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Preimplantation genetic screening reduces both ongoing pregnancy and live birth rates in women over 35

Press releases ESHRE 2007

05 July 2007

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Lyon, France:  Preimplantation genetic screening (PGS), often considered to hold out the best chance for older women undergoing IVF to have a pregnancy and birth, does not increase on-going pregnancy or live birth rates, an embryologist told the 23rd annual conference of the European Society of Human Reproduction and Embryology today (Wednesday 4 July).   The research is published simultaneously in the New England Journal of Medicine*.  Sebastiaan Mastenbroek, M.Sc, from the Centre for Reproductive Medicine of the Academic Medical Centre of the University of Amsterdam, The Netherlands, said that the results of his team’s research suggested that PGS should not be carried out routinely in women of advanced maternal age.
 
In a randomised double-blind trial, the team compared three cycles of IVF with and without PGS in women from35 to 41 years of age.   Of the 408 women, 206 of whom were given PGS and 202 were not, the ongoing pregnancy rate was considerably lower in the PGS group than in those who did not have PGS.   “We found that, at 12 weeks, 52 or 25% of the women in the PGS group were pregnant, whereas 74 or 37% of the control group had an ongoing pregnancy”, said Mr. Mastenbroek.   “And the women in the PGS group also had a significantly lower live birth rate – 49 or 24% as opposed to 71 or 35% of the controls.”
 
The investigators believe that there may be a number of explanations for the failure of PGS to improve IVF outcomes in older women.  “It is possible that the biopsy of a cell from an early embryo on day 3 after conception hampers the potential of an embryo to successfully implant”, said Mr. Mastenbroek, “though the effect of biopsy alone on pregnancy rates has not been studied.”
                                
Furthermore, say the investigators, the limitation on the number of chromosomes that can be analysed could lead to the transfer of embryos that appear normal but are in fact abnormal for one or more chromosomes not tested.   Finally, many embryos resulting from IVF may be mosaic, where a single cell does not properly reflect the chromosomal composition of the whole, so that chromosomal analysis may not be representative of the entire embryo.
 
PGS is a relatively new technique that is in increasing use in IVF centres around the world.  In 2003, more than 1700 IVF cycles with PGS for various indications were reported to the ESHRE preimplantation genetic diagnosis (ESHRE-PGD) consortium.   This figure under-estimates the total number of IVF/PGD cycles, since only 50 centres worldwide reported their data to the consortium.   “In a recent survey of 415 assisted reproductive technology clinics in the US, 186 respondents (45%) reported that they had performed a total of 2197 cycles of PGS in 2005”, said Mr. Mastenbroek.
 
The investigators are currently following up their work by investigating why PGS does not work.    Even though evidence underpinning the effectiveness of PGS was lacking until now, patients as well as doctors were attracted to this technique.   The idea of screening embryos for chromosomal abnormalities to increase live birth rates in IVF is very plausible, and women of advanced maternal age are willing to undergo any technique that may provide them with a baby”, said Mr. Mastenbroek.
 
“Our study was limited to older women undergoing PGS.  We believe that our findings imply that the efficacy of the technique also needs to be investigated in other groups of women who are offered PGS, such as those who suffer recurrent miscarriage or repeated failure of IVF, since evidence for a benefit of PGS in these groups of women is currently still lacking”, he said.

http://www.eshre.com/emc.asp?pageId=947

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Date Added: 05 July 2007   Date Updated: 05 July 2007
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Jacques Cohen   10 July 2007

On Friday, 6 July, 2007, the New England Journal of Medicine (NEJM) published a study by Mastenbroek and co-workers, describing the results of a collaborative randomized clinical trial of PGS (Preimplantation Genetic Screening) that was recently conducted in The Netherlands. The study purports that PGD for infertility or advanced maternal age (AMA) is not just ineffective but detrimental to pregnancy outcome. We would like to make you aware of several serious flaws in this work. A primary concern is that PGD was performed by groups with little or no previous experience with or knowledge of this multifaceted and complex technology. As such, the study was designed without consideration of previously published crucial details in methodology that can determine success or failure of PGD. By Reprogenetics' standards, aspects of biopsy, fixation, patient selection and FISH as described in this Dutch study were not optimized for success but for inevitable failure. In a significant number of cases (>50), the authors decided to transfer embryos that were biopsied but had no result or diagnosis; this is quite disconcerting not only because of the questionable medical decision, but because the test failed in 20% of all embryos biopsied an extraordinarily high proportion compared to previously published data by others, including Reprogenetics (less than 5%). The authors point to "biopsy failure" having occurred in 2.8% and "incomplete nucleus" in 4.9% of embryos. Yet such categories are non-existent in experienced PGD laboratories such as Reprogenetics and only reflect poor biopsy and fixation techniques used by these inexperienced groups. Once undiagnosed embryos were transferred, these embryos showed a poor implantation rate of 6%. This figure was significantly lower than the implantation rate for embryos that were diagnosed as 'normal' (16.8%) or embryos that were in the control arm of the study and were not biopsied (14.7%). This discrepancy demonstrates that the biopsy procedure as was performed at the participating clinics in the trial was detrimental to embryo viability and reduced the implantation potential of the embryos by as much as 59%. The authors do not mention this correlation. Obviously, even when only normal embryos were replaced, the selection advantage of PGD could not compensate in excess for a 59% loss in implantation potential. If damage was reduced to an acceptable range, it could have probably shown that PGD is beneficial. Indeed, if such a tremendous reduction in viability actually were to occur in PGD for AMA, one could reconsider not only PGD for AMA, but all other applications of PGD, including those that the authors of the study consider clinically useful and necessary. But in fact, such a reduction in viability is unprecedented in the PGD literature and is an observation unique to the centers involved in this trial. Even in cryopreservation models estimating the impact of blastomere loss such detrimental effects on viability have never been reported. Regarding the FISH procedure, no data on error rates were presented and no attempt was made to correct for unclear or missing results - as is routinely done in Reprogenetics laboratories. Moreover, the chromosome panel did not include probes for chromosomes 15 and 22 while it is known that these two chromosomes account for more than 10% of abnormalities in cleavage stage embryos. The patients were selected from a population of 35-41 year old women with infertility, however, the majority of these patients had fewer than 6 embryos. Our published data clearly show that the efficacy of PGD for AMA is reduced in such patients. In summary, a careful evaluation of the study by Mastenbroek and co-workers indicates that very poor biopsy technique, suboptimal fixation and FISH methods, and inappropriate patient selection rather than problems inherent to PGD are to blame for the poor results obtained in the Dutch study. You can contact us for more information by calling Laurie Ferrara, Client Services Associate, at 973-436-5013 or emailing Jacques Cohen at


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