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Questioning PGS

The Center for Human Reproduction’s Dr. David H. Barad discusses preimplantation genetic screening (PGS), a procedure that’s becoming popular among IVF centers. Despite technical improvements, PGS still doesn’t make sense for a majority of patients, says Dr. Barad.

PGS means pre-implantation genetic screening. The notion of PGS is very seductive. We have observed in our patients as they aged that there were increasing genetic problems that could lead to failure of implantation. The notion of PGS is that if you have an array of embryos to choose from (that all look the same), doing a special test allows you to peek inside at the genetics to choose the perfect embryo to transfer without genetic problems. This has been around in several different forms over time and originally the screening was done on cleavage stage embryos using a technique that involved staining a few of the chromosomes and looking at them with fluorescence microscopes. There were problems with that process that made it hard to read how many chromosomes there were and as a result there were several papers published that showed doing the PTS didn’t improve pregnancy outcomes. The promise was there of picking out that perfect embryo, but in fact it didn’t work out when people looked at it empirically. The pregnancy rates were lower in people who were biopsied. The issue was that biopsying a cleavage stage embryo meant pulling one cell away, which at that point was 12 percent of the volume of the embryo, so you are taking a big piece of the embryo away and technical problems in doing the testing itself contributed to wrong diagnosis and possible damage to the embryo.

What’s done today is called a trophectoderm biopsy. You can think of that as a biopsy that’s done on a blastocyst, a five-day embryo, which looks like a little ball, and inside that ball is an inner cell mass that’s going to be the baby. The biopsy is done not on the inner cell mass, but on that outer part that is destined to be the placenta. And that’s why it is touted as being safer, because you are not biopsying the baby. The technical ways of testing those chromosomes have progressed over time so that they’re really highly accurate in telling you the genetics of the cells that have been biopsied. So we have a combination of something which is theoretically much safer and technically much more accurate, which should translate into a better test. But when you try to take that one-size-fits-all approach to the typical patient who comes to CHR (who may or may not produce more than 2, 3, or 4 embryos), the first problem is that most of our patients who have very few embryos may never even get to a stage that could be biopsied. Then, when you biopsy it, you aren’t testing the cells that are going to be the baby, you are testing the cells that are going to be the placenta.

Placenta is the repository of all the odd cells that pop up in the pregnancy that actually get segregated. The normal ones end up being the baby and the abnormal ones are being pushed out into the trophectoderm. Placental cells often have more than one nucleus, and so by definition they will have bizarre karyotypes if you are looking at their chromosomes. You can think of the trophectoderm as being more like a quilt than like a mosaic. Certain patches of the trophectoderm are probably descended from a particular cell. Even though you are testing four or five cells, they are probably all daughter cells of the same progenitor. And so there may be other cells that are normal that you are not testing, more like a patch in the mosaic – the technical term for an embryo that has set of genes is a mosaic. What that means is that the cells that you test may not reflect the genetic health of the inner-cell mass, which is going to be the baby. Now, many times they will. The centers that have been doing these studies have shown that when they have a normal result they are very likely to end up with a normal baby. However, the rub comes when you get an abnormal result, because the abnormal result may not reflect what’s true of the baby. In fact, one of the centers has recently published data where they looked carefully at the embryos that they had deemed to be abnormal and they found that 23% of the time, repeat biopsies didn’t show the same result as the original abnormal biopsy. This is that mosaic state. What happens over time is that the normal cells have a tendency to take over and to prevail. It’s very rare that the abnormal cells will grow out and actually become an ongoing pregnancy. The net effect is that when you are dealing with a group of patients who are very likely to have some degree of genetic abnormality (where those genetic abnormalities are segregated into the area that is going to be biopsied), what you end up with is a large number of people who start cycles and never have transfers. A large number, in fact – I think they have shown that 60-80% of patients in the age group that we usually take care of will never get to transfer. So what we’d rather do at CHR is not subject these embryos to the potential of damage by biopsy and give them a chance to prove themselves. The kinds of results that appear to be abnormal on the average PGS result are so bizarre that they wouldn’t become babies if they were true. So what you’re betting when you’re doing these transfers is that the result is wrong, because the wrong part of the embryo is biopsied and that the embryo will prove itself when you do the transfer. In fact, our pregnancy rates show that taking this approach and transferring the embryos gets us more pregnancies than the other centers would predict on a per cycle basis, just based on their findings.

CHR has written several editorials over the years about PGS and the essential message of those editorials is that PGS is not for everyone, especially not for the typical patient that comes to CHR. PGS is a way of selecting an embryo, but if you’ve already identified the embryos that you are willing to transfer, there is no point selecting among them. It is better not to damage an embryo and to transfer the embryo, give it an opportunity to implant and try to become a baby. And that is what we do. We would rather not do that biopsy. We’d rather give each embryo a chance to establish itself. Everybody who does PGS today recommends that their patients have amniocentesis anyway. No test is perfect. Our patients become pregnant, like those patients, they need to have amniocentesis. When they do PGS they’re taking embryos and saying, “we aren’t going to transfer them”. The fact is nobody gets pregnant if you don’t do a transfer and we would rather help our patients achieve their goal.