The controversy about when to transfer embryos

When embryos were transferred in IVF cycles used to be one of the few completely uncontroversial issues in IVF practice. Embryos, of course, were transferred on day-3 after fertilization, at the so-called cleavage stage of embryos, when the good ones reached 6-8 cells. That, however, started to change almost 20 years ago, when colleagues in Colorado claimed that transferring embryos at the so-called blastocyst stage, usually days 5/6 after fertilization, resulted in higher pregnancy rates.

Cleavage- versus blastocyst-stage embryo transfer

Especially over the last decade, most IVF centers around the world have switched to uniform blastocyst-stage embryo transfers for all of their patients. One would assume that such a dramatic change in routine IVF practice would be based on large scale studies; however, considering the widespread adoption by the IVF community over the last decade of many “fashions of the moment” without proper prior validation (we are talking here about preimplantation genetic screening, PGS; closed incubation systems with time lapse; embryo banking; mild stimulation, etc.), one can no longer be surprised that even this enormous decision for IVF practice lacks serious statistical underpinning.

The opposite is, indeed the case: When other investigators attempted to repeat the reported Colorado experience, they uniformly failed. It also very quickly became apparent why that was: The Colorado investigators had cleverly preselected their patients and had studied in principle only very good prognosis patients. These are usually young women who produce relatively large numbers of good-quality eggs and embryos. By day-3, they, therefore, face a good problem to have: Which of these great-looking embryos should be transferred first?

If in such good prognosis patients all of these by day-3 great looking embryos are in the embryology laboratory continued in culture, marginal embryos fall by the wayside and arrest, or at least slow in their development in comparison to “stronger” embryos. Culturing embryos in extended culture to blastocyst-stage, therefore, is a good selection process for finding “best” embryos. And these “best” embryos, as many studies, including so-called meta-analyses, have clearly demonstrated will achieve marginally higher implantation rates than the average embryos transferred on day-3 at cleavage stage.

But these same studies also demonstrated that extended culture demonstrates this beneficial effect only in good prognosis patients. In average prognosis patients, there usually is neither a positive nor a negative effect to be found; in poor prognosis patients, who usually only have relatively few embryos by day-3, and whose embryos often are more fragile and don’t survive extended culture to blastocyst-stage, the overall effects will be seriously negative.

Moreover, meta-analyses have also suggested that cumulative pregnancy chance from a single cohort of embryos, as is created in a single IVF cycle (i.e., the cumulative pregnancy chances after all of these embryos have been transferred), are uniformly higher with day-3 than days-5/6 transfers. And this applies to all good-, intermediate- and poor-prognosis patients.

In other words, blastocyst-stage culture, likely, reduces cumulative pregnancy chances in all patients, significantly reduces immediate pregnancy chances in poor prognosis patients and marginally improves immediate pregnancy chances only in good-prognosis patients. Why extended blastocyst-stage embryo transfer has become such a vogue in worldwide IVF practice is, therefore, quite a puzzle but explains why CHR considers it to be another unsupported “fashion of the moment.”

A widely heard argument in favor of blastocyst-stage transfer has been the notion that it facilitates best outcomes with elective single embryo transfer (eSET). To a degree, this is, indeed, a correct argument but only valid in good prognosis patients who do not wish to conceive twins. In all other patients, extended embryo culture to blastocyst stage and eSET, independently, reduce pregnancy and live birth chances. Combined, they are even more harmful to IVF outcomes.

One, therefore, is left with the mystery: How come most IVF centers now culture embryos of almost all of their patients to blastocyst stage? The answer, unfortunately, may explain why the recent U.S. national IVF live birth rates have been declining for the first time. Indeed, as CHR researchers recently reported after reviewing IVF live birth rates worldwide, increasing utilization of blastocyst-stage culture and eSET all over the world, from Japan to Australia and New Zealand, and including Canada, is universally closely associated with declining live birth rates over the last decade [Kushnir et al., Systematic review of worldwide trends in assisted reproductive technology 2004-2013. Reprod Biol Endocrinol 2017;:15(1):6]. Quite obviously, the most common practice is not always the best practice!

Fresh or frozen embryo transfer

To stay with the subject of “fashions of the moment,” yet another such fashion gaining traction in recent years has been the concept of “all-freeze” cycles. This concept is based on the hypothesis that freezing all embryos at the end of an IVF cycle rather than transferring at least some, improves outcomes if these embryos are later transferred in a frozen-thawed cycle. The proposed explanation for this alleged benefit is that, through use of fertility drugs during ovarian stimulation, the endometrium is “out of phase” with the embryos, resulting in lower pregnancy chances.

As increasingly frequently the case in recent years in reproductive medicine, the studies that have made those claims, uniformly, either improperly selected patients, were incorrectly analyzed or misinterpreted outcomes (or all of the above). The principle still holds that fresh is better than frozen!

This was again demonstrated by CHR investigators in a recent publication involving fresh versus frozen donor oocytes [Kushnir et al., Outcomes of fresh and cryopreserved oocyte donation. JAMA 2015;314(6):623-624], and recently confirmed with even more statistical power in a manuscript presently in press.

Also in this regard, CHR has not been following “the trend,” and by doing so has continued to represent the best interests of our patients. At least for poorer prognosis patients, which represent a large majority of patients CHR serves, day-3 fresh embryo transfers are, still, the gold standard!

This is a part of the December 2017 VOICE.

Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned reproductive endocrinologist, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.