Live birth rates in very poor prognosis patients who are defined as poor responders under the Bologna criteria with nonelective single embryo two embryo and three or more embryo transfers

Capsule:
By presenting age-specific live birth rates in a population of very poor prognosis patients, we demonstrate that such patients even in their mid-40s can still achieve acceptable live-birth rates.

Authors:
Norbert Gleicher, M.D., Mario V. Vega, M.D., Sarah K. Darmon, Ph.D., M.S., Andrea Weghofer, M.D., Ph.D., M.A., M.B.A., Yan-Guan Wu, Ph.D., Qi Wang, Ph.D., Lin Zhang, M.D., David F. Albertini, Ph.D., David H. Barad, M.D., M.S., Vitaly A. Kushnir, M.D.

Volume 104, Issue 6, Pages 1435-1441

Abstract:

Objective:
To determine live-birth rates (LBRs) at various ages in very poor prognosis patients, who are defined as poor responders under the Bologna criteria.

Design:
Retrospective cohort study.

Setting:
Academically affiliated private fertility center.

Patient(s):
Among 483 patients, who under the Bologna criteria (three or fewer oocytes, >40 years of age, and/or antimüllerian hormone [AMH] <1.1 ng/mL [2/3 criteria minimum]) were poor responders, 278 (381 fresh IVF cycles) qualified for the study because they had at least one embryo on day 3 for transfer. Intervention(s):
IVF cycles in women with low functional ovarian reserve, involving androgen and CoQ10 supplementation and ovarian stimulation with daily gonadotropin dosages of 300–450 IU of FSH and 150 IU of hMG in microdose agonist cycles.

Main Outcome Measure(s):
Age-specific LBRs per ET.

Result(s):
Ages did not differ between nonelective (ne) single ET (SET), ne2-ET, and ne≥3-ET cycles (41.3 ± 3.9, 41.7 ± 3.1, and 42.4 ± 2.1 years, respectively). Patients with neSETs demonstrated significantly lower AMH and higher FSH levels and required higher gonadotropin dosages than ne2-ET and ne≥3-ET patients. LBRs declined with age. Above age 42, three or more embryos are required to achieve reasonable LBRs and two or more to avoid futility under American Society for Reproductive Medicine (ASRM) guidelines.

Conclusion(s):
Very poor prognosis patients can still achieve acceptable pregnancy rates at least till their mid-40s if they reach ET. The degree to which egg donation is emphasized as the only treatment option in such patients, therefore, requires reconsideration. Above age 42, at least two, and preferably three embryos, are however required to exceed futility, as defined by ASRM.

  • Nikolaos P. Polyzos

    The authors present interesting findings, suggesting that very poor prognosis patients can still achieve acceptable pregnancy rates at least till their mid-40s if they reach embryo transfer (ET ) and suggest that “The degree to which egg donation is
    emphasized as the only treatment option in such patients, therefore, requires
    reconsideration.”

    Although the results are presented per ET, and the authors claim that this is uniquely
    provided for the first time in the literature, counselling of infertile patients is performed prior to the ET stage and patients need to know their chances of success prior to initiate treatment.

    Based on the figures presented by Gleicher et al., results are presented only for the 278 patients reaching the ET stage and still more than 40% of their poor responder patients who started treatment did not manage to reach the ET stage. Several reports up to date have demonstrated that the chances of live birth in these patients are severely limited and results appear to be uniform across different studies (Busnelli et al. A retrospective evaluation of prognosis and cost-effectiveness of IVF in poor responders according to the Bologna criteria. Hum Reprod. 2015;30:315-22. La Marca et al. Live birth rates in the different combinations of the Bologna criteria poor ovarian responders: a validation study. J Assist Reprod Genet. 2015;32:931-7, Polyzos et al.Live birth rates in Bologna poor responders treated with ovarian stimulation for IVF/ICSI. Reprod Biomed Online. 2014;28:469-74.).
    In this regard, we believe that it would be extremely interesting to see the results of
    the current cohort by Gleicher et al after including all 483 patients initially
    recruited, in order to allow comparison of the results between studies.

    In addition, although the authors carefully decided to omit any formal comparison between groups (possibly owing to the small number of patients in the different age
    groups), the decision on whether to guide patients towards oocyte donation or
    stimulation with their own eggs cannot be based on simple figures without
    proper statistical testing. The statistical analysis used in the current
    article appears to overlook key issues such as the non-independent nature of
    data (i.e some patients may have contributed more than one cycle, given the
    fact that the number of patients was lower to the number of cycles), and the
    presence of confounding bias (several confounders do exist in retrospective
    data analysis and proper adjustments through logistic regression are essential
    for the reliability of the results). Consequently, it might be difficult to
    interpret the results properly.

    In conclusion, it is interesting to read that live births do occur in women of advanced age if they reach the ET stage. Nevertheless, this is not something new and this has
    been reported in several registry analyses published in the UK and the US with
    live births even in women of 45 years old (Sunkara et al . Association between the
    number of eggs and live birth in IVF treatment: an analysis of 400 135
    treatment cycles. Hum Reprod 2011;26:1768–74, Steward et al. Oocyte number as a
    predictor for ovarian hyperstimulation syndrome and live birth: an analysis of
    256,381 in vitro fertilization cycles. Fertil Steril 2014;101:967–73). However, the crucial question is not how many transfers we need to perform in order to achieve a live birth, but on the contrary how many patients we need to enroll in our treatment programs in
    order to have a live birth, and this is not answered by the current study.

    In this context, we should agree with the The American Society for Reproductive
    Medicine (ASRM) defining ‘‘futility’’ as a 1% and ‘‘very poor prognosis’’ as
    >1% to 5% chance of achieving live birth per cycle of treatment and not per
    ET. If the results per patient treated in the study by Gleicher et al, fall
    within the range or “very poor prognosis” or even “futility” in women at their
    mid-40s, then it is really questionable whether “The degree to which egg
    donation is emphasized as the only treatment option in such patients,
    therefore, requires reconsideration.”

    Kind Regards

    Prof NP Polyzos and Dr P Drakopoulos

    • Norbert Gleicher

      We appreciate the comments of Prof Polyzos and Dr. Drakopoulos to our paper. We, quite obviously, failed to communicate the main arguments of our paper well enough for them, and hope that this format will allow us to do a better job.

      Our group is quite well known for rather ferociously arguing that IVF outcomes principally should only be reported by “intent to treat” (i.e., with reference point cycle start). In here discussed manuscript we, however, make the point that very poor prognosis patients may represent the one clinical circumstance in ART where an exception to this rule may be appropriate.

      The reason is simple: In such patients pregnancy and, as we here report, live birth chances are strongly associated with number of available embryo for transfer.

      Unfortunately, projections of how many eggs and embryos will be obtained in very poor prognosis patients are practically impossible. With appropriate informed consent, such very poor prognosis patients, however, do fully understand that their pregnancy and delivery chances will almost exclusively depend on oocyte/embryo production. At the extreme, this, of course, means that if no eggs/embryos are obtained, and embryo transfer is impossible, there is no pregnancy/delivery chance. What chances, however, are if there are 1, 2, 3 or more embryos for transfer in such very poor prognosis patients in our opinion has never before been reported. To determine the answer to this question, therefore, was the goal of the study.

      What our data offer for our patient population and our treatment protocols for very poor prognosis patients (and on a side note, we do not believe that any of the cited references report a similar patient population because we do not know of any IVF center in the world that treats such patients) is a very clear understanding that goes beyond the obvious in very poor prognosis patients that, with no embryos to transfer there is no pregnancy chance.

      In such adversely selected patients, we, therefore, conclude that appropriate informed consent now can include reemphasis of the obvious but also allows us now to predict what live birth chances are if, after they passed the first important hurdle and produced embryos, we are able to transfer 1,2, 3 or more embryos.

      At least in our patient population, this used to be a question we were constantly asked but could never before answer except with generalities. Now we can give quite concrete answers that not only refer to clinical pregnancy rates (which in such an adversely selected patient population are of relative little value because of high miscarriage risks) but to live birth chances.

      Likely the most important point our Greek colleagues do not understand in such very adversely selected patients is that having no embryo for transfer often allows patients relative easy closure and progression into egg donation. Having embryos for transfer makes such a decision, understandably, much more difficult, and we see it as our responsibility to give patients maximal informed consent prior to any further cycle starts.

      We want to reemphasize to our Greek colleagues our strong commitment to IVF outcome reporting by “intent to treat.” In poor and very poor prognosis patients such reporting may, however, be much less helpful to patients in reaching a decision about whether to continue with their own eggs or whether to go onto egg donation.

      Finally, we reemphasize the conclusion in our paper that very poor prognosis patients, if they succeed in producing embryos, often do surprisingly well. By advising such patients on IVF outcomes based on “intent to treat,” in roughly 60% of patients strong recommendations to go into egg donation may, therefore, be premature.
      Best regards,
      Norbert Gleicher, MD
      (for all authors_

      • Nikolaos P. Polyzos

        We Appreciate the prompt reply of our Austrian colleague and
        his effort to help us understand that very adversely selected patients is that having no embryo for transfer often allows patients relative easy closure and progression into egg donation.

        However, we still believe that proper statistical analysis is essential in order to drive robust conclusions. Otherwise based on the data
        presented by Gleicher et al., it seems that women 35-37 years old with 2 or >3 embryos to transfer, have a 0% chance for a live birth. Does this mean that these patients should be counselled towards oocyte donation or potentially the rule does not apply to them?

        Prof NP Polyzos and Dr Drakopoulos
        From the Center of Reproductive Medicine UZ Brussel Belgium

        • Norbert Gleicher

          We are sorry we located our colleagues erroneously by name in Greece. Their Brussel address was simply not visible to us.

          Once again, we have to refer our colleagues to our paper, where we, where appropriate, point out our inability to reach valid statistical conclusions in some very small patient sub-groups. Further diluting numbers would produce less, not more usable information.

          We also want to point out again, as we did in our manuscript, that we do NOT see it as our responsibility to tell our patients how to live their lives (i.e., when to go into egg donation). This is a very personal decision, which patients have to reach on their own. We, however do see it as OUR responsibility to provide patients accurately and with ‘brutal’ honesty with information about what their options and outcome chances with the various options are. Then it is up to the patients to make the right choice for themselves.

          With here published study, we feel we have significantly added to the information we can share with patients and, by doing so, will, hopefully, make their decision making process easier.

          Best regards,
          Norbert Gleicher, MD
          The Center for Human Reproduction
          The Foundation for Reproductive Medicine
          The Rockefeller University

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