Does a frozen embryo transfer ameliorate the effect of elevated seen in fresh transfer cycles

Capsule:
Elevated serum progesterone on the day of trigger was negatively associated with clinical pregnancies in fresh in vitro fertilization transfer cycles but not in frozen embryo transfer cycles.

Authors:
Mae Wu Healy, D.O., George Patounakis, M.D., Ph.D., Matt T. Connell, D.O., Kate Devine, M.D., Alan H. DeCherney, M.D., Michael J. Levy, M.D., Micah J. Hill, D.O.

Volume 105, Issue 1, Pages 93-99

Abstract:

Objective:
To compare the effect of progesterone (P) on the day of trigger in fresh assisted reproduction technology (ART) transfer cycles versus its effect on subsequent frozen embryo transfer (FET) cycles.

Design:
Retrospective cohort study.

Setting:
Large private ART practice.

Patient(s):
Fresh autologous and FET cycles from 2011–2013.

Intervention(s):
None.

Main Outcome Measure(s):
Live birth.

Result(s):
A paired analysis of patients who underwent both a fresh transfer and subsequent FET cycle and an unpaired analysis of data from all fresh transfer cycles and all FET cycles were performed. We analyzed 1,216 paired and 4,124 unpaired cycles, and P was negatively associated with birth in fresh but not FET cycles in all analyses. Interaction testing of P and cycle type indicated P had a different association with birth in fresh versus FET cycles. When P was ≥2 ng/mL at the time of trigger, live birth was more likely in FET versus fresh cycles in the paired analysis (47% vs. 10%), in the unpaired analysis (51% vs. 14%), and in unpaired, good blastocyst only transfer subgroup (51% vs. 29%). Live birth was similar in FET cycles, with P ≥2 ng/mL versus P < 2 ng/mL (51% vs. 49%). Conversely, live birth was lower in fresh cycles, with P ≥2 ng/mL versus P <2 ng/mL (15% vs. 45%). Conclusion(s):
Elevated P levels on the day of trigger during the initial fresh cycle were negatively associated with live birth in the fresh transfer cycles but not in subsequent FET cycles. Freezing embryos and performing a subsequent FET cycle ameliorates the effect of elevated P on live-birth rates.

  • Mario Gilberto Vega, MD

    Thank you Micah for such an interesting paper. Many centers use 1.5 ng/mL as a cut-off for deciding fresh/frozen transfer. Figure 1 shows a marked increase in the difference of live birth rates when approaching a P value of 2ng/mL, based on your results would you recommend using 2 ng/mL as the cutoff? Also, since evidence points towards a negative effect of elevated P in the endometrium as opposed to the oocyte, would you change your practice to a more aggressive stimulation disregarding elevated Ps and proceeding with freeze alls?
    Thanks

    • Micah Hill

      Thank you for the comments Mario. We certainly see a small decline in pregnancy with P > 1.5 and a dramatic drop with a P > 2 ng/ml. I tend to counsel patients on the risks of lower pregnancy over 1.5, but strongly recommend freezing when P > 2. That being said, P assays can vary significantly, especially in the lower limits of the assay that we are talking about. This may be part of why different studies have different recommendations. So I think its helpful for practices to track their own internal data with their assay and establish their own thresholds if they have enough volume to do so.
      If I see a high P, yes I will often make a plan to continue an aggressive stimulation and freeze all. There is some suggestion that increasing the LH activity in the stimulation may help decrease P, in theory by increasing CYP17. So we will sometimes add more LH activity to the stimulation if we are seeing the P creep up. I would love to see a trial to evaluate if this actually helps.

  • Micah Hill

    Thanks for the comment Jason. Yes, I believe more latitude in the window of implantation is exactly the potential benefit of the FET in these cases of elevated progesterone. Its even more compounded with an embryo that develops to the blastocyst stage more slowly (say day 6), where you then have an advanced endometrium and a slow embryo.

    I believe your practice uses both the value of the progesterone and the amount of time between progesterone rise and embryo transfer in the decision to proceed with fresh transfer versus freezing?

    • Jason M. Franasiak

      Thank you so much for your reply Micah! Yes, that is correct – the progesterone rise sets the secretory transformation and the embryonic blastulation rate helps determine embryonic synchrony. Thank you again for such an interesting article!

  • Jason M. Franasiak

    A very interesting study design and finding. Given P4 impacts fresh cycle but not FETs, would you hypothesize this may be because the other factor in synchrony–the embryo–is fixed in the FET and thus allows for slightly more latitude with the endometrial window?

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