Chances are you probably have. Then when you realised that testing can cost between $3000 – $9000 on top of your IVF cycle costs1 put this idea on the back burner as quickly as you thought to Google it.
Finances aside, logically, it makes sense that preimplantation genetic screening (PGS) should increase live birth rates significantly –you are testing your embryos so that only those which are chromosomally normal are chosen for transfer and after all, how many times have you heard that chromosomal abnormalities are one of the major reasons that a lot of IVF transfers fail? A lot.
In reality, although some evidence does exist to support this logic, overall it is scarce and IVF live birth rates following PGS, can drastically differ depending on the stage of growth your embryo is at when tested, what laboratory technique is used and not to mention the issue of ‘mosaicism’ which just ads next level confusion to the situation.
Is it PGS or PGD?
Although the two terms are often used interchangeably and to be fair the actual procedure of PGS and PGD are very similar, there are some subtle differences between the two terms. PGS, or preimplantation genetic screening is, as the name suggests, a screen of embryos for couples who have known fertility problems to try and improve their IVF success rates. This is done by routinely checking the 23 chromosomal pairs in an attempt to ensure there are no abnormalities. PGD, or preimplantation genetic diagnosis is used typically for fertile couples who carry a chromosomal mutation for a particular disease or gene, such as muscular dystrophy or cystic fibrosis and want to ensure that these conditions are not passed on to their children. It is generally used to diagnose a particular condition that the parents are known to be carriers for.
Different approaches to PGS
PGS has been around for over 20 years now2 and over this time there have been several approaches1.
The first approach was to test cells obtained from the polar bodies of fertilised eggs. Unfortunately it was found that this method was not very accurate and often resulted in lower implantation rates and therefore was believed to not be a reliable predictor of pregnancy and birth rates3. Additionally, because it was less accurate, more samples ended up needing to be tested which again increased the cost.
The next approach was to remove one or two cells from the embryo when it was at cleavage stage (and therefore only had around eight cells to begin with). Embryos tested in this fashion showed no increase in live birth rates and at times reduced birth rates3. This was thought to occur due to the damage being down to such a young embryo4.
The third, and current approach that is most likely what your IVF clinic supports, is to take five to ten cells from the outer layer (or trophectoderm) of a day 5 or 6 blastocyst. By this stage the embryo has up to a couple of hundred cells and it is believed that taking these cells is unlikely to cause any damage.
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Once the cells are taken they are then analysed in a laboratory. There are several different techniques to do this which can differ from laboratory to laboratory. One of the newer ways by which testing is done is using Next Generation Sequencing which has shown promising clinical results3.
Evidence supporting the use of PGS
One recent meta-analysis3 examined the results from three random control trials looking at the cycles of 659 women and showed that PGS testing on blastocysts reported a higher implantation rate (implantation rate greater than 50%) and a higher ongoing pregnancy rate (over 45%). This means that for women testing their embryos at day 5 or 6 there is a 15 to 45% chance of increasing implantation rates and 21 to 60% chances of a higher ongoing pregnancy rate than by just choosing an embryo based on morphological information (or what it looks like when examining under the microscope).
This led the authors to recommend two things. Firstly, when transferring embryos chosen after PGS single transfers should be the standard of care (no more transferring multiple embryos) given the higher success rates.
The other conclusion authors came to was that for women with normal ovarian reserve it seems possible to achieve higher pregnancy rates by using PGS than just using standard IVF practices. It has been noted, however, that unfortunately it is generally not women of ‘normal ovarian reserve’ that most need this technology and more studies are required before it can be relied on to be a standard treatment for women of advanced age, those with low ovarian reserves, recurrent pregnancy losses or where the male partner as very low sperm count.
Per transfer versus cycle start success rates
Additionally, these results, although very promising, are only looking at success rates when there are day 5 and 6 embryos to transfer and test. Although the success rates are higher for women who PGS test and can do a day 5 or 6 transfer it does not take into account the women who may have started a cycle though did not have any embryos survive to day 5 or 6 to test and transfer. In this way the results are kind of skewed.
A 2016 article5 did address the potential confusion between ‘per transfer’ success rates and ‘per cycle starts’ success rates. Examining the 2011-2012 US data it was found that particularly for women under 37 years of age PGS was found to reduce the chances of a live birth in both transfer only reports (39% live birth rate for PGS tested embryos vs. 46% for non PGS tested) and per cycle start (25% for PGS vs. 29% without PGS). With miscarriage rates hovering around 14% for both PGS and non PGS embryos it was suggested by the authors that not only does PGS not improve IVF outcomes but actually negatively affects them in the clinical reality of the national US data. Interestingly, for women over 37 years of age PGS was found to have a significantly lower miscarriage rate (17% of PGS embryos miscarried vs 26% of non PGS tested embryos) and higher live birth rate per cycle start and embryo transfer. So this research suggests that PGS is a of benefit for those women aged 37 years and older.
Regardless of this review of the data (after all, it is not a randomised control trial, there is plenty of room for misinterpretation of data with even an article that published contradictory opinions when examining the same available data (Chang et al as cited in 5)) and all the potential conflicts in the current literature, if you had the money and thought it would mean an implantation rate of over 50% you’d still be keen though, right?
The concern is though as to the accuracy of PGS testing. It would be logical to assume that if you are told that your embryo was ‘normal’ or ‘abnormal’ than that is a pretty black and white issue. Either it has the accurate number of chromosomes and chromosomal arrangements or it doesn’t.
It seems it doesn’t necessarily work this way and that is due to ‘mosaicism’. Mosaicism occurs when the embryo can contain both normal and abnormal chromosomal arrangements in the cells that are tested. There is a very small but thought provoking pool of research that suggests that just because an embryo contains these abnormal cells it does not necessarily mean that the embryo itself will be ‘abnormal’ or wont correct itself.
The extent of the issue of mosaicism is documented in a 2016 article6. Medical staff working in an IVF clinic noticed that some women were having statistically improbable high numbers of abnormal embryos being reported after testing. This was especially in younger women, who you would expect to have a higher number of normal embryos. To cut a long-ish story short, after joining forces with other IVF Clinics who also noticed this trend, it led to the establishment of the ‘International PGS Consortium’ which was dedicated to investigating the effectiveness of PGS in IVF.
The consortium completed the following research6. Five women whose embryos underwent PGS and all their embryos were found to be ‘abnormal’ were allowed to transfer these abnormal embryos back into their uterus. That is, in the absence of any ‘normal’ embryos these women were allowed to have ‘abnormal’ embryos transferred to see if they would implant and result in a live birth. These are embryos that traditionally would have been discarded; however, from these five transfers three normal births were recorded. This trend was supported when in Italy 18 mosaic embryos (that is embryos with both normal and abnormal cells which would have been considered ‘abnormal’) were transferred which resulted in 6 chromosomally normal live births (that’s a 33% success rate for embryos that were deemed ‘abnormal’). As of the 2016 article, only 26 women with fertility problems worldwide received allegedly PGS tested abnormal embryos. This resulted in 11 chromosomally normal live births/ ongoing pregnancies and no miscarriages.
Although this is obviously only a very, very small sample size and is not the gold standard of a randomised control trial (which, to be fair, would be very difficult if not impossible to do) it does highlight doubts as to the accuracy and relevance of PGS testing. Especially for women who otherwise would have no ‘normal’ embryos to transfer. Should these women be allowed to take a chance on questionable embryos? And does taking a few cells from the outside layer of the embryo provide enough of an accurate measure to reveal what is happening inside the embryo?6
This concern was supported when the same researchers completed another study on 11 donated embryos that were deemed ‘abnormal’ and would have been discarded. Sending the embryos to another laboratory to be retested, researchers found that only 2 out of 11 embryos had the same reports across the two laboratories6. 4 out of 11 embryos that were previously reported as abnormal were now, normal and 2 out of 11 were now reported as being mosaic, having at least one normal fragment and hence a chance of a successful outcome. What is even more concerning is that even the gender identified varied between the two laboratories. Again, these results are only a very, very small sample size and is NOT statistically significant but does suggest a false positive rate for PGS as high as 55%6.
55% does seem extraordinarily high and some laboratories claim an accuracy rate of 99%. Quite a discrepancy. This 99% accuracy rate however, is thought to reflect accuracy in a clinical validation study and not necessarily the accuracy in true clinical matters that actually happen on a day to day basis in women doing IVF. Some estimates of the actual misdiagnosis rate sit around 5%4.
Time to Change?
To take into account the phenomenon of mosaicism, instead of reporting embryos as being euploid or aneuploid, or normal or abnormal, it has been suggested that embryos with less than 20% mosaicism are reported ‘normal’ and those over 80% mosaicism are reported as ‘abnormal’. This leaves those in the 20 – 80% as mosaic and depending on the advice and recommendations of the IVF Clinic, in the absence of any normal embryos potentially a consideration for transfer. Obviously though, this suggests radical change as previously any abnormality was discarded2.
Putting it together
For some women, typically those who have a good IVF prognosis anyway, with normal ovarian reserve and the funds to do so, PGS testing could very well be a reliable and valid way forward. Particularly for those who have been on the IVF ‘journey’ for a considerable time and want to give themselves the very best chance of a live birth per transfer.
For others though, there is the need to stop and think. This is particularly for those who get a high number of ‘abnormal’ results and for those who are of advanced maternal age or who are unable to grow embryos to day 5.
The cost per birth for an IVF PGS cycle is estimated at being $45,3007. So whilst some of the evidence is promising it isn’t without its critics and until further evidence can be produced that supports a significant increase in live birth rates, you might be better off redirecting some that money into another IVF cycle. Or not. There is no clear cut answer and only through careful conversation and discussion with your fertility specialist regarding your individual situation can a decision be made as to if PGS is for you.
- Twisk, M., Mastenbroek, S., van Wely, M., Heineman, M.J., Van der Veen, F. and Repping, S. (2006) Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection. Cochrane Database of Systematic Reviews 2006, 1. Art. No.: CD005291.DOI: 10.1002/14651858.CD005291.pub2.
- Gleicher, N. and Orvieto, R. (2017). Is the hypothesis of preimplantation genetic screening (PGS) still supportable? A review. Journal of Ovarian Research 10 (21). DOI 10.1186/s13048-017-0318-3
- Dahdouh, E., Balayla, J. and García-Velasco, J.A. (2015). Comprehensive chromosome screening improves embryo selection: a meta-analysis. Fertility and Sterility 104(6) 1503 – 1512.
- Brezina, P., Kutteh, W., Bailey, A. and Ke, R. (2016). Preimplantation genetic screening (PGS) is an excellent tool but not perfect: a guide to counselling patients considering PGS. Fertility and Sterility Reflections 105(1) 49 – 50.
- Kushnir, V., Darmon, S., Albertini, D., Barad, D. and Gleicher, N. (2016). Effectiveness of in vitro fertilization with preimplantation genetic screening: a reanalysis of United States assisted reproductive technology data 2011–2012. Fertility and Sterility 106 (1) 75–79.
- Gleicher, N., Vidali, A., Braverman, J., Kushnir, V., Barad, D., Hudson, C., Wu, Y.G., Zhang, L., Alberini, D. and the International PGS Consortium Study Group (2016). Accuracy of preimplantation genetic screening (PGS) is compromised by degree of mosaicism of human embryo. Reproductive Biology and Endocrinology 14(54). DOI 10.1186/s12958-016-0193-3
- Murugappan, G., Ohno, M., Lathi, R. (2015). Cost effectiveness of preimplantation genetic screening and in vitro fertilisation versus expectant management in patients with unexplained recurrent pregnancy loss. Fertility and Sterility 103 (5) 1215 – 1220.