During this event, Dr Alan Thornhill, Fertility Expert & Coach, and Founder of The Fertility Guy discussed what is Preimplantation Genetic Testing for Aneuploidy (PGT-A), how it works, its benefits and limitations, who should consider it, and why.
What is PGT-A? It stands for pre-implantation genetic testing for aneuploidy, a relatively new terminology or naming system. It used to be called PGS, pre-implantation genetic screening. In a sense, it still is a kind of screening test, but now the term PGT is used for any embryo testing, with another letter indicating the specific test.
Pre-implantation refers to the stage before an embryo implants in the body. It’s a genetic test focusing on chromosomes—the way genes are packaged. It’s a test, but it’s not considered a diagnostic test; it’s more of a screening test. The term “aneuploidy” (or another phrase like “chromosome abnormality”) is used. However, the test doesn’t specifically look at female age-related aneuploidy. Typically, it’s due to having an older egg from an older patient. Roughly 85 to 90% of aneuploidy in embryos comes from the female side, but the test doesn’t specifically discriminate between causes unless you have a special test. Female age-related aneuploidy is the most common cause of IVF failure.
The real aim of embryo testing is to identify embryos with either a normal set of chromosomes (euploid) or an abnormal set of chromosomes (aneuploid). The goal is to selectively transfer or do something further with normal or euploid embryos to increase success rates and reduce adverse outcomes.
A blastocyst biopsy involves obtaining cells for testing while leaving the rest of the embryo intact. It’s possible to do either a day 3 biopsy—that’s how this technique started—but many, most countries in the world don’t do this anymore. It’s mainly done on day 5 or day 6, a blastocyst biopsy.
During the biopsy, cells—usually about 3 to 5, though it could be a little less or a little more—are taken from the blastocyst, which can have anywhere from 60 to 150 cells, with an average of about 100. We’re taking a very small percentage of those total cells, putting them in a tube with a special buffering medium, and then sending them to the reference lab or testing lab, which is usually a different lab from the IVF clinic but sometimes within the same building.
The test is done in the lab, and there are many different tests available today. Over the years, this test has evolved, and the technology itself is very accurate. When validation studies are done, they’re not using embryos but cells of a known chromosome type. In practice, accuracy is about 98%, though it could be lower or even 100% in individual cases. However, it’s important to understand that no test is 100% accurate, and PGT-A isn’t either.
Another important point is that the test itself isn’t standardized across labs. There isn’t one test used worldwide in every single laboratory, so comparisons between labs aren’t always useful. Differences exist between labs, but they generally provide similar results for the same embryo. This can be proven by external quality assessments, where a professional body sends samples of known chromosome status to different labs and checks if they give the correct answer. This is a good way to see if the technologies and laboratories can deliver consistent results. However, slight differences in laboratory technologies and policies can affect results, and this is where much of the controversy lies among providers of this test.
Regarding the genetic report, there isn’t standardization either. While external quality assessments can help similarly present information, differences in policy decisions mean that interpretation and embryo classification aren’t completely standardized. Most PGT-A today, when done on day 5 or day 6, requires a frozen embryo transfer.
One of the claims is an increased success rate per embryo transfer. This is because the embryos are selected, making sure that we have the ones with the best chance of succeeding. The reality is that a chromosomally abnormal embryo has 3 main outcomes: it either stops growing and doesn’t implant, leads to a miscarriage, or, in very rare cases, results in a child with a chromosomal abnormality. Typically, a chromosomally abnormal embryo results in an adverse outcome. Therefore, avoiding those and choosing the embryos deemed normal should, for the same reason, increase your success rate per embryo transferred.
Selecting normal embryos can lower the risk of miscarriage. Many studies have shown this. Additionally, PGT-A may reduce the chance of having a baby with a trisomy, such as Down syndrome (3 copies of chromosome 21).
Prioritizing embryos with a normal chromosome complement can shorten the time to achieve pregnancy and live birth. Also, by selecting only the most viable embryos, unnecessary expenses and medical procedures can be avoided.
If you end up keeping many embryos, freezing them, storing them, and transferring them one by one, and they fail each time, that’s still costing you. It’s costing you time, energy, and money. Additionally, undergoing multiple procedures can lead to burnout, causing some people to drop out of the process, even though they still have a chance. They might give up because they’ve become fed up with doing multiple rounds of IVF.
PGT-A can also help support single embryo transfer. By choosing a chromosomally normal embryo, you feel more confident when you transfer a single embryo.
Another point is that for a woman who has had many failed cycles or is older, with low AMH and very little chance of success, there might still be a benefit. She might want to go through the process anyway, just to see the results and perhaps to gain closure or consider a different approach, like egg donation.
PGT-A also has some limitations, these include:
Clinics and testing labs may not always make the results clear enough. The science behind PGT-A is improving and evolving, leading to differences in lab results over time. There are two main classifications:
There are also mosaic embryos. Mosaicism represents a patchwork effect in the embryo’s cells, leading to mixed results depending on where the cells are taken from. A mosaic result means that some areas of the embryo may appear normal, while others may not. The interpretation of mosaic results varies and is constantly evolving. The recommended action based on a mosaic result also depends on various factors. If you have a mosaic embryo, genetic counselling is recommended. A professional up-to-date with the latest information on mosaic embryos can help you decide what to do with the embryo. Many mosaic embryos have been discarded or not yet used, and some of these may have been viable. Clinic and testing lab technology and policies can significantly impact the interpretation of mosaic results. There is considerable variation among laboratories, indicating that not all results reflect biological reality.
In some cases, you can also receive:
Options include:
In a lab with solid testing, chaotic results usually indicate an abnormality, meaning multiple chromosome abnormalities are present. There’s a small chance that chaotic embryos could be normal, particularly with older test methodologies where chaotic could mean hard to interpret. Chaotic embryos might be candidates for retesting, but this should be discussed with your clinic and their laboratory.
The primary indication for PGT-A is advanced maternal age due to age-related aneuploidy. There’s consensus that aneuploidy is present in women of advanced age in their eggs or embryos. The definition of advanced maternal age varies by region and laboratory, ranging from over 35 to 38 years old.
Another indication is severe male factor infertility. There’s some evidence that severe male factor infertility can impact embryo quality. While aneuploidy is more commonly a maternal issue, it can sometimes be related to the male partner.
Repeated miscarriage or implantation failure. Those are two of the adverse outcomes that we’re trying to avoid, it stands to reason they could be indications for doing the test.
In this scenario, PGT-A means selecting 1 euploid embryo for transfer, which would be the potential benefit of doing PGT-A.
Depending on what her need is and what her reason for doing it is, she might want to do PGT-A to avoid miscarriage because she’s had miscarriages before, not just due to the trauma of miscarriage but also the time spent and the potential medical ramifications. Therefore, performing PGT-A is not for selecting an embryo but to avoid having a miscarriage.
Given that there’s evidence that time to pregnancy can be reduced, and that also means fewer procedures, the overall cost could be reduced with PGT-A, even though it has a cost itself. It’s an extra cost on top of doing IVF. Ultimately, it’s your choice for your specific situation. In studies, it’s done on a statistical basis, but in your particular case, you have to weigh up the pros and cons, of what your budget is. You can only make the right choice after you’ve received all the relevant information.
Information and support: you need to ask all common questions such as how to choose a clinic, additionally you need to find out whether the clinic does the test or not, what its experience is, what its cost is, and what its success rates are.
Boundaries and costs: You need to have your boundaries set up because there’s going to be a cost implication which might exceed your budget. You’ve got to be able to say no. It’s good to understand success rates because when you add in the further complication of PGT-A, this extra test, and this extra selection, then you need to understand the success rates properly.
Understanding PGT-A: One size doesn’t fit all. Decision-making, should I do PGT-A or not, or should I transfer an embryo or not, is a common issue. Being independent but knowledgeable about this helps to make the decision. You don’t have to be told what to do. You can think through all the information you have and make an informed decision.
Asking the right questions: Adding this extra layer onto IVF means you have to become a mini-expert in this as well.
Consulting experts: One of the best things you can do for yourself if you have any questions about PGT-A and any questions about your results is to speak to a genetic counsellor. They’re non-directive, they won’t tell you what to do, and they talk through the basics, understanding what you’ve been through and the information you get at the end.
Pricing strategy: Pricing strategy is really important these days. Sometimes you may get charged for a batch of embryos when you might have only 1 embryo.
Batching of cycles: Doing multiple rounds of IVF before testing or using an embryo, is something for discussion because you have to ask yourself the question: Who’s the strategy benefiting? Is it benefiting you, or does it also mean that the clinic gets to do multiple cycles of IVF?
Additional considerations: Doing PGT-A isn’t free. There are additional procedures that cost time and money, so you have to consider that. Throughout, the clinic and the testing lab can influence the results. It’s not just about the test itself and the biology, but also the decision-making and the interpretation.
Consult a genetic counsellor: If you’re planning to have or have had PGT-A and still have questions, book a call or get in touch with a genetic counsellor. Not all genetic counsellors will discuss tests they’re not familiar with, but you have nothing to lose; you’ll almost certainly learn something and probably save some time and money.
Related reading:
On the balance of probability, that’s true, but you can’t rely on it. Although you’re most likely to have more normal embryos if you’re younger, some young patients have lots of abnormal embryos and older patients have at least a few normal embryos. I wouldn’t rule it out entirely.
If you’re not making blastocysts, it makes it difficult for PGT-A, as it typically requires reaching the blastocyst stage for biopsy. In your situation, since you don’t necessarily have a high risk of aneuploidy, transferring embryos earlier, potentially at day 3, might be the best option. If you’ve been to multiple clinics and never got good blastocysts, there could be an underlying problem. If it’s only 1 clinic, consider trying a different clinic to experience different stimulation protocols and culture systems. They might help your embryos reach the blastocyst stage.
Your primary goal in IVF should be to get embryos for transfer, not necessarily to do PGT-A, especially at your age.
Although miscarriage is a common cause of pregnancy loss, it is not the only cause. If you’re concerned about miscarriage, you should have a miscarriage workup to check various endocrine factors and other possible issues. It would also be a good idea to have your chromosomes and your partner’s chromosomes tested to rule out any underlying genetic problems, although this is less likely (probably less than 5%).
If you’re considering IVF, especially since you don’t have a problem getting pregnant, testing your chromosomes first is advisable. If you have chromosomal abnormalities, you might have a higher chance of abnormal embryos. However, having a miscarriage or a T21 pregnancy doesn’t automatically mean a high risk of the same issue in the next cycle.
If you want to avoid the risk of miscarriage and are open to all intervention steps, IVF with PGT-A could significantly reduce the chance of miscarriage or aneuploidy.
If you have 2 embryos, you should consider whether they are already frozen or not. If they are not frozen and this is happening in real time, your decision should be based on your experiences and concerns about miscarriage.
Given your age, the chance of chromosomal abnormalities is higher, but the chance of having a miscarriage is also quite high. A common outcome for abnormal embryos is failed implantation rather than miscarriage, which would take up more time in your reproductive journey.
There isn’t a definitive answer, as it depends on your situation and preferences. If you need more time to decide, you could freeze the embryos. However, if you freeze them, you would need to thaw and biopsy them later, which might be less effective than doing the biopsy right away.
Discuss with your clinic about their success rates with and without PGT-A for patients of your age to make an informed decision.
Doing a hysteroscopy and an ERA test can potentially increase the success rate of transferring a single euploid embryo. If you haven’t had these tests before, they might help ensure that your uterine lining is optimal for embryo implantation. Additionally, microbiome testing could be considered to assess the uterine environment. Since you’ve invested a lot in creating a euploid embryo, it makes sense to explore these tests to maximize your chances of success. Be sure to ask the clinic for detailed information and success rates, and find out if they routinely use ERA or equivalent tests in their practice.
For mosaic embryos, it is crucial to consult with the clinic, which should have information from the lab. Many labs have genetic counsellors who can provide valuable insights. The impact of mosaicism depends on the degree of mosaicism, the chromosomes involved, and the specifics of the lab’s testing. Mosaic embryos should not be automatically discarded. They may still be viable, and transferring them could be considered. The same approach applies to segmental losses; the extent and chromosome involved matter, and rebiopsy is an option. Thus, the mosaic embryos and those with segmental loss should not be written off without further consideration.
Since you have 3 untested embryos that are likely frozen at the blastocyst stage, you might consider having them tested based on your age and AMH level (1.8 ng/mL). The decision hinges on how much time you feel you have and whether you are comfortable with the risk of miscarriage. If you are 33, you have some time on your side compared to someone older. Weigh whether you prefer to test these embryos or transfer them without testing. If the results are inconclusive or mosaic, you may end up transferring them anyway. Thus, transferring them without additional testing could be a viable option.
The problem with this is that people have to be a bit more honest about the fact there are lots of things we still don’t understand. The kind of glib answer of “if your embryos don’t develop, it’s probably down to the sperm” doesn’t have strong evidence to support it. There could be much more to it, such as a genetic component from either partner. If you keep seeing this issue, it suggests some sort of genetic component. However, unless the laboratory has a particular problem, which is unlikely, it does seem like a problem specific to you as a couple. We are still a few years away from understanding why embryos arrest or don’t grow as they should, whether in the body or the incubator. If embryos never go to the blastocyst stage, transferring them to the body may not help.
This is where we move from biology to medicine and ask if people really want to keep doing IVF the same way—using the same sperm and egg multiple times—hoping for a better result. Since you are open to sperm and/or egg donation, it’s important to consider this because, after so many cycles without success, it’s time to think about what can be done to increase your chances. A significant step backwards, such as considering sperm or egg donation, could be a solution. When I host “Ask Your Doctor” sessions, I always ask if similar cases have worked at their clinic. If they say no, that might be your answer. While it’s good to believe in miracles, we’re in the business of things with a high chance of working. Egg donation, for example, has a high success rate for most people. It’s a big shift, but trying it could be a more viable option than continuing with the same approach.
When the result states that DNA failed to amplify, it usually indicates a technical error, not someone’s fault. It’s a rare chance that something didn’t go well. Sometimes, cells from the embryo might lack nuclei where the DNA is or might not reach the tube properly, leading to no amplification. Another possibility is that the test itself didn’t work on that tube. These are all questions you can ask the clinic and the testing lab to rule out. For example, if you had one embryo and received a failed result, and you found out that similar issues happened frequently at the lab, it might not be the embryo’s fault but rather the testing lab’s. However, this is very rare. A little detective work can help, but the reality is you need to decide what to do next. You could either have the embryo rebiopsied, or you could transfer the embryo blindly, hoping for the best. It’s a valid option if no results are available, though it’s not a guaranteed solution.
This is a great question. Although it’s not necessarily related to pre-implantation genetic testing (PGT), I’ll answer from a PGT perspective. Many other webinars discuss diet, supplements, and antioxidants, which might impact egg quality. However, specifically about reversing age-related aneuploidy (an abnormal number of chromosomes), the answer is no at present. There might be future drug therapies impacting certain patients, but it is not well understood and is not available now. Turning back the clock isn’t possible at the moment. Just having a healthy embryo doesn’t guarantee success, so improving egg quality remains important. While older women may have a lower chance of having a normal embryo, it doesn’t mean all other efforts to improve egg quality should be abandoned.
When biopsying an embryo, the aim is not to touch the inner cell mass, as that becomes the embryo proper. Instead, the biopsy is taken from the trophectoderm, which will become the placenta. These cells are already diverging, so they may not be identical throughout development. However, studies show that the trophectoderm provides a very good representation of the inner cell mass, around 90% or possibly higher. This has been confirmed in studies on non-invasive approaches. While it’s not perfect, it’s a very good representation. We’re not aiming to take the inner cell mass because it’s not feasible at this time. Future approaches might involve taking fluid containing DNA released from different parts of the embryo, which could provide a more accurate representation of the inner cell mass, but current data indicates that it’s no better than trophectoderm biopsy.
The best way to approach mosaic embryos is to get the latest information from a professional, as the interpretation has evolved. Although the embryos themselves haven’t changed, the testing and its interpretation have. Some good work has been done on embryos called mosaics. Calling an embryo mosaic is just a label used to make decisions. Studies have shown that embryos with various types and degrees of mosaicism have been transferred, and results indicate that if you have a certain type of mosaic result, the success rate can be similar to normal.
For other types of mosaic results, the chance of pregnancy is reduced but not zero. In rare cases, mosaic results may carry through to the pregnancy and the baby, but this is very uncommon. There is now a schematic that helps determine where your embryo fits within the scheme. It indicates whether it is more likely to be normal or abnormal. Testing doesn’t make the embryo more mosaic or abnormal; it just reveals the existing condition. If you had never tested, you would face the same risks. Speak to a genetic counsellor about the latest information for your specific case.
Balancing the benefits of PGT-A with the risk of false positives is complex. Rather than focusing on specific numbers, which can be confusing and change over time, consider comparing the lab’s quoted false negative and false positive rates with the general miscarriage rates. Add a personal dimension: your attitude towards miscarriage. It’s important to weigh both the numerical risks and your personal feelings. If the numbers were significantly skewed, the decision might be easier, but since they are closer, and people have different attitudes towards risk, the decision becomes more personal. Discuss your boundaries and what matters most to you.
I can provide the name of the author, which should help. The last name is M Viotti. The study is quite recent, and Viotti has published on this topic. He is likely to continue publishing because he has a registry of mosaic transfers. Although hundreds of thousands of embryos have been tested and called mosaics, only a few thousand have been transferred. The problem of calling them mosaics exists because we don’t yet have enough information to provide clear guidance on what to do with this result. The study is called “Using Outcome Data from 1,000 Mosaic Embryo Transfers to Formulate an Embryo Ranking System for Clinics.” This is useful and practical, and while the sample size is still relatively small, it provides clear indications of what actions to take. Even if there were something concerning in the results, it would not be created by PGT-A; it would already exist in the embryo.
There are two significant genetic tests to consider if you can afford them and have weighed the risks. One is carrier screening, which helps determine the chance of having a mutation that could cause a genetic disorder in a future child. This test checks both partners for mutations that might combine to cause diseases like cystic fibrosis or sickle cell anaemia. Carrier screening is a standard test in some countries but not in others, often due to cost. Studies show the chance of being a carrier is about one in 50. If both partners are carriers for the same condition, the chance of having a child with that condition is higher. This test is useful for identifying risks before conception.
The other test is a basic chromosome analysis, which is important in IVF and reproductive medicine. While abnormalities in the general population are rare, their incidence increases in the infertility world. This test helps determine if sperm or eggs might produce embryos with chromosomal abnormalities. It’s often included in infertility workups and is relatively inexpensive. It’s also useful for addressing issues like recurrent miscarriages or abnormal sperm parameters.
You can choose to wait and perform PGT-A on embryos to assess genetic health, or do these tests beforehand for a clearer picture. The decision depends on your attitude towards risk, budget, and what you consider sensible before trying to conceive.
Immunology testing and PRP are not my areas of expertise. For immunology testing, unless you have a specific risk factor, there is no strong evidence supporting its use. Some clinics do offer it, but it’s not widely endorsed based on current evidence. PRP (Platelet-Rich Plasma) is generally used for egg quality, though I may be mistaken about its application. Regarding special embryo transfer protocols, you might want to discuss with your doctor whether a natural cycle or a medicated cycle would be better for you. Some doctors report better results with natural cycles, though medicated cycles offer more control, especially if using tests like endometrial receptivity. The choice depends on the protocols and success rates in your clinic. It’s not about the specific embryo, but about how much you’ve invested and whether you want to do more tests or make different decisions.
The basic chromosome test is called a karyotype. It’s a fundamental test that has been used for decades in its original form. Generally, it’s sensible to test both partners rather than just one. If you test only the male and find an abnormality, you might miss issues with the female. Conversely, testing simultaneously avoids potential biases and ensures a more comprehensive evaluation. It’s a relatively inexpensive test, and in some countries, it’s part of standard infertility workups. If these tests were free or very low cost, many doctors would likely use them routinely. Carrier screening and karyotyping are useful tests that provide clear results and have actionable implications if abnormalities are found.
