Deciphering Embryo Grading: What's in a Grade?

So today we're going to talk about embryo grading , because one of the most common questions I get asked in my medical practice and in my coaching practice is you know a patient or a client who's gotten a recent embryo report and they truly don't know what to make of the alphabet soup .

And so what I will say is I actually didn't know this until I was a fellow , so I had gone through an OBGYN residency already , and even though I had done REI rotations , the grading just didn't make any sense to me . And so let's start with talking about how embryos develop .

So what I'll tell you is that we start with the eggs and the sperm , which I think is fairly intuitive . But what happens is not every single egg is a mature egg , so unfortunately , the immature eggs cannot be fertilized by sperm Of the mature eggs .

Either they are inseminated , which means that they are sort of surrounded or bathed in sperm like a recipe , or they are injected with sperm in a one-to-one ratio , which is called ICSI or intracytoplasmic sperm injection .

Of those mature eggs at best on average 70% to 80% will fertilize , and so if you check the next day , it takes about 18 hours to see if an egg is fertilized .

You will then see if there is what's called a 2PN embryo , which means that there's one pronucleus from the person who donated the egg and there's one pronucleus from the person who donated the sperm , and that then sets the stage for embryo development . So it's basically two cells at that point .

So , if we remember from biology , those cells are going to undergo a series of divisions , and so from that point there should be exponential growth of the embryo in terms of the cell number and also differentiation .

So the 2PN embryo then goes to four cells , which goes to eight cells , and ideally three days after the egg retrieval , which we call day three , ideally an embryo will have eight cells . Now there can be a range there can be six cells , there can be 12 cells , there can even be an odd number of cells .

In general , even numbers tend to be better than odd numbers , although we do see live births from embryos that started with odd numbers on day three . But it basically means that the cells are dividing and that sort of on a day three embryo grading you can see like if maybe it's a 6A , right , it means it's six cells .

That number six pertains to the cell number and then A or B refers to the grading of those cells . So it looks at like fragmentation and how the cell looks in terms of cohesiveness and structure and morphology . And when you're actually looking at it you can zoom up and down on a microscope and you can actually see every single cell , which is pretty amazing .

And so 8A is the best you can get on day three , although 8B is wonderful , 10a is wonderful , there's a whole range but it just helps to characterize how many cells are present and how does the grading out of the cells actually look ?

Now , if you are thinking about undergoing a day five embryo transfer , a lot of growth happens between day three and day five , so that exponential growth keeps going and ideally by day five what we have is what's called a blastocyst .

So cyst means fluid-filled structure and ideally the blastocyst has basically sort of two different structures that we can identify and grade . So if you're looking at a day five embryo and thinking about grading , most labs will follow this , not every single lab , but sort of of the labs that I've been a part of and reading a lot of the papers on this as well .

There's basically six stages of embryo development in terms of hatching . Between the day three and the day five stage , the embryo becomes a morula , which is like this very compact ball of cells and people say all the time well , why don't you look on day four ?

You know there are embryoscopes which give you real-time imaging , although those haven't been proven to , you know , optimize outcomes . When you look at the data Day four embryos , they're really hard to grade , they're really hard to characterize because they are so compact and you really can't tell too much about the quality on that day .

So most labs don't even look on day four because they're sort of trusting that they're undergoing the process of development and by day five hopefully , we can see some of the milestones that are important for embryo development . So on day five , typically there's a number that's assigned and there's two letters that are assigned .

Now the number doesn't refer to number of cells like it does on day three . What the number refers to is actually the degree of expansion of the blastocyst .

So what I tell my patients and clients is that embryos are looking for a home and as they're looking for a home they undergo this expansion , this hatching process , and so stage one is sort of the first stage , then stage two and then stage three , or stage three embryo is basically where you can start to see the different layers .

There's an outer rim of cells which we call the trophectoderm , and that's basically what becomes the placenta , and then there's an inner cluster of cells which is the inner cell mass .

There's an inner cluster of cells which is the inner cell mass , and so you can Google an image of this , you know , on Google images , and see there's different sort of morphologies of the cells et cetera , but that sort of structure where you can see an outer room of cells , an inner cluster of cells along the edge , and then the fluid in the middle that is

a blastocyst , and then the fluid in the middle that is a blastocyst , and so in most labs a grade three basically means that it's not quite hatching yet . Four is that it's starting to hatch , five is that it's hatching even more . And six is fully hatched , meaning it's completely outside of the zona pellucida .

And so you know , six is not better than four necessarily , you know . I think that there's some experience that goes along with this as well . But what you want to see is you want to see that the embryo is alive , that the cells look healthy and that it's expanding and it's truly looking for a home .

Sometimes you can even see the cells start to herniate out as they're looking for a home , which is kind of cool . But if you think about it . So people ask all the time well , I got this embryo report . How do I tell what's the best ? How do I tell what's the worst ?

And when we're thinking about untested embryos , generally the embryos with the best grades are the ones that we transfer preferentially . So , for instance , like a 4AA , a 5AA , those are very good grades and we might transfer those first , maybe before something that's like a 3BB or something like that .

However , we do see live births from embryos with those other grades as well , and so , unless it's a very , very poor quality embryo where we think there's no chance of a live birth , you know , often we'll give it a shot . Now I didn't yet describe what the letters mean .

So the first letter of the grading system pertains to the inner cell mass , and so oftentimes in many labs you'll see an A grade , a B grade , a C grade , again , just like school grades , a is better than B , which is better than C . I have seen some labs give a D designation as well and you kind of have to calibrate to what your lab does .

But the point is that A is the best , b is still very acceptable . C we do see live births from C grade embryos , however . It's less likely . And then D is a poor quality embryo if your lab gives those designations . My lab right now where I practice clinically , has an A through C grading system .

The second letter of that embryo grade is the true effectoderm grade , and so that's the part that's going to implant . That's why that is important . And so that is the part that's going to implant . That's why that is important .

And so that is the part that becomes the placenta , and so you want a strong grade in that letter because those are the cells that are going to connect with the endometrium and then start allowing that embryo to access the nutrients . So again , the first letter is the inner cell mass grade . That is the part that hopefully will become the baby .

The first letter is the inner cell mass grade . That is the part that hopefully will become the baby . The second letter is the trophectoderm part which hopefully will become the placenta , and then you know from then on that sets the stage for , hopefully , a successful pregnancy . So I hope that clarified a little bit about the alphabet soup .

There are some labs that give you know plus , like 8B , plus , 8b , minus , again , pluses are better than minuses . But again we do see live births with all sorts of embryo grades . If you have two Cs in the grade you know that's generally not the best quality embryo , although even still sometimes you can see a live birth from those embryos as well .

So I usually err on the side of giving an embryo a chance rather than discarding that something that could potentially make a baby .

But I think also in the era of genetic testing of the embryos it does get a little bit more complex , because not only do we have the embryo grade which pertains to embryomorphology , but also we have the embryo grade which pertains to embryomorphology , but also we have the genetics , and so typically our embryos are graded on day five and day six .

There are some labs which grow embryos after day seven , especially if genetic testing is going to be done , because even though day seven embryos have lower success rates if you can get to a chromosomally tested embryo on day seven , those embryos do have a small chance of making a baby and a live birth as well .

So thinking about day five versus day six , this is hotly debated . Now , again , if you know the chromosomes , that's a whole other story because then you can use that in your ranking .

But thinking about day five versus day six , I recently talked with our own embryologist about this and truly , in a setting where you know that you're timing the embryo transfer to the endometrium like a frozen embryo transfer cycle , for instance , day five versus day six is not really thought to have too much bearing because those are both very acceptable days for an

embryo to meet its milestones . Now if you're talking about a day seven embryo , that gets into where the embryo is really not meeting its milestones on the appropriate timeline and so that's why those embryos do have a lower success rate . But day five and day six , pretty much those are equivalent .

Most of the studies would show that If you look at the A's and the B's and the designation like do you , would you choose a you know 3BA or a 3AB ? Again , that is hotly debated . You may want to ask your own lab about their internal data about day five , day six , whether the inner cell mass grade matters more , the trifecta grade matters more .

You know all those things you can have internal data about . Day five , day six . Whether the inner cell mass grade matters more , the trifecta grade matters more all those things you can have internal data for . But again , those grades represent different parts of the embryo and so they have different functions .

Ideally you'd have solid grades in both of those letters , but sometimes you do need to sort of make a choice based on those things .

In my practice I'm a physician and I love to know what the embryo rate is so I can counsel my patients . But at the end of the day the embryologists are the ones who are looking at the embryo and I trust them entirely .

So in a reputable lab I really do leave this up to the embryologist , especially in untested embryos , to say tell me what embryo looks the best and we'll start there , because typically that's what's going to yield the best chance of success . Right , and sometimes I do get curious and I ask to see the embryo through the microscope myself .

But again , when it comes to those sorts of decisions I really do trust the lab because they are very good at this . They do this day in and day out . They have their degrees in this and we work as a team to help our patients and our clients have the best possible outcome . So that's the embryo grading .

Day three and day five there is genetic testing of the embryos , and so what that means is that on day five or day six or day seven , instead of putting an embryo back in like a fresh embryo transfer , what's done is there is a trophectoderm biopsy of just the few cells on the outer rim of the embryo , the trophectoderm layer , the part that becomes the placenta

, which is helpful to know because some people say well , is this going to affect a potential fetus ? It's not that part of the embryo , it's a different part , and a few cells are obtained .

Basically a laser is used under most circumstances and a few cells are obtained , the embryo reseals , it's frozen , and then those cells say you have maybe , if you're lucky enough to have three or four embryos to work with , those cells are then sent off for genetic analysis to understand what the chromosomes of the embryo are .

So , for instance , you know certain cells would be in one container for embryo , one other cells , you know , in a different container for embryo , two and so forth , and so when you get the report you can see embryo one , you might see 46XX , which would be , you know , a typical chromosomes for a female embryo .

Maybe you get embryo two says Turner syndrome , or embryo three says 45XY , and also there's an aberration on chromosome 16 . A lot of these anomalies that we see in the chromosomal patterns are very random and many times they are very complex in terms of different chromosomes being affected at the same time .

But sometimes we can see certain patterns in the genetic testing of the embryos that then give us a little bit of a sense . Say , a couple has many of the embryos follow a typical pattern . Maybe there's something about the parents that might promote that with more frequency , such as a translocation of their germline .

So there are things we can glean from genetic testing . But I think that when you're looking at genetic testing , the genetically quote unquote euploid embryos are going to have a higher rate of success compared to the mosaic or the aneuploid embryos .

Every lab has their own sort of distinction with the lab that they work with , the genetics testing lab , in terms of whether mosaics is supported . Now we're getting really kind of nuanced . But I think it's important because people ask me all the time . And then , what threshold do you use to call an embryo euploid ?

What threshold do you use to call an embryo low-level mosaic or high-level mosaic or , frankly , aneuploid ?

A lot of those things actually depend on the percentage of the DNA , the cells , and also looking at the particular chromosomes involved , because I think there's a lower threshold to call an embryo potentially aneuploid or mosaic if it involves an embryo that could potentially go on to yield a trisomy pregnancy , as many of them can .

And so the genetic information does give some nuanced information about the embryos , although you know , I will say , it is not indicated in many circumstances and I think a lot of young , healthy women , in my experience and based on the data , truly do not need genetic testing of the embryos and actually do not benefit from genetic testing .

There's actually some evidence that people who are young , who do genetic testing of embryos you know , for aneuploidy risk , actually may do worse . You know it's not a completely benign process . The technology is not a hundred percent perfect and also you know it is .

It is an additional step to put the embryos through right To , to sort of take a few cells out and then , rather than leaving the embryos intact and so , and generally speaking , if a woman is 38 or above , you know there has been shown to be some clear benefit in those scenarios in terms of optimizing the you know pregnancy rate per embryo transfer and also

reducing the miscarriage rate , because we know that women who are on the older side for reproduction do tend to have higher aneuploidy rates and higher miscarriage rates .

Also , if somebody is seeing me who has a history of recurrent pregnancy loss , either documented or believes to be due to aneuploidy , that's another scenario where oftentimes that is entertained and possibly even recommended .

I will also say that many people are now doing expanded carrier screening for recessive disorders or they may have an autosomal dominant trait that runs in either of the parents and so they know about this and genetic testing can be done oftentimes for those particular gene disorders and also at the same time for aneuploidy as well .

So if I have a 28-year-old who maybe Huntington disease runs in their family or something like that , and we're already doing genetic testing , I typically also will do the aneuploidy as well , just because the cells are already being taken .

So why not know that you're putting in most likely with the resolution of the technology and you put embryo without that particular mutation , for instance . So again , this gets very nuanced and that's why you have your REI or me to guide you in making these decisions . But I think you know just , it can be very anxiety provoking .

You know , either to show up for a fresh embryo transfer and to hear , okay , these are the grades of your embryos , this is what we recommend , and just to feel like it's like completely unknown territory . Or also , you know , to get an embryo report and look at it and say , okay , well , you know , some are male embryos , some are female embryos , like the .

You know , different grades look different and you know , maybe you have a preference for one sex over another to start . But the best decisions you can with the available information and just kind of get oriented to the vocabulary and the landscape so that it's not so disorienting . So again , that's embryo grading and genetic testing in a very brief nutshell .

If you'd like to know more , book a call with me . I'd love to talk more about this . As you can tell , I get excited to talk about it because I think it's just so fascinating what we're able to do . But stay tuned , we'll talk about more evidence-based topics and I hope this helps . I love you , as always . Take care Bye .