Adding short-duration gonadotropin-releasing hormone antagonist and gonadotropin to natural cycle frozen embryo transfer allowed scheduling of transfer day without compromising live birth.

Objective: To determine whether there is an association between the type of natural cycle frozen embryo transfer (FET) (scheduled vs. traditional) and live birth outcomes.

Design: Retrospective cohort of all natural cycle FETs across a single network of fertility clinics in the United States.

Subjects: All natural cycle FETs performed in ovulatory patients between January 2019 and April 2022.

Exposure: Scheduled natural cycle FET cycles that received a short-duration of gonadotropin-releasing hormone antagonist (1 ampule/d) with low-dose gonadotropins (75 IU/d) to delay ovulation to enable more flexible scheduling of the FET were compared with cycles without delay.

Main Outcome Measures: Live birth.

Results: There were a total of 1,087 natural cycle FETs that met the inclusion criteria. The scheduled natural cycle FET protocol was used in 114 (10.5%) of these cycles. The mean age was 35 (interquartile range, 33-38) years. Preimplantation genetic testing for aneuploidy was used in 76.3% (n = 87) of scheduled natural cycle FET cycles and 68.9% (n = 670) of natural cycle FET cycles. The scheduled natural cycle FET group had a significantly higher estradiol level (318 vs. 249 pg/mL) and a lower luteinizing hormone level (5.7 vs. 13.4 mIU/mL) at ovulatory trigger but a comparable peak endometrial thickness (9.4 vs. 9.7 mm) compared with the natural cycle FET group. Overall, there was a significant increase in the rates of positive human chorionic gonadotropin (scheduled natural cycle, 81.6%, vs. natural cycle, 64.3%; relative risk [RR], 1.26 [95% confidence interval {CI}, 1.15-1.38]) and clinical pregnancy (scheduled natural cycle, 68.4%, vs. natural cycle, 57.1%; RR, 1.21 [95% CI, 1.06-1.38]) in the scheduled natural cycle group. There were a higher proportion of live births in the scheduled natural cycle group; however, this did not reach statistical significance (scheduled natural cycle, 57.0%, vs. natural cycle, 49.4%; RR, 1.15 [95% CI, 0.97-1.36]). A subanalysis of preimplantation genetic testing for aneuploidy cycles yielded similar results.

Conclusion: A scheduled natural cycle FET protocol using a short duration of gonadotropin-releasing hormone antagonist along with low-dose gonadotropin add-back did not reduce live birth compared with traditional natural cycle FET cycles. These results suggest that this is an alternative FET protocol that may serve as a viable strategy to provide flexibility in scheduling the day of FET while still allowing a patient to undergo a natural cycle protocol. This protocol modification may enable more clinics to offer natural cycle FET.