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PGS: a valid approach for Repeated Implantation Failure?

Danny Daphnis, PhD
Scientific Director at Mediterranean Fertility Institute, Mediterranean Fertility Institute

Genetics PGS / PGT-A

Is PGS a good approach in cases of RIF?
From this video you will find out:
  • What is the right definition of Repeated Implantation Failure (RIF)?
  • Am I a RIF patient if I had failed cycles with low-quality embryos?
  • How to properly assess the embryo quality and what can we learn from that?
  • How does PGS work?
  • What are the PGS biopsy techniques?
  • What are the PGS analysis techniques?
  • What is the scientific data on PGS and RIF?

PGS: a valid approach for Repeated Implantation Failure?

Should I have my embryos PGS tested after many failures?

In this webinar, Danny Daphnis, Scientific Director at Mediterranean Fertility Institute, Chania, Greece has talked about PGS as an approach for repeated implantation failure (RIF) patients.

Should I have my embryos PGS tested after many failures? - Questions and Answers

Are there any factors other than euploidy that impact the quality of the embryo? Such as the metabolism of the embryo due to poor quality egg? I tend to produce only 1-2 blastocysts, and I had 1 PGS normal embryo that failed to implant with no other explanation.

There are, of course, but at the moment we don’t have the necessary technology. All metabolomic studies have shown us quite a little information, they’re not giving us enough information. At the end of the day, the embryo is not just chromosomes and beauty morphological criteria, it’s everything else, but we’re not able to pinpoint them correctly. Like I said before, euploidy is only the embryonic aspect of implantation failure, not the endometrium part because the endometrium is another ball game, but I really like the endometrium aspect. Remember, during implantation, there is a dialogue between the embryo and the endometrium, so the difficult part at the moment is that we have no idea what these two are saying to each other. When we find this sound, then we will make implantation much better, and we’ll know exactly, what’s going on, so by having one euploid, and I have no idea how old you are by transferring just one embryo, one normal embryo back, doesn’t mean that that’s the end of the day. The fact that you are producing one or two blastocysts is a sign that maybe egg quality is not good, but again one normal embryo doesn’t necessarily mean that it’s an embryo that is going to give you a baby if the embryo is the problem, I repeat because it also might be the endometrium.

I would like to know if despite, having done PGD, the embryos may be wrong. My husband only had FISH sperm for PGD. Out of four transfers, we have only had one biochemical pregnancy. As well as a natural pregnancy that ended in a biochemist too. My doctor says that the next step would be to do another PGD with double-stranded sperm or donor semen. The doctor thinks it may be a male factor. I am 36 years old. I had 5 normal embryos out of 32.

It’s very difficult to imply that it’s a sperm problem even if we have a very low count, for example, less than one million, and he might have low sperm quality, you cannot very easily say that it’s his problem or it’s your problem. I get that you’re having biochemical pregnancies and that you had 5 normal embryos out of 32, which is a low number, but you did get some normal embryos. I would suggest before saying that it’s a problem of the sperm and changing to donor sperm, again I’m not disagreeing with your doctor, I’m just putting out ideas. Make sure that it’s not an immune parameter that is affecting your womb, your actual uterus because it has been mentioned. It has been shown that some ladies have a very strong immune system, which might see the embryos as foreign bodies, and they don’t allow the embryos to attach, that’s one reason. But, you’re saying that there’s not an immune problem. If that’s the case, then by having so low embryos, so 5 out of 32 being normal, I don’t know why your doctor said to go to donor sperm and not donor eggs, probably there was an idea behind this because you’re making loads of eggs. Remember, usually, the egg is responsible for 80 to 85% of the problems and not the sperm, just keep that in the back of your mind. Other than that, I would suggest having one more attempt maybe, with less medication. Just so, you don’t produce so many eggs, you want quality, not quantity. Perhaps, you’ll get better quality either chromosomally and morphologically embryos.

They have made a transfer to me. The embryologist said the embryo collapsed. It was a blastocyst beginning to hatch. With PGD. What does it mean that it was contracted? Is it bad that they transfer it like this?

A blastocyst is like when we are cold, we become smaller, a blastocyst. If you change its parameters, its conditions collapse, so from a big size, it becomes smaller, so it collapses. Usually, this happens more likely when it’s about to hatch, and the reason is simple, that by doing this expanding and collapsing, it’s able to break the zona pellucida, which means the outer membrane, so it can go on and Haich. It’s not necessarily a bad thing. Usually, though, we do tend to wait for the embryos to come back and re-expand before we transfer them but again, that’s not necessarily a bad thing to have a collapsed blastocyst.

We are currently awaiting the results of PGS. Can you tell me why when 18 eggs were fertilized, only 3 embryos are suitable for PGS? Is this low? I am 46, and it was an egg donor.

Yes, it is a little bit low. Probably, if only 3 reached the blastocyst stage. I’m guessing, so in general, that is a low number because if you got only 3 blastocysts out of the 18 embryos, that is a low number. Now, there are two reasons for this. Either, egg /embryo quality or laboratory problem. There’s no other explanation or other simple explanation than that. It’s either the problem on the actual egg/embryo quality that it is like that, so there’s nothing you can do, or it’s a problem with the laboratory, that means that the laboratory is not, I don’t know capable enough to have good quality embryos. The answer to your question is that it is a low number, you expect a little bit more. As you said, it is with an egg donor now, then definitely it has to do with the eggs or with the laboratory, it’s down to the IVF lab or center to explain what’s going on there. It is low especially, with donor eggs, you would expect at least 30 to 40% of the embryos reaching the blastocyst stage.

What is the difference between PGD-A and PGD-T and PGD-P?

They’re all the same. There is a difference if you already have a specific chromosome abnormality or you’re doing it as a screening technique, it used to be that it was PGD and PGS, then they changed it to PGD-A and PGT. Now, there’s not even that, it’s called PGT-A, so it’s not PGD-A or PGD because PGT-A and PGD-T is the same thing. Now, they’re calling it PGT-A, but any way to make your life easy, it’s two simple aspects. If you have a known chromosome or genetic abnormality like translocations, deletions like cystic fibrosis, muscular dystrophy, neurofibromatosis, thalassemia anything that is a known chromosomal issue. It’s a normal PGD because you look for a specific problem. If you’re doing it as a screening technique, just to check the chromosomes if they’re doing well because you are a RIF patient, or because you’ve done 5 attempts and it’s not working. Or because you have repeated miscarriages, then that is usually the screening technique, which we call the PGT-A, so these two are different things. The simple PGD when you have a known abnormality and the PGT-A, which is a screening technique to look at chromosomes in general without the previously known abnormality.

My husband has an inversion on chromosome 9, would this has an impact on fertility? They say it is a variant of the norm.

We do get different variants, I’m guessing you did the karyotype, you and your husband, that’s what we usually do, and you found this specific abnormality. It does happen that we do get inversions or small deletions or even insertions. A piece of DNA is being inserted into the chromosomes. If the geneticist, because these are the people who usually, look at the karyotypes have found that it is within normal variants, then usually, that does not affect your fertility, and it will not cause any problems during fertilization. Remember, all the problems arise when you have an inversion like your husband, those happen during fertilization, when his chromosome number 9, for example, opens up from double-stranded, it becomes single-stranded, and your single-stranded chromosome goes to link with your husbands then that’s when it creates a problem, but if there is a normal variant 95%, I’m not going to say 100% because nothing is 100%, will not affect your fertility. If, however, you see that you’re having problems, then I would suggest speaking to a clinical geneticist to help you.

If, the patient has a chromosome Y deletion. Do you believe that PGS can help the future child?

I’m guessing your husband has a Y deletion, and he’s either azoospermic, or he has a very low sperm count. By doing PGS might help to get a child without this deletion. However, the Y chromosome is extremely difficult to pick up because it’s the smallest chromosome. If you’re thinking that doing PGS is to find out if the resulting baby has this Y deletion, then you’ll find that a little bit difficult, but it is possible to do. I don’t know if anybody has done that because usually, the men who you get the sperm from do not have sperm, so if you have a Y deletion, usually you don’t have sperm, therefore you can’t go on and fertilize and make embryos and test them for it. Unless, you have the AZFc, as it’s called deletion, which you might have some sperm, very little but some sperm. If you have the other two deletions AZFa and AZFb, then in 99%, your husband is not going to have sperm.

What could cause a high number of abnormal forms of sperm? How can we improve the number of sperm with a normal form?

Many urologists, andrologists, embryologists have tried to address this point. Again, it’s multi-parameter and not necessarily easily solved. First, it might be just how his sperm is like if your husband is born with blue eyes, then you can’t change them to green eyes or brown eyes, so there is a possibility that that’s his sperm cannot be changed. If the sperm has become like this, it’s usually due to environmental factors. Ether his diet, his way of living, his work, or for example, smoking or if he has a problem like diabetes, for example. Anything environmental, so usually what all scientists advise patients is to change the way you’re living, change your diet, if you’re smoking – stop smoking. If you’re doing any kind of recreational drugs, then stop doing them. Increase very important exercise, and sometimes people even said to increase sexual activity to 2 to 3 times a day, the more the ejaculates, the better the spermatogenesis. If you can take some supplements, unfortunately, all these supplements seem to be quite expensive, around 60 to 100 EUR per month. There are quite many out there, so I would suggest if there are high abnormal forms to also, take one of these supplements to help alongside everything else. I mean don’t just go out and fork out 100 EUR per month taking supplements hoping that it will solve the day, you need to change your lifestyle, diet, and everything else.

Are embryos capable of ‘repairing’ themselves to some extent? If yes, could you give us an example of such a self-repairment?

It has not been proven that this exists, the only thing that has been referenced, it is very important, it’s not been demonstrated, so it’s not been shown scientifically is, for example, I mentioned mosaicism on day -3. Now, we have found, and this is one of the self-repairments that you might think, it’s not necessarily self-repairing. What we’ve seen is if we have abnormal embryos or some abnormal cells within an embryo on day-3 usually, these cells instead of becoming part of the actual embryo, they’re thrown to the placental part. Remember, when we look at the blastocyst on day-5, that’s only 2 days later, you have 2 different parts of the embryo, the inner cell mass, which gives rise to the embryo and the baby. The outer cells, which give rise to the placenta, one of the self-repairment mechanism that people have suggested is all abnormal cells are hopefully sent to the outer cells, which give rise to the placenta. That’s why we found completely normal babies, but they have abnormal placentas, so that’s one of the hopefully self-repairment mechanisms. However, I do stress out that these are not demonstrated, but that’s one thought.

My husband and I can’t make embryos. We had 3 rounds of ICSI with only 3 blastocysts. I am 40, my husband is 42. What else can we do? We did the karyotype test – all looks ok. My husband has fragmentation, but he is seeing a urologist to fix it. We will go for PGT-A on our next round. What do you think? Anything else we can do?

I would not advise doing PGT-A. The reason is, you only have 1 blastocyst and you’re going to pay for this, and most likely it’s going to tell you that it’s probably abnormal. I think your initial problem is the fact that you’re not making enough egg, so that means probably, your AMH is slow or diminishing and probably your FSH is not as high. There are other ways of going around it, don’t do more stimulations because you’re only getting a very low number of eggs, don’t stimulate yourself, don’t get too many drugs. Find other ways to get eggs hopefully, make them reach blastocysts and then transfer 2 or 3 together if possible. Do what we call the freeze-all protocol, so egg collection, fertilization, and then freeze it and then do it a couple of times and then transfer all embryos into one go, maybe that will help you. To do another round of ICSI, where you get 1 blastocyst, and you test this blastocyst, I think it’s too much of a hustle for your expensive and you’re not going to get what you want at the end of the day. You’re going to get information for sure, you’re going to find out what this embryo is and if it’s normal, but that’s one not what you want, you want a baby, you don’t just want information. My suggestion is to check that everything is good with your endometrium like hysteroscopy, immunology, etc., before doing another transfer. Then try and see if you can transfer 2 or 3 blastocysts in 1 go, just increase your chances of implantation.
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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 managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.
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