Read Doctor Gleicher’s Response to ASRM & SART’s newest publication

The Box below offers a word-by-word copy of an abstract, currently only electronically published, for a new combined 2024 ASRM & SART Practice Committee opinion which for the first time acknowledges what the CHR has been communicating in innumerable papers since 2007: PGT-A (its earlier name being preimplantation genetic screening, PGS) is ineffective in improving IVF outcomes.1 Finally, acknowledging this fact, one is left wondering why PGT-A then should be performed at all.

One is also left wondering why this opinion does not – loudly and clearly - also state that there now are equally solid data to demonstrate that in certain patient populations PGT-A not only does not offer outcome improvements, but, actually, reduces a woman’s chance of pregnancy and delivery.2-4

Unfortunately, this new ASRM and SART opinion is, therefore, still missing its logical conclusions and treatment recommendations. A statement that, as a procedure – which at substantial costs (to return to above cited paper on the cost-effectiveness of PGT-A5) - does not offer patients any outcome benefits, PGT-A cannot be cost-effective and, therefore, should not be offered to patients, except in experimental settings and with full informed consent. What also is missing is a reckoning by the infertility field why it had to take so many years to reach these conclusions, when the CHR (and others) already in 2015, after having offered several other important arguments why PGT-A should not be utilized, reported the first healthy euploid offspring after transfer of by PGT-A as “abnormal” declared embryos.6

A RADICALLY CHANGED POLICY STATEMENT REGARDING PGT-A FROM ASRM & SART1

      The use of preimplantation genetic testing for aneuploidy:

      A committee opinion

     The use of preimplantation genetic testing for aneuploidy (PGT-A) in the United States has been increasing steadily. Moreover, the underlying technology used for 24-chromosome analysis continues to evolve rapidly. The value of PGT-A as a routine screening test for all patients undergoing in vitro fertilization has not been demonstrated. Although some earlier single-center studies reportedhigher live-birth rates after PGT-A in favorable prognosis patients, recent multicenter, randomized control trials in women with available blastocysts concluded that the overall pregnancy outcomes via frozen embryo transfer were similar between PGT-A and conventional in vitro fertilization. The value of PGT-A to lower the risk of clinical miscarriage is also unclear, although these studies have important limitations. This document replaces the document of the same name, last published in 2018.                               

How many embryos with substantial pregnancy potential have over all these years been disposed?  How many infertile women have, therefore, been prevented from conceiving or - at least from conceiving with use of their own eggs - because they were advised that only donor eggs could help them in conceiving? The answer is unfortunately unprecedented in the degree its devastating impact.

Medicine - and science in general – are fortunate that the truth, ultimately, always prevails. To get to that point, however, often unfortunately can take time, - in this case frequently too much time. Consequently, large numbers of infertile women all over the world, because of PGT-A, have over the last 20 years lost their chance of genetic motherhood through use of their own eggs. Our profession will never be able to make up for that! 

As a final word, one can also only wonder, where the FDA has been in all of these years? Since PGT-A has been brought to market as a laboratory developed tests (LDT), the procedure has so-far completely escaped FDA attention. One can only hope that – with the recent announcement by the FDA of finally assuming active supervision of LDTs, the agency will find the time (and political will) to end the absurdities of current PGT-A utilization in the U.S. which according to most recent available national IVF data, paradoxically, is still increasing.  

AND NEWS ON THE INCREASING POPULARITY OF PGT-P: Considering the disaster brought upon the infertility field by PGT-A, it is amazing to watch how history appears to repeat itself: Mimicking the beginning of PGT-A (then called PGS), the utilization of PGT-P in association with IVF has been starting slowly. Only a handful of genetic laboratories and their affiliated fertility clinics are currently offering this method of embryo testing and they do so despite – as noted above – widespread agreement among professional organizations that have issued relevant opinion papers (for references, see above) that PGT-P is scientifically not ready for clinical use in association with IVF and, therefore, defining its use as “unethical.”

That, in itself, is, of course, astonishing and one, once again, must wonder where are ASRM, SAR, ACOG and the FDA in addressing this issue? But reading the recent literature on the subject, the growth in PGT-P utilization should not surprise. PGT-P, indeed, increasingly appears to be promoted as the “next big thing” in IVF. For genetics laboratories and IVF clinics, PGT-P may, indeed, be destined to replace the expected utilization loss that may occur as a consequence of above noted recent ASRM opinion on PGT-A1 and, based on several recently published papers, could become the next big revenue source for the IVF field and the genetic testing industry. 

Unsurprisingly, none of these papers offer any scientific outcome data on PGT-P, - because such data really do not exist. Instead, several papers proclaimed to query the attitude toward the clinical utilization of PGT-P. So, for example, a U.S. group of investigators performed so-called semi-structured interviews with REIs and IVF patients and concluded that both groups held favorable views of screening human embryos for physical or psychiatric conditions, though REIs expressed certain “specific caveats.” In general, the paper described REIs as “more skeptical” than patients and patients as “more interested” in utilization of PGT-P than REIs.7 The authors, though, must be given credit for describing PGT-P at least as “uncertain terrain.” 

Basically the same group of authors (though in different order) – published almost in parallel, though obviously performed later since this paper quotes the former - a more profound paper on the same subject in a different journal, basically investigating the same questions in the form of a survey in two distinct general study populations representing the general public, one stratified sample and one nonprobability sample.8 Whether the study populations for the two papers overlapped in some ways is unclear but the results were practically identical to above described first paper: 72.0% of  1,427 individuals in sample 1 approved of the use of PGT-P and even more among respondents to the survey undergoing IVF expressed interest in the procedure (81.9%). As noted in the earlier study, interest was especially high for embryo selection for Physical and psychiatric issues (77.7% and 72,0%, respectively). One, however, also must note that there was significant concern about the potential of promoting eugenic practices in both surveyed groups (53.3% and 54.8%). 

The authors concluded that, despite quite high societal concern, there was high approval and even higher interest regarding PGT-P reflected in public sentiment. Commenting on the clinical availability of PGT-P, the authors also pointed out that this practice is obviously unregulated and, therefore, should generate “informed dialogue and guidance.” We, of course, could not agree more, - but are wondering how well-informed study participants really were about PGT-P? 

That they were only poorly informed is almost certain, as most of their information, likely, came from parties interested in PGT-P. Considering how uninformed over decades even many REIs remained about PGT-A because they received most of their information from obviously “interested parties” in the performance of PGT-A (i.e., genetic testing laboratories and IVF clinics which usually shared in the revue generated from PGT-A), one must conclude that insufficient objective information about PGT-P must be even more prevalent (both in general populations and among REIs) because understanding the shortcomings of PGT-P is even more complex than understanding the shortcomings of PGT-A.

Interestingly even though all PGT-P related publications express serious concerns about its current clinical utilization, none of them calls for the discontinuation for these services. This, for example, also applies to a relatively recent Canadian paper.9 Concerns about PGT-P and the creation of “designer babies” have also been expressed on ethical and legal grounds, accompanied by demand for proper regulatory controls.10 But special credit is due to a group of international colleagues with lead author Antonio Capalbo from Italy, several among them originally among very committed proponents of universal PGT-A use, who recently published an excellent review article on the subject of PGT-P )or as named by them, polygenic embryo screening, PES) in Human Reproduction Update which we strongly recommend to everybody interested in PGT-P.11 These authors concluded and we are quoting: “Given the large number of practical limitations and possible harms, particularly unnecessary IVF treatments, and discarded viable embryos, PGT-P should be offered only within a research context,” while concomitantly stressing the need for unbiased genetic counseling. We couldn’t agree more! 

And for those readers in general interested in the concept of PGRS, here is a very interesting paper in cell genomics, proposing a new method for developing enhanced ancestry-specific polygenic risk scores via Bayesian hierarchical modeling and ensemble learning leveraging summary statistics from genome-wide-association studies across multiple ancestry groups, which has the potential to reduce the current performance gap in polygenic risk prediction across different ancestry populations.12 If this sounds complicated, - it is! This, however, demonstrates how, even in adults PGRS still faces many unresolved issues before it can enter into routine medical care.

REFERENCES

1. Practice Committee of the ASRM and SART. Fertil Steril 2024;May 18-S0015-0282(24)00241-3. Doi:10.1016/j.fertnstert.2024.04.013. Online ahead of print.

2. Gleicher et al., Hum Reprod 2022;37(12):2730-2734

3. Gleicher et al., Nat Med 2022;28(3):442-444

4. Gleicher et al., Trends Mol Med 2021;27(8):731-742

5. Nadgauda et al., Fertil Steril 2024;121(4):693-702

6. Gleicher et al., Fertil Steril 2015;104:e59

7. Barlevy et al., J Assist Reprod Genet 2024;41(5):1221-1231

8. Furrer et al., JAMA Network Open 2024;7(5):e2410832

9. Ginod P, Dahan MH. Reprod Biomed Online 2023

10. Rahim H. Petri-Flom Center at Harvard Law School. https://blog.petrieflom.law.harvard.edu/2024/03/11/designer-babies-the-ethical-and-regulatory-implications-of-polygenic-embryo-screening/

11. Capalbo et al., Him Reprod Update 2024; dmae012.doi: 10.1093/humupd/dmae012. Online ahead of print.

12. Jin et al., Cell Genomics 2024;4:100539