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PGS: It ain't what you do it's the way that you do it...and that's what gets results

17 July 2007
By Dr Alan Thornhill
Scientific Director; Mr Laurence Shaw, Deputy Medical Director; Professor Gedis Grudzinskas, Medical Director; Professor Alan Handyside, Director, The London Bridge Fertility, Gynaecology and Genetics Centre
Appeared in BioNews 416
Embryo selection following cleavage stage embryo biopsy and chromosome analysis to identify aneuploid embryos(those which have an abnormal number of chromosomes) in every couple having IVF/ICSI or all women of advanced maternal age is rightly considered by most clinics to be too invasive and potentially damaging for routine use. The well-executed clinical trial carried out by Mastenbroek et al (1), reported in last week's BioNews, confirms this expectation and is valuable in quantifying the negative effect of using PGS (preimplantation genetic screening) for aneuploidy routinely for all women over 35 on pregnancy and live birth rates. Nevertheless, for some women in their late 30s and early 40s, a high incidence of aneuploidy is clearly a major factor contributing to pregnancy failure, suggesting that the level of aneuploidy risk varies between patients.

At our centre, PGS is targeted to women with previous failed IVF cycles, miscarriage or termination of an abnormal pregnancy and, importantly, the single cell test is followed up by analysis of the abnormal embryos to confirm that patients are at medium or high risk. Even with the current test limitations, detailed follow up of developmental and chromosomal abnormalities in embryos is an extremely powerful way of assessing risk for some patients. PGS should be considered a diagnostic procedure incorporating confirmatory molecular cytogenetic analysis of any screened embryos remaining after transfer. Confirmatory analysis provides quality assurance, an assessment of true aneuploidy risk and a detailed assessment of a patient's future prospects Including clinical closure in some cases.

The results of the trial will certainly have come as a shock to some and perhaps vindication to others. However, the results were not entirely surprising to us. Essentially, there are two main reasons for the poorer results in the PGS treatment group: (i) embryo biopsy and (ii) false positive results due to chromosomal mosaicism (the situation in which the genetic make-up of a single cell may not reflect that of all the cells in the embryo). Clearly embryo biopsy is invasive and can compromise embryo development particularly when applied to embryos with already compromised development. There are question marks surrounding the efficacy of embryo biopsy in the hands of the centres involved in the trial since biopsied embryos with no result that were transferred showed a much reduced implantation rate compared with non-biopsied embryos. Embryo biopsy is therefore only justifiable when the benefit of testing outweighs the cost to the embryo. With respect to chromosomal mosaicism, our experience shows that the incidence of false positives decreases as the embryos are more at risk of aneuploidy. It follows that routine application of PGS, irrespective of a priori aneuploidy risk, will result in more unwanted false positive results and is clearly inappropriate. Since no follow-up analysis of embryos was reported, it is impossible to establish the actual aneuploidy risk for the patients and the accuracy of the PGS test used in the trial (both of which are critical when considering the efficacy of PGS).

Leaving these criticisms aside, there is a clear message from this trial about the futility of indiscriminate application of PGS for advanced maternal age. However, it is irresponsible to say categorically that PGS has no clinical benefit. This is simply not our experience and may deprive high-risk patients of treatment they need. Indeed, this trial has confirmed our belief that, to be effective, PGS must tip the cost-benefit ratio towards benefit by providing safer biopsy (2), more accurate and comprehensive chromosome analysis (3) and most importantly, targeted application to high risk groups (4,5).

The incidence of uniform chromosome abnormalities increases dramatically in the embryos of some women in their late 30s and 40s. and, even for the limited number of chromosomes we can detect currently, averages 40 per cent and, in some cases, can affect all embryos. In such cases, the result of PGS is safer IVF. Furthermore, we now believe that it would be irresponsible not to offer PGS, to the full extent of our ability to do so, to patients we know or can show are at high-risk. While we have the technology to identify aneuploidy to transfer unscreened potentially aneuploid embryos is not acceptable. Safer IVF, wherever and whenever possible, is and should remain our primary objective.

SOURCES & REFERENCES
1) Mastenbroek S, Twisk M, van Echten-Arends J, et al. In vitro fertilization with preimplantation genetic screening
N Engl J Med. 2007;357(1):9-17 | 
2) Cohen J, Wells D, Munne S. Removal of 2 cells from cleavage stage embryos is likely to reduce the efficacy of chromosomal tests that are used to enhance implantation rates
Fertil Steril. 2007; 87(3):496-503 | 
3) Le Caignec C, Spits C, Sermon K et al. Single-cell chromosomal imbalances detection by array CGH
Nucleic Acid Res. 2006; 34(9): e68 | 
4) Mantzouratou A, Mania A, Fragouli E, et al. Variable aneuploidy mechanisms in embryos from couples with poor reproductive histories undergoing preimplantation genetic screening
Hum Reprod. 2007;22(7):1844-53 | 
5) Steuerwald N, Bermudez M, Wells D, Munne S, Cohen J. Maternal age-related differential global expression profiles observed in human oocytes
Reprod. Biomed. Online 2007;14: 700-708 | 
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