Bruce S. Shapiro, M.D., Said T. Daneshmand, M.D., Forest C. Garner, M.Sc.,

1. Contrasting patterns in in vitro fertilization pregnancy rates among fresh autologous, fresh oocyte donor, and cryopreserved cycles with the use of day 5 or day 6 blastocysts may reflect differences in embryo-endometrium synchrony. Bruce S. Shapiro, M.D., Said T. Daneshmand, M.D., Forest C. Garner, M.Sc., Martha Aguirre, Ph.D., and Richard Ross, M.Sc. Fertili Steril 2008;59;20-6 台北榮民總醫院 婦產部 張昇平

2. Objective: To compare the effect of day 5 and day 6 blastocyst transfers on patterns of implantation rates and pregnancy rates (PRs) among fresh autologous, oocyte donor, and frozen ET (FET) cycles. • Design: Retrospective study. • Patient(s): The study included 377 fresh autologous cycles, 106 autologous FET cycles, and 56 fresh oocyte donor cycles. • Main Outcome Measure(s): Implantation rates and clinical PRs.

3. RESULTS • During the study period, there were 377 fresh autologous blastocyst transfer cycles, 106 FET cycles, and 56 donor cycles that met the basic inclusion criteria. • These criteria required that embryos must have been transferred or frozen as day 5 or day 6 blastocysts during the 20-month period from January 1, 2004 to August 31, 2005. • The oocyte donor cycles must have used donors 35 years of age.

4. Result(s): The clinical PR for day 5 blastocyst transfers was higher than for day 6 blastocyst transfers in fresh autologous cycles (PRs, 51.0% and 33.3%, respectively). However, there was no significant difference between transfers of blastocysts cryopreserved on day 5 and day 6 in FET cycles (PRs, 63.6% and 58.9%, respectively). Furthermore, day 6 blastocyst transfers significantly outperformed day 5 transfers in donor cycles (PRs, 63.0% and 86.2%, respectively), a reversal of the pattern seen in the fresh autologous cycles. Day 6 blastocysts were associated with a significantly greater PR in FET cycles than in fresh autologous cycles (58.9% and 33.3%, respectively).

10. DISCUSSION • Studies of shared oocyte cycles, where oocytes are split between oocyte producers and recipients, revealed that the recipients have higher PRs and implantation rates than the producers (Check JH et al.J Assist Reprod Genet 1999;16:416–20.).

11. Substantially different success rates in fresh and FET cycles must reflect different receptivities of the endometrium, less any negative effects of cryopreservation on the embryos. • However, cryopreserved day 6 blastocysts in FET cycles outperformed day 6 blastocysts in fresh autologous cycles. • Furthermore, cryopreserved day 6 blastocysts performed on a par with cryopreserved day 5 blastocysts in FET cycles. • It seems implausible that cryopreservation could have improved the embryos.

12. The superior PR for day 6 blastocysts in donor cycles, compared to their day 5 counterparts, contrasts with the pattern seen in fresh autologous cycles. • The artificial cycles have a shorter and more precisely controlled duration of P exposure, enabling optimal and reproducible synchronization that results in consistently better synchrony of day 6 blastocysts with the endometrium in these donor cycles.

13. The greater PR (86.2%) with day 6 transfers in donor cycles corresponds with a greater duration of P supplementation, perhaps with resultant better synchrony. • Embryo-grading systems that emphasize rapid embryo development are appropriate for fresh autologous IVF cycles. • However, grading systems for donor cycles should favor those embryos best synchronized with the endometrium; this, in turn, will depend on the timing of P initiation.

14. It was suggested that the solution to the asynchrony problem in fresh cycles may be the use of antiprogestins to block the action of P. • Antiprogestins administered with proper timing might reduce or prevent such endometrial advancement. Initial research in this area has been promising (Paulson RJ et al. Fertil Steril 1997). • Another approach might be to control E2 production and the resulting uterine hypersensitivity to P because of up-regulation of P receptors.

15. From the data here. However, synchrony may have the larger effect, owing to the reversal of the relative performance of day 5 and day 6 blastocysts in donor cycles. • The effects noted here suggest that many IVF cycle failures may be caused, in part, by suboptimal synchrony between the endometrium and otherwise viable embryos.

16. Recommendation 1.Eencourage the cryopreservation of supernumerary embryos reaching the blastocyst stage beyond day 5. 2.The greater PR (86.2%) with day 6 transfers in donor cycles corresponds with a greater duration of P supplementation, perhaps with resultant better synchrony. (P initiated on the day of oocyte retrieval, day 6 blastocysts transferred on day 7 of P supplementation)

17. 3.The solution to the asynchrony problem in fresh cycles may be the use of antiprogestins to block the action of P. 4.That many IVF cycle failures may be caused, in part, by suboptimal synchrony between the endometrium and otherwise viable embryos.

18. Delayed blastocyst transfer: is the window shutting? Thank you for your attention