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expert reaction to study looking at preimplantation genetic testing (pgt) and live births in IVF

Researchers, publishing in Human Reproduction, looked at preimplantation genetic testing (PGT-A) in women of advanced maternal age (36-40) and whether it’s use increased the likelihood of a live birth after a year.

 

Prof Darren Griffin, Professor of Genetics at the University of Kent, said:

“The is an interesting study that contributes to an already heated debate on the pros and cons of PGT-A.  The study appears to be well designed and performed and the authors are to be congratulated for their perseverance.  The significant result is the secondary endpoint (that of an improved miscarriage rate); it is to be welcomed and, for some couples, would be reason enough to undergo PGT-A.  Not finding a significant difference in cumulative live birth rate however may be due to a number of factors.  The first of course it that there may not actually be any benefit to PGT-A.  If this were the case it would be at odds with some other studies, e.g. the recent STAR trial (which could of course be criticised).  Other reasons however might be not enough patient numbers, indeed I believe that the trial was truncated (i.e. did not treat as many patients as it originally intended).  It also however might be due to the fact that the technology used is not current.  For instance, the hybridization-based chromosome detection method has now been superseded by a DNA sequencing approach, which is more sensitive. Also, their means of sampling genetic material (so called polar body biopsy) inherently will miss a large proportion of chromosomal abnormalities and, again, is not one that is now widely used.  This is not necessarily a criticism of the study itself, at study onset this approach was state of the art, however it is a commentary on the difficulty of getting studies such as this off the ground and published.

“Where I have an issue however is the assertion that PGT-A not improving live birth rates is a “widely accepted view.”  Quite simply, it isn’t.  There is a broad range of (often polarised) viewpoints associated with PGT-A and a range of studies, some of which support its use, some of which do not.”

 

Prof. Alan Thornhill, Country Manager UK and Senior Scientific Advisor, IGENOMIX, said:

“This well-designed study has been a long time in coming but has a number of important limitations which could limit its relevance to current IVF practice. It employed what is a now obsolete approach of investigating polar bodies from eggs using array CGH which limits is ability to identify all chromosome aneuploidies. The first important and reassuring conclusion is that the technique did not harm the chance of having a live birth. The second is that the identification of maternal aneuploidies leads to a reduced incidence of miscarriage in line with many other aneuploidy screening studies which is good news for IVF patients.”

 

Prof. Jan Brosens, Professor of Obstetrics & Gynaecology, University of Warwick, said:

“All too often couples requiring IVF treatment are taken for a ride when it comes to a bewildering array of unproven tests and adjuvant treatments. Patients need to be empowered to make choices based on clinical evidence. This smartly designed and well conducted study was designed to give couples clear-cut information on whether PGT-A increases the chance of having a baby within one year. The answer is no. Yet the finding that PGT-A reduces the number of procedures and decreases the risk of miscarriage may sway some couples to opt for this intervention.”

 

Prof. Ying Cheong, Professor of Reproductive Medicine, University of Southampton, and Clinical Director, Complete Fertility, Southampton, said:

“Verpoest and his team showed, in a study involving 9 IVF centres, that Preimplantation Genetic Testing (PGT) of the biproducts of the egg division process (1st and 2nd polar bodies) was not useful in increasing the chances of live birth in women aged 36-40 years. This is not surprising as other studies have also showed the lack of benefit of PGT albeit that the timing, method and technique used for analysis varied.

“The authors stated that as a result of PGT, there were less embryo transfers and a lower miscarriage rate, and many IVF clinics may well erroneously seize this as a ‘selling point’ for PGT-A. It needs to be emphasized that these are secondary end-points which the study was not powered to definitively answer and so must be interpreted with caution.

“Removing cells out of the developing egg or embryo, without evidence of clear clinical benefit, is poor clinical practice.  We still do not understand fully the developmental biology of the egg and the embryo, and as such, may cause more harm than good. For these reasons, it is my opinion that PGT-A should not be offered to women with advanced maternal age.”

 

Prof. Dagan Wells, Associate Professor at the NIHR Biomedical Research Centre, University of Oxford, said:

“This study looked at the question of whether screening eggs for chromosome abnormalities could benefit patients undergoing IVF treatment.

“An incorrect number of chromosomes, more or less than the usual 23, is a very common defect in human eggs, affecting more than half of those produced by women over 40.

“The wrong number of chromosomes in eggs is the main cause of miscarriage as well as being the principal reason why some embryos produced using IVF fail to yield a pregnancy, leading to a negative pregnancy test result after the embryos are transferred to the uterus.

“In theory, if eggs with the correct number of chromosomes could be accurately identified, and the embryos they produce transferred to the uterus in preference from those derived from abnormal eggs, then the efficiency of IVF treatment could be improved and the risks of some distressing problems, such as miscarriage, could be reduced. The results of this study confirm that screening for chromosome abnormality can provide some of these benefits.

“This was a well-designed, high-quality study, but unfortunately it took so long to complete that the technologies used have become obsolete during the course of the trial. I believe this was the main reason why the professional society ESHRE chose to cut funding for the study midway through. As a result, the findings have little relevance to the type of genetic testing carried out in clinics today. The concept of testing eggs was abandoned several years ago in favour of testing the embryos themselves, which is thought to be more accurate and more informative. Only a handful of countries with restrictive embryo testing laws still consider this strategy.

“Testing of eggs in the way described in the study is problematic because the method of analysis has a considerable error rate. It is likely that modern testing methods, applied to embryos rather than eggs, would give superior results. Nonetheless, it is clear that even this imperfect form of testing yielded significant benefits for the patients.

“Patients required fewer embryo transfers to become pregnant. This means women undergoing IVF didn’t need to undergo as many medical procedures and there would have been fewer occasions where the couple’s anticipation and excitement following an embryo transfer was crushed by a negative pregnancy test result.

“The miscarriage rate, which can be high, especially in older patients undergoing IVF, was halved after chromosome screening was used. This is an extremely important benefit given the medical and emotional impact of a miscarriage.

“This study confirms that chromosome screening is not a magic bullet. It cannot guarantee a pregnancy using IVF. However, it does succeed in reducing some of the challenges that make IVF such an emotional rollercoaster for patients. It improves the efficiency of treatment and reduces the risk of certain negative outcomes, such as miscarriage and abnormal pregnancy.”

 

Prof. Peter Braude, Emeritus Professor of Obstetrics and Gynaecology, King’s College London, said:

“What a joy it is to read a such a well-designed truly multicentre multinational study of embryo aneuploidy screening (PGT-A) where the outcome is based on an intention to treat, and outcome measured by the only appropriate index that a patient cares about – live birth per cycle started. In this study, biopsy was undertaken at an early stage (polar body) where errors that might occur within the egg are most relevant – meiotic errors make up 90% of oocyte / embryo abnormalities, and is not susceptible to difficulties of diagnosis due to mosaicism (differences between individual cells within the embryo that may occur at later stages).  Cutting edge technology (aCGH) for the time (2012) was used, although those clinics uncomfortable with its highly relevant negative findings, will now no doubt blame the technology as outmoded in the face of newer more powerful genetic methods (next generation sequencing) and later stage (trophectoderm) biopsy.

“Nevertheless this was a well-designed pragmatic trial asking the simple question: for older patients (36-40y) within a clinic, and without changing any medication, does adding the significant cost and hazard of biopsy and genetic analysis for aneuploidy really make any difference to the likelihood of taking home a baby within a year – and the answer was no!

“Sadly for such older patients hoping to use IVF to overcome their infertility now, newer technology that is more expensive and less easy to interpret will be sold as a magic bullet without nearly such a thorough and carefully thought out study being undertaken.”

 

* ‘Preimplantation genetic testing for aneuploidy by microarray analysis of polar bodies in advanced maternal age: a randomized clinical trial’ by Willem Verpoest et al. was published in Human Reproduction  on Monday 6 August 2018.

 

All our previous output on this subject can be seen at this weblink: http://www.sciencemediacentre.org/tag/ivf/

 

Declared interests

Prof Darren Griffin: Prof Griffin has no direct financial interest in PGT-A but has in kind and small amounts of financial support for basic research projects from companies (iGenomix and Cooper) that do.

Prof. Alan Thornhill: “I am an employee of Igenomix UK.”

Prof. Ying Cheong: “I am the medical director for Complete Fertility in Southampton. Otherwise no conflict.”

Prof. Dagan Wells: “I have no conflict of interest relevant to this work. I am an Associate Professor at the NIHR Biomedical Research Centre at the University of Oxford. I also direct research at IVI-RMA Global.”

Prof. Peter Braude: “No conflicts of interest.”

None others received.

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