Preimplantation genetic testing for aneuploidy versus morphology as selection criteria for single frozen-thawed embryo transfer in good-prognosis patients: a multicenter randomized clinical trial

Article In Press

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Authors:

Santiago Munné, Ph.D., Brian Kaplan, M.D., John L. Frattarelli, M.D., H.C.L.D., Tim Child, M.D., Gary Nakhuda, M.D., F. Nicholas Shamma, M.D., Kaylen Silverberg, M.D., Tasha Kalista, M.A., Alan H. Handyside, Ph.D., Mandy Katz-Jaffe, M.D., Dagan Wells, Ph.D., Tony Gordon, Ph.D., Sharyn Stock-Myer, Ph.D., Susan Willman, M.D., on behalf of the show STAR Study Group 

Abstract:

Objective

To evaluate the benefit of next-generation sequencing (NGS)–based preimplantation genetic testing for aneuploidy (PGT-A) for embryo selection in frozen-thawed embryo transfer.

Design

Randomized controlled trial.

Setting

Not applicable.

Patient(s)

Women aged 25–40 years undergoing IVF with at least two blastocysts that could be biopsied.

Intervention(s)

Randomization for single frozen-thawed embryo transfer with embryo selection based on PGT-A euploid status versus morphology.

Main Outcome Measure(s)

Ongoing pregnancy rate (OPR) at 20 weeks' gestation per embryo transfer.

Result(s)

A total of 661 women (average age 33.7 ± 3.6 years) were randomized to PGT-A (n = 330) or morphology alone (n = 331). The OPR was equivalent between the two arms, with no significant difference per embryo transfer (50% [137/274] vs. 46% [143/313]) or per intention to treat (ITT) at randomization (41.8% [138/330] vs. 43.5% [144/331]). Post hoc analysis of women aged 35–40 years showed a significant increase in OPR per embryo transfer (51% [62/122] vs. 37% [54/145]) but not per ITT.

Conclusion(s)

PGT-A did not improve overall pregnancy outcomes in all women, as analyzed per embryo transfer or per ITT. There was a significant increase in OPR per embryo transfer with the use of PGT-A in the subgroup of women aged 35–40 years who had two or more embryos that could be biopsied, but this was not significant when analyzed by ITT.

Clinical Trial Registration Number

NCT02268786.


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6 Comments

Go to the profile of M. Blake Evans
M. Blake Evans 24 days ago

Very interesting work on a hot topic in our field. In light of the authors acknowledging the difficulties of large-scale multicenter RCTs and the importance of standardizing diagnostic tests: I'm interested to know what the cut off was amongst the labs when classifying embryos as segmental mosaic vs normal?

Go to the profile of Luis Hoyos
Luis Hoyos 24 days ago

This is an enlightening study with important implications in the way we practice. I would be interested in knowing the authors', and everybody else's, opinion about the role of PGT-A in our field moving forward.

Go to the profile of Samuel Santos-Ribeiro
Samuel Santos-Ribeiro 23 days ago

Very interesting results from this very much anticipated study! I am curious to know if the authors are considering a post-hoc follow-up of cumulative live birth rates? Such could bring into light the true importance of mosaic embryos for overall ART success.

Go to the profile of Pandiyan  Natarajan
Pandiyan Natarajan 15 days ago

Interesting study and paper. I have been following the development of Preimplantation genetic diagnosis from 1987. The technique which was introduced to avoid the birth of  an  abnormal baby was slowly extended for other unproven indications. PGT-A as it stands today is really on very shaky ground. The extrapolation from PGT-M and PGT-SR to PGT-A for all was an overkill with considerable damage to even the existing indication. The paper clearly proves the futility of PGT-A for all. Are there really any indication for PGT- A? With increasing trend towards Single Embryo Transfer, the technique would soon be phased out and avoiding known genetic defects would remain the only indication.

Go to the profile of Luis Hoyos
Luis Hoyos 8 days ago

I understand your point but I don't entirely agree. I do agree that it was widely adopted too soon resulting in an overkill just like most new technologies in our field, nevertheless this study only proves that in "good prognosis" patients PGT-A offers no advantage, but how about patients with "poor prognosis"? 

Overall, I do think that PGT-A has a role but not the current one. We are using a screening test as a diagnostic test and that is the main problem I have with it. I believe that PGT-A (and may be we should change the name again to PGS to emphasize that after all it is just a screening test) should be used to prioritize embryo transfer in "poor prognosis" patients but embryos should not be discarded based on the results. PGT-A will not phase out but I think it will transform. I can imagine a future where PGT-A is done non-invasive and the result used along with other parameters to prioritize embryo transfer in "poor prognosis" patients. I do agree with you about PGT-M and PGT-SR continuing to play a crucial role in the future.

Go to the profile of Pandiyan  Natarajan
Pandiyan Natarajan 6 days ago

Thank you very much for your valuable feedback and the points raised.  


In poor prognosis patients also PGT- A is unlikely to improve pregnancy rates over the long term. Transfer of 2 embryos is more likely to improve pregnancy rates with the attendant risk of twin gestation. . Sequential transfer of available embryos- 1 in the first cycle and 2 in subsequent cycles is likely to be of greater benefit than PGT-A.


 PGT-A has many inconsistencies; there is confusion about the definition of aneuploidy and mosaicism ( current definitions are arbitrary) and the recommendation to discard aneuploid embryos is even more worrisome. Cells in the inner cell mass, blastocyst fluid and trophoblast are not the same and do not have identical karyotype. Mitotic errors may have crept in trophoblast cells which are not reflective of the cells of the inner cell mass.


As for the terminology, all was well when it was PGD. The test was designed to primarily diagnose certain genetic defects in embryos prior to implantation. The test was also used to exclude sex chromosome linked disorders. 


Preimplantation genetic diagnosis and HLA typing of the embryo and transfer of a HLA compatible normal embryo was a later development leading to the birth of a saviour sibling and the popular term Designer baby. The term was the invention of Journalists with a penchant for exaggeration as was the term Test tube baby. A true Designer baby is a far cry as science stands to day. All major human attributes, intelligence, musical talents, athleticism and sporting skills are not just inherited. They are 99% (nurtured) perspiration and 1% (genetic) inspiration. We now know that DNA is not our destiny. They are part of our destiny and much more important, they are our history.


Current PGT-A testing does not screen for genetic defects. It only screens for chromosomal aneuploidy. So strictly speaking, ipso facto, it should only be termed as Pre implantation Chromosome Testing for Aneuploidy PCT- A or Pre implantation Chromosome Screening- PCS as you would prefer to call.


Screening the embryo was done only for a few chromosomes earlier. Now with NGS, we are able to screen for all the 24 chromosomes. To expect this screening  to improve prognosis is a huge jump in faith with no substantial data to support this claim. Failure of implantation is due to several factors, chromosomal aneuploidy is just one of them.


Intervention of an early embryo was clearly harmful when it was cleavage stage embryo biopsy. The results were poor. Is  Trophectoderm biopsy safe ? Only time will tell, with more follow up studies of these babies in to adulthood. I have my own reservations about the safety, specificity  and sensitivity of these procedures.


The first principle of medicine is, 'Primum non Nocere.' 


Simple, non invasive Sequential embryo transfer should achieve this purpose rather safely. Non invasive testing of the embryo is ideal; morphology does that with all its attendant limitations. Proteomics, metabalomics to aid in embryo selection is an utopian idea with no clear light visible at the end of the tunnel.


Professor Dr Pandiyan Natarajan,


Professor and Head, Chief Consultant in Andrology and Reproductive Medicine,


Chettinad Super Speciality Hospital,


Kelambakkam, Tamil Nadu.


India-603103