Understanding the science behind embryo grading improves IVF decision making

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1:01Hi and welcome to the show. Subscribe at KevinMD.com slash podcast. Today, welcome back, Erica Boeve, obstetrician gynecologist, and reproductive endocrinology and infertility specialist. Today's KevinMD article is a clinician's guide to embryo grading in IVF. Erica, welcome back to the show. Thanks so much, Kevin. It's great to be here. All right. What led you to write this article and tell us what this article is about? Absolutely. So I'm a reproductive endocrinologist, which means that day in and day out, I help people understand IVF, the results, and part of that is, you know, the quality of the embryos. And what I'm finding is that people come to me with their head spinning, just not understanding. Okay. I have five embryos. How does the lab know which one to transfer? How does they rate? Does day five versus day six matter? And people are really anxious about understanding what I call the alphabet soup of embryo grading. So I really wanted to make that more accessible to people as they're undergoing the IVF process. All right. I'm excited to relearn about this too, because the last time I learned about this is probably

2:05all the way back in medical school like 30 years ago. So give us a primer in terms of the basics for those who are new to this area. Absolutely. So one of the big sort of assets of IVF is that we can use the embryos sort of against each other for embryo selection. So when I think about it, it's kind of like which is going to win the race in terms of giving the best chance of a person getting pregnant with that embryo. So we have different methods to look at that. We have an egg and a sperm that come together. And we do this. We retrieve the eggs through a transvaginal egg retrieval. And the lab then sorts through that fluid, picks out the eggs. And then there's two different ways to fertilize those eggs, either conventional insemination, which is like a recipe mixing the eggs and sperm together. And the second way is called intracetoplasmic sperm injection or X-E for short. And that's physically injecting one good sperm into one good egg, right? That's sort of the different way. So the next day after the egg retrieval, the lab looks at what's in the lab and can really

3:09see which of those eggs has fertilized. At that point, right, it goes from two independent cells, ideally to an organism that has two pronuclei, one from the egg and one from the sperm in terms of the DNA contributions. Those two PN embryos mean that they are normally fertilized eggs with a diploid set of chromosomes. And then from that point, that's the denominator to look at embryo development. So in our field, we can either do two types of transfers, a day three transfer, or a day five transfer, right? And when we're talking about fresh IVF cycle, so day three means that the embryos have divided to the point where they are around eight cells each. And so we can look at the number of cells on that day, and we can also look at the grading of the cells, how those cells look under the microscope, and then make our best determination. Eight A is like the best that we can get on those days. Although anything, you know, six cells, ten cells can certainly make a baby. We like to see A's and B's in the grade because that sort of helps us understand that

4:14they're the embryos are median or milestones, and the cells look healthy, right? On day five, it's actually very different because by that point, thinking of exponential cell growth, the embryos should really be blastocyst by that point, which means they have an outer rim of cells, the part that becomes the placenta, and then this inner cluster of cells, the part that becomes hopefully the baby with fluid in between, and that's called a blastocyst. And so when you look at those gradings, it's actually a much different scale or language, and I'm happy to go into that as well. So when you're looking at these cells underneath the microscope, tell us some of the things that you're looking for, and is the grading as a subjective or the objective measures. So what are you looking at under the microscope? Absolutely. So it's interesting, like you can't see all the cells in one plane. So you see, you know, remember, I don't know if you use a microscope on your day-to-day basis. I don't typically, unless I'm in the lab, you kind of zoom in and out to look at the different cells. And so you can count the number of cells in the state of the embryo.

5:14And ideally, you want to see eight cells because the embryo goes from two cells, right? We talked about that before, and then there's the mitotic divisions and then four cells, and then eight cells. So those are very symmetric cell divisions, and then even numbers, which we like to see. So you can look and truly count the number of cells. And then from the qualitative appearance of the cells, you want to see cells that are whole, circular, not fragmented. Sometimes you can see these little granules. It almost looks like the cells are degenerating. So you want to see these nice crisp round structures that are the cells. And then, you know, as we know, these cells then end up differentiating. But that's a nice, very nice structure is, you know, ideally eight cells without self-fragmentation. And then each cell looks very cohesive and nice, even numbers. Now, you know, to your point about the subjectivity, I would say it's a lot easier to grade a day three embryo with less subjectivity compared to day five, because there's more parameters. But in general, I mean, nobody's going to argue with the number of cells that are counted

6:15for the most part. But then I think that's cellular fragmentation. Is it in A? Is it a bee? I will tell you in my lab, we have even more distinctions, again, that's where that subjectivity comes in. There's an 8B plus, which is almost an 8A, but not quite an A. We have an 8B minus. And then when you get into like season Ds, that's when we're talking about, you know, a lot less cell cohesion and fragmentation. What are some of the variables that affect the viability or grade up in embryo? Yeah, absolutely. So maternal age still seems to be the most important predictor of ed quality. So it's super fascinating. If you look at like a 40 year old woman and you look at, say she even makes five or six blastasis, then we know that like 80% of those blasts will be abnormal. But if you look at somebody who say 32, roughly about half or maybe even up to 60% of those blasts, this will be normal on the chromosomal level. And so, you know, certainly ed quality and which is related to age is the most important predictor of that. And then also sperm quality is interesting.

7:16If it's a sperm issue, we will even see good day three quality because the male genome is not even turned on until day three. So you might see poor day three to day five progression. It suggests more of a male etiology, but it can be really hard to tell other variables that can affect ed quality endometriosis does seem to play a role in ed quality where even younger women can have worse ed quality. Same thing with polycystic ovarian syndrome that can really have an effect on ed quality. Also, you know, even obesity, it's controversial, but there are some data that women who have higher BMI's do have worse ed quality and that can impair embryo progression. Now, how do you transmit all this information about the egg quality to the patient? That's a great question. So when I see a patient, so first of all, we decide if a patient is wanting a fresh transfer because there's some people who actually want a frozen embryo transfer, typically we're talking about a blastocyst about a blastocyst that's frozen. So if we're talking about a fresh embryo transfer, you know, I'll look and see how many eggs fertilized and I'll look at their age and say, okay, are we more likely to do a day three

8:20embryo transfer or a day five embryo transfer? And so on day three, what I'll say is, okay, you know, if there are one or two embryos that are really clearly ahead of the rest in the path and the others look like they're much worse quality, then we're going to be able to choose which embryos to put in and the Americans that have reproductive medicine does have a very clear guideline of how many embryos to put in under different circumstances. We're doing a lot more single embryo transfers because we put in two and they both take at the risk of twin pregnancies are higher. And so really saying, okay, this is your, this is how many eggs you had, this is how many fertilized, you know, I go through these are the number grades and the letter grades, this is how we'd rank your embryos and based on your age of 39 and your diagnosis, we recommend putting in two day three embryos, you know, is everybody in agreement with that and I go through these are your success rates for you, your age, your diagnosis. This is the twin rate if we put in two, there's always a very, very small chance that one of those embryos will split and then, you know, if everybody's in agreement, then

9:22we move forward. Now there are patients who say my worst nightmare is twins ever various reasons, right? Like maybe people already have children at home or they're a single parent, again, everyone's situation is different, but we tailor the number, we look at the recommendations and then we tailor our, you know, recommendation based on their situation and their desires. So it's very numbers based obviously. So we'll be a common scenario just to kind of give these numbers to life. Oh, yeah, absolutely. Okay. So say there is a 36 year old woman with male factor infertility and we get say 15 eggs from her on the day of the egg retrieval. I always say that not every egg is mature and only mature eggs can be fertilized by sperm. So say we get 15 eggs, say 12 are mature, say 10 fertilized with the XE technique that we talked about and then I would say we can expect probably anywhere between three and five lasticists from that cycle. So somebody who's good prognosis like that so relatively young, you know, male factor IVF can exist to bypass that, you know, traversing of the sperm up into the reproductive

10:23track, that person has a pretty good prognosis. And so, you know, I would recommend typically that looking at, we'd look at the day three embryos, but if they were all kind of neck and neck for the most part, then we would then grow those embryos out to day five days six and then say, okay, this is what you've got. We typically will do a transfer on day five and, you know, just to share a little bit about the grading. So it's a much different scale. By this point, you know, you can actually see the embryos in the dish and with the naked eye, they're very small, but you can see the little spec. They've got 80 to 100 cells, you know, obviously those exponential cell divisions have taken hold. And so, typically we grade the embryos stage one through stage six. Stage one and two are very kind of small lasticists, you can't really distinguish that outer rim of cells called the trifectiderm with the placental layer from the inner cell mass, which is that cluster of cells that becomes hopefully the baby, right? So stage one stays still very early blasts as although we can transfer them sometimes with good rates. And then stage three, four, five, six, that means that the blasts is in various stages

11:24of expansion. And so, as I like to say this to patients, blasts is really looking for a home, right? They're trying to find the uterine wall, the endometrium, and invade into the internal vasculature because that's how they'll continue to get the nutrients for their continued development. So stage three is like still, you know, you can see those layers, but it's still kind of compact. Stage four is, you can see the blast is starting to expand. Five is hatching, right? You can really start to see the embryo itself hatching out of that outer layer and then six is fully hatched. And so, you know, one is not necessarily better than another, but I like to help my patients understand like where we're at. So say, you know, we get to day five, and this woman that we talked about has a four AA embryo, and say she has maybe three or four other really strong kinets as well. Four AA is a gorgeous, you know, embryo means that the first letter represents the inner cell mass, which is hopefully the baby part, right? So that's an A, say the outer rim of cells, the part that becomes a plus and a, that's an A. That's a beautiful embryo for transfer. Now we might then freeze, you know, three or four high quality embryos after transferring

12:29them one, hoping she gets pregnant with that embryo. And then, you know, all those other embryos that are frozen have about a 50% chance each of success. So, you know, the tricky part is you can go from, you know, a whole cycle where you got 15 eggs, not every eggs mature, not every mature egg fertilizes about 70 to 80% is typical. And then even in young patients with a good prognosis of even a 50% blast conversion rate from the 2PN stage to the blast sis, that's a good blast is conversion in older women it can be even higher. So I try to say, you know, obviously I only want my patients to have one egg retrieval of possible, but we want to maximize what we can. And for that 36 year old, she's probably got a couple kids in that cycle, but maybe not if they wanted a third kid, they might need to go back to the drawing board and do another cycle. Yeah. Is that helpful? So it sounds like an overwhelming amount of information that it could only imagine for the patients and, and their families as well. So how do you guide them through that? These are obviously life altering decisions, a lot of numbers, a lot of layers of grading.

13:31Yeah. How do you guide patients through that decision making process? Sure. I think one of the biggest things is you have to know the patient and you have to know their history. And it's a little tricky because sometimes I'm doing a transfer for my partner's patient and I may not know them intimately in terms of knowing their values and their goals and their desires. And so I make sure I always read the chart, you know, thoroughly ahead of time. So I really understand, okay, you know, do they have a unicorn or a uterus? Would we really only be thinking about one transfer? Do they have a history of preterm delivery? You know, I'm definitely less likely to put in more embryos. So, you know, for me as the, as the clinician, I really want to have a good understanding of that patient going in. And then I then explain to them the embryo grading, either day three or day five, say, this is what you have. And this is how I break it down, Kevin. I say, if you were my sister, if you were my sister, this is what I'd recommend because I find that, you know, we've, we've sort of gone away from some of the paternalism in medicine. I almost think we've swung in the other direction in terms of like, choose anything. It's all going to be okay. And so I, I find that patients want some direction.

14:32So I might say, hey, you know, if you're my sister, I'd really think about putting into embryos. Maybe the quality isn't so great. So I don't, I think the risk of twins in your situation is going to be like less than 10%. But if that's your worst nightmare, then let's only consider one. And we have that conversation in real time. Sometimes I even like take a step back, go back into the fish bowl, like a collar where I sit and do my charting. And then come back after the couple has had a chance to really talk among themselves about their goals and their values and everything. I mean, cost comes into play too. It's a lot less expensive to put into embryos than to keep paying for storage and all those things. But again, you know, we really don't, we want to minimize the risk of twin and triple, gosh, triple justation, which can certainly happen the more embryos we put in. So it's a very nuanced conversation. And I think we have to sort of take everything into consideration. So simplifying it down, is there an overall correlation rate? And I know this is really, really reductionist between the quality of embryos and the success of having a baby. Yes.

15:32So what are some, what just give us some context in terms of what that correlation is in terms of percentages? Yeah, absolutely. So say you have like an 8A embryo and it's a good pregnancy patient, that embryo can have a 40 to 50% chance of taking because it's a high quality embryo. And if you're looking, say it's like a 6B embryo, you know, that embryo, and I'm throwing out numbers, I need to see the chart, but like say roughly like a 20 to 25% chance of taking because it's lower quality. And so, and then you can also look at, okay, if we put in two embryos at once, what is your chance of a successful outcome going to be roughly speaking with high quality embryos? If you put two in at once, it about, it gives about a 10% increase advantage to the success of that transfer. So maybe it goes from like, you know, 40 to 50% or something like that, but you also have to say, well, then there's a 25% chance of having twins. And if we were to put in one embryo, keep that other embryo frozen, return it in a different cycle, you'd probably have an even higher cumulative pregnancy rate after two transfers. And so I go through the numbers and say, okay, you know, your highest chance of one healthy baby at a time is to do this, whatever it is.

16:36It may be one embryo, maybe two embryos, but really looking at the quality and the numbers. Last assist, you know, it's a little bit easier. I think that blast assist are at such a farther stage of development in a really a lot of milestones have to be reached between day three and day five, but that the blast to success rates are a lot higher. So, you know, if you have a blast assist, now we're talking frozen embryo transfer, but say we've tested the chromosomes, that embryo can have a 65 to 70% chance of taking, which is far higher than anything outside of, you know, natural conception. And we really only put in one tested embryo at a time when we have that information. And so, I think what I think about this is like, it's a lot of tools that we have at our disposal, making it accessible for patients is like in the context of their situation. We use the ASRM guidance, but I think at the end of the day, it really is a nuanced conversation between the patient and the doctor. We're done Eric above, obstetrician gynecologist and reproductive endocrinology and infertility specialists. Today's Kevin M. Diarticle is a clinician's guide to embryo grading in IVF. Eric out of that was a take-home message is they want to leave with a Kevin M. Diarticle

17:38audience. Sure. So, one thing I would say is some people go from clinic to clinic, you know, say things don't pan out at one clinic. They still have embryos frozen and they go to a different clinic. Not all of the grading is the same clinic to clinic and every clinic has their own success rates. So, it's a really important question to ask, like, you know, some clinics rate embryos at grade D. So, I was always used to that in my career and then I went to a place where the sort of the lowest grade they gave was a C. And so, then I had to readjust my brain to be like, okay, well, a C in this system is actually a D in my previous system. And some clinics have, you know, I wish there was one true standard, but there's not. And so, really understanding clinic specific success rates, whether it's day five versus day six, you know, those are really, really important questions to ask your REI and your lab staff, you know, for your own clinic, but then especially if you change clinics and are used to a, you know, a different, if you're switching clinics and you're used to something else, make sure that you're really comparing apples to apples. So I would say that, and I would always say, you know, I think as patients, you know,

18:38we really do want to empower ourselves with the information. I really trust my embryology team, even as a physician to help me make these decisions. Because sometimes say you have two for a A's that are graded that way, but maybe the lab sees something different, maybe one's expanding versus not as rapid expansion, and these are dynamic processes. And so, really trusting the lab staff, because that's what they do. They are embryology, that is what they are trained to do. Sometimes they'll grab me and say, hey, look under the microscope, do you see this? But really leaning on your clinic to help you understand, like which embryos to transfer and in which order, I think it can be really helpful. Now there are tools out there called embryoscopes, I want to just give a brief word on that. That's where you have like 24, 7 capturing of the data where you watch the cells divide in real time. Obviously slow practices, but you can sort of see if there's chaotic divisions and all those things. These tools sound really great on paper, but they have not been shown to improve outcomes and they're really expensive. They add cost to patient care. So, I would love to put stock in those and just say that, oh, this technology is going

19:39to help us, but I don't think we're really there. And so, as of right now in 2026, it really is looking at trusting your lab, looking at their individual success rates, and then leaning on your team to help you decide how best to be far. Erica, thank you so much for sharing your perspective and insight. Thanks again for coming back on the show. Thanks Kevin. Thank you for listening to the podcast by Kevin M.D. To share your story and appear on the show, visit KevinM.D.com