BREAKING NEWS: Another Nail in the Dogma of Embryo Selection in IVF -Beyond Basic Embryology

By Norbert Gleicher, MD, Medical Director and Chief Scientist at The Center for Human Reproduction in New York City. He can be contacted though The Reproductive Times or directly at either ngleicher@thechr.com or ngleicher@rockefeller.edu.

An excellent paper that just appeared in Nature Medicine, accompanied by an equally good, signed Commentary, put another nail into the sarcophagus of the dying dogma that embryo selection (ES) beyond embryo morphology will improve IVF cycle outcomes.

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December 9, 2024

In comparing embryo selection (ES) in IVF (in vitro fertilization) between a deep learning artificial intelligence (A.I.) program and manual morphology, an excellent just-published study in Nature Medicine found no difference.1 Because we have been arguing for years that beyond morphology, ES is biologically illogical, to us this result was not a surprise. To may others in the field, however, it apparently was. It, otherwise, would not have been accepted in such a prominent medical journal and, in addition, given an accompanying commentary.2

The concept of embryo selection is almost as old as in vitro fertilization (IVF) itself and, therefore, has to be considered a founding dogma of IVF. It assumes that in a cohort of embryos produced in a single IVF cycle, there must be a “best” – or at least several “best” – embryos. While embryo cohorts, indeed, vary in quality (defined by pregnancy and live birth chances), none among several widely practiced ES methods in IVF have ever been demonstrated to exceed the efficacy of manual morphology assessments.

A concept first explored when embryo morphology was recognized to predict IVF cycle outcomes, it has since been the single most investigated subject in IVF, with no other subject in the fertility field receiving more funding. Yet hardly any other major investment has produced fewer rewarding results. No wonder then that all the search for ES over more than 40 years achieved, was the introduction of to this day unvalidated clinical IVF practices, such as routine embryo culture to blastocyst stage, time lapse incubation systems, preimplantation genetic testing for aneuploidy (PGT-A), and others. All of these ES practices have been demonstrated not to improve IVF outcomes and, in certain patient populations, to even adversely affect outcomes.3,4

With A.I. being everywhere (and not only in medicine), it also cannot surprise that most recent attempts at ES have involved deep learning systems. with start-ups from all around the world having reported alleged claims of superiority over standard embryo morphology. Our review of these claims has, however, left us skeptical; none in our opinion, indeed, properly validated their statements. A recently published prospectively randomized multicenter study, just published in Nature Medicine, moreover, actually refuted this claim, demonstrating no significant outcome differences between an A.I. – driven ES and standard manual embryology.

One can only hope that this recently published study1 and its equally excellent accompanying commentary2 will, finally, convince the IVF field that the continuous pursuit of ES beyond basic embryology makes biologically little sense and has already wasted too much effort and investments. Resulting useless IVF practices have just continued to increase the costs an already far too expensive and for many unaffordable IVF process.

If a clinically relevant difference in embryo quality really exist, good manual embryology is highly efficient in selecting out “best” embryos. That was recently also demonstrated by several papers which reported no outcome differences between embryo transfers at cleavage and blastocyst-stages in general populations but suggested some outcome advantages for cleavage-stage transfers in poorer prognosis patients (mostly older and/or women with small embryo numbers).

To return to economics, one can only imagine how much cost could be saved for providers and patients in IVF if fertility clinic would not culture every embryo to blastocyst-stage, but transferred at least a majority of embryos already at cleavage-stage on day-3 after fertilization, as used to be routine until one single study in a highly biased and favorably patient population alleged outcome benefits from blastocyst-stage embryo transfers for all – by now clearly refuted.

The only outcome benefit after embryo morphology has been established that blastocyst culture potentially offers is a minor shortening of time to pregnancy if there is more than one obviously “best” embryo. But so what, if the first embryo does not implant? One tries in the following month again; and, if this was really the better embryo, the patient will be pregnant one cycle later. And, as the literature suggests, even this tiny benefit applies only to good-prognosis patients.

Is this worth the effort and additional costs of blastocyst-stage culture for everybody? We don’t think so!

And how about PGT-A for everybody, as many IVF clinics have established as almost a mandate for patients?  No longer able to hold back the conclusion that PGT-A in general populations offers not a single established outcome benefit in IVF (though it may harm outcomes in some sub-populations), the most recent opinion paper of the Practice Committees of ASRM and SART, finally acknowledged publicly what everybody who can read the literature already figured out quite a while ago, such mandate or even recommended – utilization of PGT-A no longer seems feasible (the recently filed class action suits regarding this subject may also turn out to be helpful).

Just imagine the cost savings for clinics as well as patients that an IVF cycle would bring without a need for automatic blastocyst-stage culture and PGT-A. And then there is so much more junk science being practiced in association with IVF; but that remains on the docket for another time.

REFERENCES

1.      Illingworth et al., Nat Med 2024; 30:3114-3120

2.      Kieslinger et al., Nat Med 2024;30:3059-3060

3.      Gleicher et al., Nat Med 2022; 28::442-448

4.      Kieslinger et al., Lancet 2023;401:1438-1446