficiently investigated. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included 490 true NC-FET cycles performed at a single tertiary IVF center between 2022 and 2025. Cycles were analyzed according to the ovulation timing strategy used for embryo transfer scheduling: progesterone-based timing (n = 286) or LH surge-based timing (n = 204). PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovulation was monitored using serial ultrasound and serum hormone measurements. Embryo transfer timing was scheduled according to either detection of the LH surge or the rise in serum progesterone concentrations. The primary outcome was live birth. Adjusted relative risks were estimated using modified Poisson regression with robust standard errors, adjusting for infertility duration and etiology, endometrial thickness at transfer, embryo quality, and number of embryos transferred. Adjusted absolute risk differences were calculated using marginal standardization. An exploratory threshold-based assessment was performed on the risk-difference scale. MAIN RESULTS AND THE ROLE OF CHANCE: Live birth occurred in 162 of 286 progesterone-timed cycles (56.6%) and 106 of 204 LH-timed cycles (52.0%) (unadjusted RR 1.09, 95% CI 0.93-1.28). After adjustment, ovulation timing strategy showed no evidence of an independent association with live birth (adjusted RR 1.09, 95% CI 0.93-1.30; P = 0.264). The adjusted absolute risk difference was +4.9% (95% CI -3.8% to +13.6%). Clinical pregnancy, hCG positivity, and miscarriage rates were also comparable between groups. In exploratory analyses, follicle size measured 1 day before ovulation was positively correlated with progesterone levels on the embryo transfer day (Spearman r = 0.36, P < 0.001), and embryo-transfer-day progesterone levels were positively correlated with estradiol levels measured 1 day before ovulation (Spearman r = 0.29, P < 0.001). LIMITATIONS, REASONS FOR CAUTION: The observational design may introduce residual confounding despite statistical adjustment. The timing strategy was not randomized and reflected an evolving institutional protocol. In addition, the progesterone thresholds were derived and applied within a single-center assay environment, which may limit generalizability to other clinical settings and laboratory platforms. WIDER IMPLICATIONS OF THE FINDINGS: Progesterone-based timing may represent a feasible alternative to LH-based scheduling in true NC-FET, although confirmation in adequately powered multicenter studies is required. STUDY FUNDING/COMPETING INTEREST(S): No external funding was received for this study. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.
Aydin et al. (Wed,) studied this question.