A matched cohort comparison of single embryo transfers in fresh and frozen thawed embryo transfer cycles

Capsule:
Impaired endometrial receptivity following ovarian stimulation appears to be primarily through embryo-endometrium asynchrony.

Authors:
Bruce S. Shapiro, M.D., Ph.D., Said T. Daneshmand, M.D., Humberto Restrepo, M.D., Forest C. Garner, M.S., Martha Aguirre, Ph.D., Cynthia Hudson, M.S.

Volume 99, Issue 2, Pages 389-392, February 2013

Abstract:

Objective:
To discern the potential effect of ovarian stimulation on implantation potential by comparing ongoing pregnancy rates from matched blastocysts in fresh and frozen-thawed single-embryo-transfer cycles.

Design:
Matched cohort study.

Setting:
Private fertility center.

Patients:
Ninety-three matched pairs of single blastocyst transfer.

Intervention(s):
Fresh and frozen-thawed embryo transfers were matched on embryo parameters and patient age.

Main outcome measure:
Ongoing pregnancy at 10 weeks’ gestation.

Results:
The fresh and frozen-thawed groups did not differ significantly in blastocyst diameter, inner cell mass size, trophectoderm cell count, patient age, use of genetic screening, or the presence of supernumerary embryos. The ongoing pregnancy rate was significantly greater in the frozen-thawed group than the fresh group for transfers of day 6 blastocysts (54.3% vs 17.1%, respectively), but not for day 5 blastocysts (60.9% vs 56.5%, respectively). This resulted in the overall ongoing pregnancy rate to be significantly greater in the frozen-thawed group than in the fresh group (55.9% vs 26.9%, respectively).

Conclusions:
Autologous day 6 blastocysts transferred in frozen-thaw cycles have significantly greater chance of viable implantation than morphologically equivalent embryos transferred in fresh cycles. This advantage appears to result from impaired implantation of day 6 blastocysts in fresh transfers following ovarian stimulation, suggesting embryo-endometrium asynchrony is a major cause of impaired endometrial receptivity following ovarian stimulation.

  • Micah Hill

    Thank you Dr Shaprio for your paper and coming on-line to discuss it in the journal club! In our fellowship we each have to chose one interesting presentation from ASRM and discuss it at our post-ASRM journal club, and I chose your oral presentation of this data. It was the first time I had considered that day 6 transfers might do worse because of asynchrony with the endometrium, as opposed to the slower morphokinetics indicating a poorer quality embryo.

    A question I had wanted to ask and Dr Bosch touched on in the online discussion was the role of early rises in progesterone advancing the endometrium even further in a subgroup of patients. So if some patients have an even more advanced endometrium in combination with a slower growing embryo, the asynchrony would be magnified. Do you measure progesterone levels prior to hcg triggering? It would be interesting to control for this and see how much elevated progesterone negative impacted day 6 versus day 5 fresh transfers.

    Thanks

    Micah

    • for those who might have missed it Dr Hill is referring to our online journal club which reviewed this article with a team of experts from around the globe– here’s a link to watch the video

      http://fertstertforum.com/journalclubmarch2013/

    • Forest

      Thank you for this insight. We measure progesterone levels on the day of trigger and the following morning, about 12 hours after trigger, when we also measure hCG and LH levels. We concur that a study designed to look for an effect of early progesterone just might find such effect, as many authors have already. A matched design like that might match high progesterone cycles to low progesterone cycles, while matching on age and embryo parameters (morphology, blastulation day) in fresh autologous single embryo transfers. We shall consider this idea. Again, thank you.

      • Micah Hill

        Thank you for the reply Forest. A very thought provoking paper!

  • Forest

    Hi Juan.

    Thank you for your interest in our paper. We agree it is consistent with many prior publications on the effects of ovarian stimulation on endometrial development and receptivity.

    We did not match on BMI. However, I can compare BMI in JMP 7 and I see the Fresh group had mean BMI of 24.8 while the PTEC (frozen) group had mean BMI of 24.2. The P-value for this paired comparison (using Wilcoxon’s test) is 0.3149. Not significant.

    In some ways, this matched study was superior to the RCTs we ran. In measuring the difference in (presumably) endometrial receptivity, we had a slight confounding effect of different embryo quality in the RCTs. The inferior cohorts after freeze-thaw caused transfers of potentially inferior embryos in the frozen-thawed arms of those studies, potentially reducing the success rates in the frozen-thawed arms relative to what would have potentially been achieved with embryos as good as in the fresh arms, and therefore also reducing the apparent or estimated effects of ovarian stimulation on the endometrium. In other words, we suspected the endometrial effect was somewhat larger than our two RCTs found.

    The current matched embryo study improved on the RCTs by ensuring comparable quality of transferred embryos in the two study groups. In this way, the endometrial effect can be better isolated and characterized.

    We look forward to further RCTs to compare fresh autologous and autologous FET.

    Forest

  • Juan Giles

    I have read with great interest your
    study, in which comparison of single-embryo transfer in fresh and frozen-thawed
    embryo transfer cycles is presented.

    Probably it would be interesting to
    know if patients were matches also by BMI, as being overweight clearly related with decrease in pregnancy
    rate, and the distribution between arms of patients with a prior history of
    implantation failure (perhaps a potential confounding variable).

    With the limitations of a no RCT, the
    findings showed in this manuscript are very interesting. Autologous day 6
    blastocyst transferred in frozen – thawed cycles have significantly greater
    chance of implantation than morphologically equivalent embryos transferred in
    fresh cycles, while there was no difference in day 5 between groups.

    These data are in line with previous
    studies in which pregnancy rates of frozen-thawed embryo transfers are on par
    with, or superior to those, associated with fresh embryo transfer. Although a
    recent systematic review and meta-analysis of observational studies have shown
    that singleton pregnancies following frozen-thawed embryo transfers have better
    perinatal outcome when compared with fresh embryo transfer. The possible
    mechanism of action, as you mention, is the supra-physiological levels of estrogens
    produced by the growing follicles during COS. Our previous results also reflected
    also the deleterious effect of estradiol on embryonic implantation (Valbuena
    2001).

    It seems necessary randomized trials
    to evaluate elective cryopreservation versus fresh embryo transfer.

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