“How Could PGT Be So Wrong?” – When the Problem Isn’t the Test, It’s the Interpretation

Can embryos labeled as “abnormal” still lead to healthy babies? Are fertility clinics discarding embryos that could result in a pregnancy?

In this episode of Taco Bout Fertility Tuesday, Dr. Mark Amols breaks down the controversy surrounding Preimplantation Genetic Testing for Aneuploidy (PGT-A). You’ve seen the headlines — abnormal embryos resulting in live births — but was the test actually wrong, or was it the interpretation?

Learn the truth behind PGT-A and mosaicism, the evolution of embryo testing methods (FISH, aCGH, SNP, and NGS), and what the latest data says about success rates when transferring embryos diagnosed as aneuploid.

Whether you're trying to understand your PGT-A results, deciding whether to transfer a mosaic embryo, or just looking for clarity in a confusing area of IVF science, this episode is your guide.

🎯 What You’ll Learn:

• The difference between aneuploid and mosaic embryos
• Why older tests misclassified embryos
• How NGS changed the game in embryo testing
• What prospective studies show about live birth outcomes
• Whether you should worry about throwing away viable embryos

Tune in to get the facts, ease your fears, and feel empowered in your fertility journey.

Thanks for tuning in to another episode of 'Taco Bout Fertility Tuesday' with Dr. Mark Amols. If you found this episode insightful, please share it with friends and family who might benefit from our discussion. Remember, your feedback is invaluable to us – leave us a review on Apple Podcasts, Spotify, or your preferred listening platform.

Stay connected with us for updates and fertility tips – follow us on Facebook. For more resources and information, visit our website at www.NewDirectionFertility.com.

Have a question or a topic you'd like us to cover? We'd love to hear from you! Reach out to us at TBFT@NewDirectionFertility.com.

Join us next Tuesday for more discussions on fertility, where we blend medical expertise with a touch of humor to make complex topics accessible and engaging. Until then, keep the conversation going and remember: understanding your fertility is a journey we're on together.

Transcript

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Today we talk about how could PGT be so wrong? I'm, Dr. Mark Amols and this is Taco about Fertility Tuesday. Today we're talking about a topic that causes a lot of confusion and sometimes unnecessary fear. Preimlantation genetic testing for anapodyy, also known as pgta. Specifically why it seems like some embryos labeled as abnormal have gone on to have healthy babies. You may have seen the headlines or heard stories claiming that PGTA was so wrong at these so called abnormal, embryos led to live births. So what gives? Was PGTA actually wrong or was the data just misunderstood? Well, let's dive in this episode and learn a little bit more about this. To truly understand this podcast, we're going to have to define some terms. An anaploid embryo has the wrong number of chromosomes in all of its cells, and these are almost always incompatible with a healthy pregnancy. A mosaic embryo, on the other hand, has a mix. Some normal, some abnormal cells. Think of it like baking a batch of cookies. You mix everything together. But if a few pockets have too much salt or not enough sugar, some mites will taste great, while others might be slightly off. The ingredients are all there, but not evenly distributed. That's mosaiism. Some cells are normal, others aren't. All depending on how things were mixed in the early stages of development. Now, I'm simplifying this a bit, because true mosaicism can be everywhere. Where all the cells in the human body can have mosaic DNA, where some of the DNA is normal and some of the DNA is abnormal, like mosaic turners. There are other situations where you can have mosaic, where the placenta has one type of DNA and then in the embryo it's different. The point is, when you look at a mosaic embryo, you almost have to think of it having three states. The first state would be a completely normal embryo, but when they took the biopsy, they got some abnormal cells and so it looks like the embryo is mosaic. The other state would be if the embryo abnormal. And when they took the biopsy, they got some normal cells and now the embryo looks mosaic. And then the third state would be a truly mosaic embryo where every cell in the embryo has the mosaic DNA. Now, over the years, PGT has evolved. In the very beginning we used what's called fish fluorescent in Sittu hybridization. And that is not really used anymore because basically what they would do is you would take a probe that would then go to the chromosomes and attach and then it would light up with a certain color and would let you know if something is There is not. That methodology cannot detect roaicism. After that came array cgh, which stands for array Comparative Genomic hybridization. Much better than fish, but had a low sensitivity to detect mosaicism, especially any type of osaicism thats under 40%. So a lot of things were called abnormal, meaning anaploid, even though it might have had mosaicism. Part of the issue with this method is it could not quantify the portion of abnormal cells. So it was more of like a it'either there or not there type of readout. SNP arrays that came around were a little bit better than array CGH at detectiveonaiitn but they still struggled with quantifying the percentage of abnormal cells. This means that some embryos were called abnormal mean and deployed when in reality they could have been normal. Then came NGS next generation sequencing. This is now the gold standard for mosaicism. It can detect and quantify the mosaic system down to about 20 to 30%. There are times it can even be lower with certain platforms. Now labs take that gradient and say okay, if it's under 20% abnormal then they're going to call it upoid. If it's 20 to 40% abnormal, they call it low level mosaic, 40 to 80% high level mosaic. And if over 80% of the cells show anaploidy then they call it anaploid. But the question is how did they get to this state? When did someone start calling them mosaic? When? Before it was either euloid or unemloed? Well before 2015 everything just got lumped into Andloyed. In 2015 there were some reports that some embryos labeled as antaploed by PGTA still led to healthy birds. That sounds amazing, right? But when those embr were actually analyzed closely, what they found was they were actually mosaic embryos and not truly anemloed. The problem wasnt the test, it was that the mosaic system wasnt fully recognized and was reported at that time as being unemoyed, even though it was incorrect. Now what you will hear is people will say oh yes, your abnormal embryos will lead to live births. But this was based on studies in the past that looked at embryos that were lumped into anaploid even though they weren't anaploid, they were mosaic. So now we fast forward to today and now we have much better data, especially from large blinded studies. One of the most striking studies looked at over 100 embryos labeled as truly antapodied using modern next day generation sequencing found that not one of them led to a Live birth. Now, somei implanted and may even started to go into heartbeat, or something like that. But then eventually it failed. It had zero percent sustained success. Now this study was really important because what it did was, is they tested all of the embryos with pgta, but they didn't look at the results. And then they went and they transferred this into patients and then later unblinded the results to find out which embryos were euloid, which ones were unaploid, which ones were mosaic, and what happened. And in that study, none of them that were anaploid led to a live birth. Now if you compare that the mosaic embryos, which, depending on the degree of the mosaic system, some did leave the liveerss 30 to 50% of the time. So what this tells us is the misclassified embryos as anaploid instead of mosaic is what led to in the past abnormal embryos becoming live birth. Now, it's important to understand it's not that they were wrong, it's just at that time we didn't realize this methods like array, CGH and snip arrays didn't have the resolution to detect mosaicism very well. So unfortunately these were called abnormal, being anemloed and were not transferred. When next gen sequencing came around, it changed the game. It can detect these subtle ships and give a much more accurate picture. So we can determine if the embryo might just have a couple abnormal cells in it versus the whole embryo being abnormal. And it's not stopping there. Matter of fact, Cooper Genomics has gone even further recently. They now preserve the original DNA rather than just making copies of the DNA. So when you get the sample, you have to amplify it with whole genome amplification, but you keep making copies of copies. So now they have a technique that actually uses the original DNA, which then lowers the noise in the data so you can get better resolution. They also now are integrating SNPs into the analysis, which then allows them to look at other things such as copy number so they can rulel out conditions like triploidy and to detect uniportal disysamey. This is when both copies of the DNA came from the same parent. So it looks like both came from one from the mom and one from the dad, but in this situation it's from the same parent. Now it's important to understand that adding the SNPs doesn't really directly improve the most sacism detection, but it does help route those other conditions. The point is we haven't stopped looking and we're always trying to get better. So here's the kicker. Even with next Gen sequencing, we can't reliably detectostaicism, below about 20%. And the question is why? Well, we're only sampling a few cells, five to ten cells at most. And Emboryo has hundreds of cells. So if you biopsy five cells and one cell is abnormal, that's only 20%. And this is the problem. We expect it to be uniform throughout, but it's not. We wish it was reflective of the whole embryo, but we know it can't always be. It would be like taking one bite of a great taco and you think that's going to represent the whole taco. But, on that bite, they messed up. I put too much sour cream and guac on one side, barely any meat, and you're like, this is disgusting. But what you don't know is the rest of that taco is amazing. Unfortunately, it wasn't distributed and your biopsy was only a small portion of the entire taco. So the sampling of a few cells like that is not reflective of the whole picture. Add to that the noise that's introduced by DNA amplification. Noise is when you have all this data, it's all over the place and you have to eventually smooth it out. If there are too many outliers in the data, then you can't utilize the data. But there are some outliers and usually what happens is those are kind of thrown out. But if it becomes too noisy, you can't distinguish the actual DNA from the noise. Think of it as technical background noise. So the 20% is kind of the limit currently that people believe in because they feel that has a good representation of not tossing to my embryos, but not overalling as well. And this brings us to one of the biggest points. Patient fear. What if we'discarding healthy embryos because of pgta? Well, heres the reassuring truth. The likelihood of discarding a, truly healthy embryo labeled as anaploidy is extremely low. Modern PGTA is very accurate. If your embryo is labeled as anapoyid by NGS and confirm not to be mosaic, the chance of resulting in a healthy baby are, near zero. There are multiple prospective studies that confirm this now. So how could it be so wrong? In the past, because there were some early missislassifications. But now that we understand mosaicism, the technology and reporting have caught up. Your clinic should be differentiating between mosaic, segmental and full anapoy. And if they are, you can feel pretty Reassured that the likelihood of discarding a truly healthy embryo is near zero. This doesn'mean things may not get better. We may learn things even later. But the one part we do know is when you look at blinded testing where they didn't know whether the was normal or not, they did not see live birds with the truly full anemloidy embryos. So back to the main question. How could PGT be so wrong? The answer is it wasn't. The test wasn't flawed. The interpretation was. When we saw anaploed labeled embryos led to libie bir we thought we had proof that PGT was wrong. But what we really had were, mosaic embryos hiding in plain sight. We thought they were abnormal leading to live birth, but they were never abnormal to begin with. Like all tools, PGTA is powerful, but it needs to be used and understood properly. Now that we know how to interpret mosaiism, we're better than ever identifying embryos that have a true shot becoming your healthy baby. So trust the process, but always ask questions. Make sure your clinic is using the most up to date methods and language when it comes to categorizing embryos. And the reason for that is if they are not categorizing the embryos correctly, then yes, it is possible that you are throwing away embryos that could lead to a live birth. If they are being called anaploid and they are actually mosaic embryos. Maybe youe re like a lot of people who have been wondering for some time, am I throwing away normal embryos? Maybe if you've been in those fors where people say, oh, I've heard of people getting pregnant with anaploid embryos. But now you know, you don't have to be as fearful because what the studies show is, is that if you look at mosaicism and you're putting back full anaploid embryos, it's not going to lead to a live birth. Sure, there might be one case every once in a blue moon that may happen, but that is the outlier and that is the rarity. When I say rarity, I mean saying almost zero. If you hear someone getting pregnant with an abnormal embryo, there's a good chance it wasn't abnormal, but that was classified wrong. And you should feel confident that you're not throwing away healthy embryos as long as your clinic is classifying both euloid andlooid and mosaic embryos. I think this is a really important topic and I really hope you pass this along to other people. I think there's a lot of misinformation out there about how PGT can be wrong. And I agree that there might be the appearance of it being wrong. But as you heard in this podcast, it's not that PGT was wrong, it's how it was interpreted. If you liked this episode, please share it with a friend. And as I always say, if you like the show, give us a five star review on your favorite medium. But most of all, keep coming back. I look forward to talking you again next week on Talk About Fertility Tuesday.