Prolonged vaginal progesterone supplementation does not improve outcomes for Day 6 frozen blastocyst transfers in...

Does extending vaginal progesterone administration from 5-6 days improve pregnancy outcomes in Day 6 (D6) frozen embryo transfers (FETs) in oocyte donation cycles?

Prolonging the time of vaginal progesterone supplementation does not improve pregnancy outcomes after D6 FETs in oocyte recipients.

Progesterone is critical for endometrial preparation prior to embryo transfer, but the optimal duration of administration remains unclear. D6 blastocysts are associated with poorer clinical outcomes compared to Day 5 (D5) blastocysts, potentially due to either intrinsic limitations in implantation capacity or a shifted window of implantation (WOI). Extending progesterone administration has been hypothesized to optimize the WOI for D6 blastocysts.

This retrospective cohort study included 485 FETs performed in 420 oocyte donation recipients, conducted from January 2020 to December 2023 in a single IVF center. Participants were divided into two groups based on the duration of progesterone supplementation: 5 days (P + 5, n = 282) and 6 days (P + 6, n = 203).

The study involved oocyte recipients undergoing single D6 blastocyst transfer following endometrial preparation with vaginal progesterone (800 mg/day). Outcomes were analyzed using univariate and multivariate tests, including logistic regression adjusted for estrogen type and endometrial thickness.

Mean recipient age (±SD) was 43.5 (±4.24) years, mean BMI was 25.1, and mean endometrial thickness was 9.6 mm on the day of transfer. Good-quality blastocysts accounted for 35% of all transfers. Clinical outcomes, including biochemical (26.24% vs 26.60%, P = 1.00), clinical (21.99% vs 20.69%, P = 0.83), and ongoing pregnancy (14.54% vs 13.30%, P = 0.79), as well as live birth (14.18% vs 10.66%, P = 0.27) and miscarriage rates (7.45% vs 7.39%, P = 1.00), were all similar between 5 and 6 days of progesterone supplementation, respectively. Adjusted analyses confirmed these findings.

The retrospective design warrants careful interpretation. Results are specific to vaginal progesterone in oocyte donation cycles and may not apply to other populations or progesterone delivery methods. Additionally, the D6 embryos analyzed were those that did not reach blastocyst by Day 5 (delayed, poor-prognosis, and typically transferred last), which likely biases outcomes toward lower live birth rates.

Compromised outcomes following D6 FETs compared to those of D5 blastocysts, likely reflect the intrinsic limitations of slow-developing embryos rather than a misaligned WOI. As prolonged progesterone exposure did not improve outcomes, the WOI may be broader than previously assumed, particularly in oocyte donation programs, where superior embryo quality may mitigate synchronization drawbacks.

This study was internally funded by the Eugin Clinic, with no external sponsorship. The authors declare no competing interests.

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