Embryo grading explained: the good, the poor and the baby maker

Explained by: Danny Daphnis, PhD, Mediterranean Fertility Institute
Category:
From this video you will find out:
  • What is the key role of embryo transfer in the entire IVF treatment?
  • How the timing of embryo transfer impacts the IVF outcome?
  • How do embryologists grade embryos? Embryos D2 and D3: grade 1, 2, 3 and 4
  • How useful are Time-Lapse embryo incubators in embryologists’ work?
       

What are the different embryo grades?

Watch the webinar with Dr. Danny Daphnis, Scientific Director at Mediterranean Fertility Center, Chania, Greece, in which he is explaining embryo grading.

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Questions and Answers from the event

I had a failed pregnancy with an embryo graded 2BB. This was with a frozen egg donor. Now, I’m trying a fresh donor with PGS. Will this be better? Also, didn’t I stand a good chance with embryo graded 2BB?

As I said during my talk, first of all, BB is considered to be a good quality. If you recall, the number two signifies how the blastocyst has developed, so 2 is considered an early blastocyst. Now, again an early blastocyst doesn’t mean a poor quality blastocyst. When you’re using a fresh donor egg, I do expect that the day-5 embryo will not be so well developed, that doesn’t mean that it’s a poor quality blastocyst. No, not at all, a fresh donor might give you a faster development, so instead of having a 2BB, you might have a 3BB or a 4BB, but that’s up to it. PGS testing with donor eggs, again, PGS is an invasive technique.

The lab, which does it has to be quite up to scratch with PGS and PGS, will not necessarily increase your chances, it’s just another way of selecting the embryos. In essence, I’m going to answer your question in simple terms no, a 2BB embryo is not a poor quality embryo, so please don’t feel that you were cheated in any way. Remember, an embryo is only one part of the equation, the second part of the equation is endometrial receptivity, and of course, unfortunately, luck plays a little bit of a role.

I am 42.5, I have a low AMH of 0.49- is Greece or Latvia open to known donors…meaning I would like to use my sister’s eggs but also am open to finding a clinic that I perhaps could use to use with my own eggs for an attempt first time.

I know for sure that Greece does not allow known donation, it has to be an anonymous egg donor. Regarding using your own eggs, if you’ve never, ever had an IVF attempt, you need to know that AMH is just one parameter. Although people try to link it with egg quality, it’s not proven, it just says that you have a low ovarian reserve, it doesn’t mean that you cannot get pregnant with your own eggs because you have a 0.49 AMH. Therefore I would suggest speaking to an IVF specialist, see other parameters of your medical history because, as I said, AMH is just one small part of your medical history and your fertility score. I would suggest looking more into it before you go to donor eggs.

I have 5 frozen egg and sperm donor 5-day embryos.3BA, 3BB and 3 x 4BB. My clinic rejected 4 more embryos because they were C. Is this right? My previous clinic used to transfer Cs. Also, my transfer has been canceled because my endometrium was too thick, 15 mm on 10th cycle days (taking Estrofem). Is this much too thick for transfer?

It depends on each laboratory what grade is their B or C. Usually, the best embryos you want them to be A or B. Some clinics do use a great C quality because as I said in my key facto, embryo assessment is subjective, and it does remain on the embryology’s eyes what is best, for example, I’m a very strict person, so A is very difficult for me to give, so if I give a B, C, it is a good quality blastocyst, it’s not a poor quality process so that always depends on laboratory and each laboratory has its own protocols.

Your transfer has been canceled because it was 15 millimeters and not 1.5, I’m guessing, it’s 15 or 1.5 centimeters. There have been papers on that. It would be answered better by a gynecologist but my experience says, and in all the papers that I’ve read, it is true that if an endometrium becomes more than 15-16 millimeters, you tend to abandon the cycle. It’s counterproductive to have too thick endometrium. Usually, a good endometrium is between 8 -11 millimeters.

My 3 x 4BB embryos are day 6. Does it make them worse than day 5?

No, not at all, it doesn’t make them worse because again, it depends on what each laboratory uses, what incubators they use, and what culture media they use. You can have up to early day-6, that’s the morning of day-6 to see the embryo, see the blastocyst and freeze them or transfer them at that point, so that’s not worse in any way.

Why do you need a contraceptive pill before starting a cycle?

That is usually done if you want to travel, and it’s difficult to arrange traveling dates, you tend to get a pill. Another aspect is some ladies need to have their ovaries quietened down, so a contraceptive pill usually, reduces estradiol levels, so your next cycle becomes better for us to start, but you don’t need to have a contraceptive pill, it all depends on each patient.

How do you explain to a patient when defreezing the embryo on the day of the frozen transfer, it has not survived? Why does this happen? Does it depend on the embryo quality or rather, on the day or way it has been frozen?

That is the most difficult aspect that I have dealt with by being an embryologist. There is no easy way to explain it, you have to be truthful, you have to explain what exactly took place. Usually, with the aid of vitrification, the last 10 years, this talk I have had maybe once or twice, so it is very rare, nowadays. In the old days, you used to have it more often, nowadays, vitrification has around 95% chance of surviving intact, whether that’s a day-2 or day-3, or day-5 vitrified embryos it’s called.

The answer to the question is yes, it does depend on the embryo quality, that’s why it’s important for embryologists and for IVF clinics to only freeze good quality embryos. It’s better to make a patient sad by saying, we transferred 2 good embryos, and you don’t have anything more rather than to make a patient happy during a fresh embryo transfer by saying you have 2, and we’re going to freeze 2. If those 2 that you froze are not of good quality, we have to give patients the same chances either it’s fresh or, it’s frozen and of course last it is important like I said before, nowadays, everybody uses vitrification. I doubt anybody uses slow freezing, so it does depend if they’ve used slow freezing then, chances are less.

What is considered a better quality: AB or BA?

Now, you’re picking straws, and I understand why you’re asking this question, it’s a very legitimate question. AB means that the inner cell mass is A and the trophectoderm is B, I’m just going to repeat myself here inner cell mass is what gives rise to the embryo, B is what gives rise to the placenta, so in essence, AB is better than BA because you want the embryo to be a better quality of placenta, however, both these qualities either AB or BA are very good and have high chances of implanting.

When is best to do PGS, on 3-day or 5-day?

If the laboratory has the correct experience, it’s better to do a day-5, simply because on day-5, you have more cells to analyze, which means that we have more DNA, and we have a better assessment, whereas when we do a day-3 embryo transfer. If you recall a day-3 biopsy, if you recall on day-3 embryos have 6 to 8 cells, so it’s much less invasive to take 10 cells from 15 rather than to take 1 cell out of 6 or 7 or 8 cells, so mostly we tend to do a day-5 embryo transfer. You’d get more DNA, and you also have fewer embryos to analyze, and that means that the embryos that you do analyze, hopefully, are going to be of good quality as well.

Interesting that 30% of failure is due to transfer skills. Does this mean that you would recommend changing clinics after a failed cycle?

It all depends on how you felt at the clinic that you had your IVF. When I say that 30% of failure is due to transfer skills, it’s not just the doctor doing this and putting the catheter there, although that is a very important aspect. I know for sure that in all 4 clinics that I’ve worked for, doctors were very very careful in doing embryo transfers, they were not allowed to do embryo transfers, and they actually scored themselves, so if they didn’t get many patients pregnant, they stopped doing the embryo transfer procedure, so it is a very important aspect, you mustn’t traumatize the patient, you must know how the patient’s cervix is. I should not answer this question necessarily because it’s a doctor’s question, but I’m just giving you my experience on this part. The catheter should go in, it should go out without the patient understanding anything, feeling anything, it should be completely a non-traumatic experience. If it gets traumatic, then the chances are lower in succeeding and the embryos implanting.

Should I be disappointed that in my egg &sperm donor IVF? I haven’t achieved any A quality embryos? Is that a bad sign? I was actually someway hoping to get all As.

Everybody wants to get As, it’s like when you’re in school, you want to get the best grade, that is totally understandable. However, it’s not a sign that an A is going to get you pregnant, and B is not going to get you pregnant. Please, remember that we grade them according to beauty, to how they look, so an embryo which is 3BB has a very good chance of implanting, and if another embryologist is as strict as I am, then the B is probably a spectacularly looking embryo, so please do not get heartbroken if you have a 3BB or a 4BB or a 4BA, it is still a good quality blastocyst.

Would you consider transferring embryos with BC or CB quality?

If you have better quality than that, then no, but if that’s what you have, then we need to discuss it with the patient. BC is actually not a bad quality because B, the first letter, signifies the trophectoderm, so that’s good quality. C, that means that the placenta is not that good, but again always take into consideration that pluses are dynamic entities, they do change, and we’ve seen this with time-lapse quite a bit, so I would transfer a BC, a CB I would be warier. I would talk to the patient, explain to the patient, and at the end of the day, speak to the patient and inform them if we have no other choice, then, unfortunately, we’ll have to go with the CB or CC if that’s the case.

Why some clinics don’t use time-lapse? Is it wrong?

No, it’s just expensive. Time-lapse incubators vary from 80 000 EUR to around 250 000 EUR, so as you can imagine, IVF clinics usually do not charge for time-lapse, and if they do charge, it is a very small amount. In order to make money, buying such an expensive piece of apparatus is not financially stable, so they would buy it more for the scientific aspect and, of course, to help the patients, but it is quite expensive, that’s why clinics don’t buy it.

I am currently 2 days passed an embryo transfer with 4AA day-5 blastocyst and 4AA day-6 blastocyst, my clinic grades up to 6, 6 being the best. So I am hoping my grade 4, will be okay. The day-5 looked like the best embryo, expanded than the day-6. My treatment was in Poland, I am currently isolating in the UK? My lining was 11 mm.

Your lining is good. Number 4 does not signify quality, number 4 signifies how expanded the blastocyst is. I doubt 6 is the quality, it’s not the quality, 6 is a universal grading for blastocyst, 6 is how much it’s expanded. So, 4AA is much better than a 6A, remember this because 6AA means that the embryo has completely hatched out, it’s gone out of its outer cell and it’s just withstanding, you want that to happen inside your womb, not in the lab, so if 2 x 4AA is looking quite good I hope all the best and good luck.

Would you not recommend PGT-A when I’m 42 and had a previous early miscarriage week 9 and 4 failed cycles after that? I was told that at my age, this is the way forward.

I would recommend it in your case. You are a more specific case, and I understand your predicament especially, with your early miscarriage at week 9 and the four failed cycles. I would recommend for you to do PGD because PGD and please, remember this will not necessarily give you your goal, your aim of having a baby. However, it will give you vital information about your embryos, so it will give you information if your embryos are chromosomal of good quality to give you pregnancy or if they’re not. I hope that they are and I do recommend doing PGD in your case.

My clinic told me that some of my day-5 embryos were cavitating – what does this mean?

That’s a good thing. Let me explain each stage. When you see the zero in front, that’s a morula, 1 is an early blastocyst, 2 is what we call a cavitating blastocyst, so when you look at the scoring, it means that number 2 means it is cavitating. 3 is a blastocyst, 4 it’s expanded, 5 it’s hatching, 6 it’s hatched. You have a day-5 embryo, 2 in development, and then whatever the score is. Usually, 1 and 2 are very difficult to grade. If you remember in that very busy slide that I showed you, it’s very difficult to distinguish between the inner cell mass and the trophectoderm 1 and 2 embryos. So early blastocyst and cavity blastocyst, so in essence gardener who devised this grading system said, we should all grade 1 and 2 as CCs, so keep them in the medium because we can’t grade them properly. If you have day-5 embryos which are cavitating, that means that they’re at the blastocyst stage and they’re doing what they’re supposed to do.

I had 2 embryos that were 2AA (one resulted in a successful pregnancy, and one is frozen). I also had 1 embryo grade C (5-day blastocyst from a fresh egg with Embryoscope monitoring), and the chief clinic doctor recommended against freezing as it was not good enough to freeze. To this day, I wonder if it was the right decision not to keep and freeze (through vitrification) the grade C embryo.

I would, in this case, trust your clinic doctor, he probably had information from the embryologist, and the reason is simple with an Embryoscope, which is a time-lapse incubator, we don’t only see the end result, you see how the embryo develops throughout time. That means that the grade C blastocyst did not have a good developmental step throughout its development. I’m sure it was not difficult for them to just put another embryo to freeze, it’s easy for them, it doesn’t use much effort, so not to freeze it this specific embryo, I’m sure they did a favor, it comes back to what I said before embryologists should only freeze embryos which will give patients a good implantation rate nothing else, so it’s good that they made this decision, and they did not tell you that you have 2 frozen embryos just to keep your hopes up, but then at the end of the day you would actually get a good result.

I’m planning on doing PGS. I have good hormone levels apparently, but I have PCOS. The clinic suggested either NGS, which means I would need to travel twice and wait a month and spend more money, or do PGS with another method like FISH or something else where I could do the transfer after a few days instead, so only one trip. Which option would you choose?

The reason is simple when you go for 2 trips when you do a blastocyst biopsy on day-5, you cannot do an embryo transfer on the same cycle, that’s why you have to travel twice, whereas if you do a day-3 biopsy, that means that you can do the same cycle. Don’t do FISH, it’s very old. I did FISH back in 2004 when I was doing my Ph.D., and it’s a very old technique. If they’re going to do a day-3 biopsy, at least they could do ARRAY-CGH, which should give you all chromosomes whereas, FISH will only give you 5 or 6 chromosomes, that is a very outdated way of doing PGS, so I would advise against doing FISH. If they do ARRAY-CGH, at least on day-3 embryos, yes, but coming back to my previous answer to a patient who asked if you’re going to do a day-3 or a day-5, I would suggest doing a day-5 NGS, and unfortunately, go for a second trip.

Can you improve egg quality to improve the chance of success? If so, what do you recommend?

Unfortunately, there is no way for us to improve egg quality and we can force fertilization, we can force division, but we cannot make eggs of better quality. You can attempt if you have a poor ovarian reserve or poor quality eggs to do what is called PRP to your ovaries, maybe that will help you get better eggs, however, there is no scientifically proven way to make your eggs of better quality.

Do good quality embryos that have been PGD24 (PGS) tested still have the possibility of not surviving the defrosting? How important is the temperature when defrosting and minutes to transfer to our surrogate mother?

When they do PGD24, that means that all chromosomes have been tested, yes, of course. There is always a possibility of embryos not surviving, especially embryos which have been biopsied because these embryos in order to do PGD, they have to be biopsied.
All protocols for thawing after vitrification are specific depending on each kit that you use. So an embryologist will know that, and it has nothing to do with the information that you need to know.

The minutes to transfer to your surrogate mother, again it depends on how each lab is set up, some labs want to wait for at least 3-4 hours, other want to do it within half an hour, so again it goes to the protocol, it has never been tested if it’s better to leave them for 3 hours in the incubator or to do the embryo transfer after half an hour, and so the answer to the second question is not proper, however, the is a chance that the embryos will not survive if they’ve been biopsied, even if you’ve had vitrification.

Some clinics still have some embryos frozen by the old method, which is called slow freezing. What are the chances that the embryos survive the defreezing process?

We used to say to our patients that you have around 70% chance of thawing, so I would say that is a good number, and the problem is that only the embryologists like myself know how to slow-thaw embryos nowadays. That’s also a key ingredient if the clinics do have these embryos, make sure that they have older embryologists who know how to thaw them. I think nowadays, nobody uses slow freezing, everybody uses vitrification, so the chances I would say are around 70%.

What is your opinion of 2 frozen embryos graded 6AB and 6AC and frozen on day-5? I’m 37 with low AMH.

This means that the inner cell mass is very good quality on both embryos. I am just a little bit wary of the 6, if the 6 is according to Gardner’s classification, that means that both embryos are hatched, so that means both embryos do not have the outer membrane to protect them. Usually, hatched embryos do not vitrify as well as embryos that are not hatched, the zona pellucida, the outer membrane as we call it does provide extra protection for the survival of the blastocyst. However, if you have those embryos, of course, use them, the grading looks quite a good AB and AC, is okay, AB especially is much better, but I am a little bit wary about the 6 if it actually does signify that the embryos are hatched, please ask your laboratory.

What is your view of embryo hatching – does this help?

This is a very old technique that we used to do. What we did is, we used the laser to make a couple of holes or to thin the outer membrane. I was just talking about it – the zona pellucida and that made it easier for the embryo to hatch because embryos want to get out of the zona pellucida when they’re in a lady’s womb. It hasn’t been proven that embryo hatching does have a positive effect on embryonic quality unless you’re using older age eggs and you measure the zona pellucida being very trick, otherwise, if you do it on donor eggs or just eggs, which do not have as thick zona pellucida then, it has no positive effect.

At age 41, in Canada, I had a canceled IVF cycle because the doctor said that he could not retrieve the 3 eggs and the 4rth egg was dark. I believe this might be because I would not agree to have a fibroid surgery, and he did not want to provide IVF without it. (I later went to CZ and had donor egg IVF, successful on the 1st try, and the subserous fibroids were not an issue). Does it sound realistic to you that the doctor could not retrieve any of my eggs? Again, I suspect, it was because he did not actually want to provide IVF to me.

This is a question a gynecologist would answer, and there is a possibility that if your fibroids were too big, and your ovaries were above your womb, the doctor couldn’t get through during an egg collection to the ovaries, I have seen it happen. Just because they’re behind the womb and they do not move. I have helped doctors trying to move ladies inside when she’s sedated to push everything down, so the ovary can come down and be more accessible for the egg collection, but I have experienced, not often but rarely because the off chance that you cannot access the ovaries, therefore, I would not say that he didn’t do the IVF, I think that would be unethical, he might have had a problem in actually accessing your ovaries, I have seen it, and if you have fibroids, then he would be very wary of going through.

Again, it all depends on the size and where it’s located and where your ovaries are located. I don’t want to comment on that too much because again, I’m an embryologist, not a gynecologist, but I have seen ladies were we weren’t able to access the ovaries just because they were above the womb and they were behind or that you couldn’t find a way to go through, but it happened very rarely. I am guessing it has nothing to do with the embryo transfer that you had when you did your donor eggs because the fibroids were probably out of the way, out of the endometrium. It had to do with how accessible your ovaries were or ovary, I don’t know which one had the follicles during egg collection. It is a possibility, a small possibility, but it is there.

Is age 50 (up to the 50th or up to the 51st birthday) the maximum age for embryo transfer in Greece?

The maximum age for embryo transfer in Greece, unfortunately, at the moment it is 50. The Greek authorities have told us that they want to change the law to 53, but at the moment, it is 50, not 51.

Is assisted hatching harmful to the embryo?

No, it isn’t. Especially, if you use a laser, and you don’t touch the actual embryo. It’s not harmful, it has never been said that it’s harmful. An experienced embryologist who does the hatching if they are to do one is needed for it, that is it.

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Authors
Danny Daphnis, PhD

Danny Daphnis, PhD

Danny Daphnis, PhD has been a clinical embryologist for more than 15 years. He studied Biology and Biochemistry at the Metropolitan University of London and Masters in Prenatal Genetics and Fetal Medicine at UCL, London. He continued his postgraduate studies and completed his PhD at UCL studying chromosomal abnormalities and genetic diseases in human embryos. He entered the field of embryology and completed his certification acquiring the ACE diploma of embryology. He began his career in London Fertility Centre under Ian Craft and has worked in various fertility centers since, marking a rising course. He helped found the British-Syrian IVF center and especially the organization of the laboratory. Recently he established the Aegean IVF center in Tirana. Since 2010 he has been working in the Mediterranean Fertility Center in Chania as a scientific director actively helping the center acquire certifications and the prestige it deserves. Danny Daphnis has published scientific studies in reputable journals and participates regularly in conferences as a speaker. 
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Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is an International Patient Coordinator who has been supporting IVF patients for over 2 years. Always eager to help and provide comprehensive information based on her thorough knowledge and experience whether you are just starting or are in the middle of your IVF journey. She’s a customer care specialist with +10 years of experience, worked also in the tourism industry and dealt with international customers on a daily basis, including working abroad. When she’s not taking care of her customers and patients, you’ll find her travelling, biking, learning new things or spending time outdoors.

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