Melanie Cole (Host): The increased use of pre-implantation genetic screening in recent years has resulted in improved outcomes for couples with infertility who are going through IVF, however several studies have shown that overall about 50% of human pre-implantation embryos from IVF can be chromosomally abnormal, but what does that even mean for IV and fertility treatments? My guest today is Dr. William Ziegler. He's a specialist in reproductive endocrinology and infertility, and he's the Medical Director of the Reproductive Science Center of New Jersey. Dr. Ziegler, tell us a little bit about mosaicism. What is it?

Dr. William Ziegler, MD (Guest): Mosaicism is where an embryo has two or more cell lines within the embryo itself. We do know that the genes do split as the embryo grows, however if the genes do not split normally, then it can result in two different cell lines or even more within one embryo.

Melanie: Do we know what causes it?

Dr. Ziegler: We know that there are more genetic abnormalities as a woman gets older, however mosaicism doesn't appear to be affected by maternal age.

Melanie: So is this a pretty common situation?

Dr. Ziegler: Well prior data has shown us that the clinical incidents of mosaicism is around 10% to 20%. However, with the new technology which is called Next Generation Sequencing, which is how we are testing embryos currently, we're finding out that when we biopsy blastocysts, which are day five embryos, we do remove anywhere between five to ten cells, and we're finding that those blastocysts- that number is probably higher. It's more in the area of around 20% to 30% of all embryos have mosaicism.

Melanie: So what type of conditions are caused by mosaicism?

Dr. Ziegler: That's a very interesting question. We know that mosaicism, depending on when the genes undergo abnormal separation, or the chromosomes undergo abnormal separation, that leads to how much mosaicism is in an embryo. When we test an embryo, we look at a percentage of the cells that are genetically abnormal. And that is where, again, we biopsy let's say ten cells, and out of those ten cells, if only two of them are abnormal, then we say 20% mosaic. If there's eight of them are abnormal, then 80%.

So we actually break down the embryos into how much mosaicism there is, whether it's low level mosaicism, which is anywhere between 20% to 40%, or high level mosaicism, which is higher than 40%. So that- we know  that can lead to miscarriages. We do know that it can lead to implantation failures, but the long-term or the effect that this would have on a child's development as well as affecting their adulthood, we really do not have that data.

Melanie: This is such an interesting topic, Dr. Ziegler. How does it relate to fertility? Or these embryos, does it predict them to be a mix of normal and abnormal? Tell us how this relates to what you do for a living.

Dr. Ziegler: Well it really comes down to there have been marked advances in pre-implantation genetic analyses that now with this next gen sequencing we are now able to detect this mosaicism that we were not able to detect before. And where it really comes down to is we've been probably transferring mosaic embryos for years and not know it.

In this situation, it's really affecting those patients that when we do pre-implantation genetic testing, and the report we get back is either euploid, meaning it has no abnormal genetic defects, or it is totally abnormal which is called aneuploid. But the mosaic, that's kind of the gray area. Sometimes we have patients that only have low level mosaic embryo. Then the question comes down is whether or not we're able to transfer them.

There does appear to be a consensus that you should not transfer high level mosaic or complex abnormality as well as those embryos that are truly aneuploid or totally abnormal. When we talk about low level mosaic embryos, they do have a lower pregnancy rate than transferring a totally normal genetic embryo. However, low level mosaic embryos can result in a good pregnancy. There are studies that have shown that those abnormal cells do drop to the wayside and they're not present at the time a child is born or when there's an amniocentesis they cannot detect those cells.

So that is the area that has really affected us is when you're sitting in front of a patient and they went through pre-implantation genetic testing just because they want to make sure or maximize their chances to have a genetically normal embryo or normal child and they only have low mosaic embryos, transferring them or not transferring them, that is the big discussion. And a lot of times patients will say, "Okay, yes let's give it a shot," or, "No, we want to try this again and see if we can get normal embryos." So it really puts the patient in an awkward situation as well as us and then as the provider.

Melanie: So speak a little bit about the pre-implantation genetics screening. What is it? How do you detect this mosaicism?

Dr. Ziegler: Well basically we create embryos and we grow them out to the blastocyst stage, and then what we do is we pull off, like I mentioned before, five to ten cells, and we take them off from what's called the trophectoderm, which is ultimately going to become the placenta. Inside the embryo, you have an outer cell layer which, as I mentioned before, becomes the placenta, and then you have the inner cell layer that actually becomes the baby. So we don't touch the inner cell mass, we only retake cells from the outer cell mass, and then they are analyzed. And based on the amount that are normal or abnormal comes back to us and then with a report of which embryos fall into which classification.

Melanie: Who needs to have this testing? Is it regularly done as a screening now? Is there any downside to it?

Dr. Ziegler: The patients that this technology is really indicated for are those that have had prior pregnancies that were genetically abnormal, those that have had multiple pregnancy losses and we can't find another cause for that, or there's been studies out that are showing women who are over the age of thirty-eight, it does increase the chances for having a healthy pregnancy and have a healthy baby.

The downside to this is, as I mentioned before with the mosaicism, that we don't know the long-term effects of transferring a mosaic embryo, and that's kind of the big question mark at this point.

Melanie: So as that's the big question mark, what do you say to the patients? And what do you do with the mosaic embryos created during IVF? How do you discuss this with the patients?

Dr. Ziegler: Well we let them know that low level mosaic embryos, as I mentioned before, if that's all they have, they can result in a healthy pregnancy and a healthy baby. However once they are transferred, they do need to be monitored by their obstetrician, and possibly even having chorionic villi sampling or having an amniocentesis just to verify that those cells have dropped to the wayside, or if they have become more evident, then they're counseled accordingly.

All of our patients that undergo pre-implantation genetic testing, they are given the opportunity to talk with a genetic counselor prior to the procedure and even discuss the results after the procedure. So we do have a specialist that they can talk to, and they can get as much information as they want concerning their results.

Melanie: Doctor, why is this controversial?

Dr. Ziegler: Because as I mentioned before, we do not know- there are not details of the outcome of these babies long-term. So that's why this is a controversial area. Also that we have to inform our patients that we'll be transferring embryos that are not totally genetically normal. So they have to be prepared that they could have decreased implantation rates, they may have increased miscarriage rates. But we also have to take a look at the glass half full, that it can result in live birth.

Melanie: So wrap it up for us, because this is a really fascinating topic, in what you want the listeners to take away from this message of pre-implantation genetic screening and mosaicism and what you want them to know if they start to educate themselves as they're looking at IVF.

Dr. Ziegler: In proceeding with the in vitro fertilization process, many of our patients want to get the highest- all patients want the highest success rate. However keep in mind that the technology out there is not foolproof. That even though you have genetic testing, that doesn’t mean that it's going to definitely increase your pregnancy rate. And also keep in mind that even though an embryo may not be genetically totally normal, that if it is low mosaic, and that's all the embryos in which you have, you could consider transferring it- transferring those embryos, however you would need to be monitored very closely.

And also I would recommend in looking at pre-implantation genetic testing, have a discussion with your provider as well as with a genetic counselor of what is the benefit of this technology. This technology is not used for everybody, and should not be offered to everybody unless it is indicated in your specific situation. This procedure is quite expensive if it's coming out of pocket. So you want to make sure that you're going to benefit from this technology, because if you're not, then you're just wasting your money.

Melanie: Thank you so much for explaining that for us today, Dr. Ziegler, and sharing your expertise. And it's such an important message for people to hear about being their own best health advocate when they're looking at IVF, so thank you so much for being with us. This is Fertility Talk with RSCNJ, the Reproductive Science Center of New Jersey. For more information please visit www.FertilityNJ.com. That's www.FertilityNJ.com. This is Melanie Cole, thanks so much for listening.