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IVF add-ons – embryologist perspective

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

Category:
Genetics PGS / PGT-A, IVF laboratory, Success Rates

fertility-treatment-add-ons-are-they-worth-it
From this video you will find out:
  • What is an ‘add-on’?
  • What ‘add-ons’ are available?
  • Is there any evidence that ‘add-ons’ really work?
  • Does assisted hatching, EmbryoGlue increase the chances of pregnancy?
  • What is endometrial scratching, and when is it indicated?
  • What about IMSI and PICSI?
  • What’s the evidence for PGT-A?

IVF add-ons in the laboratory - are they always helpful?

In this webinar, Danny Daphnis, PhD, Scientific Director at Mediterranean Fertility Institute, Chania, Greece, talked about IVF add-ons such as laser-assisted hatching, elective freeze all, EmbryoGlue, endometrial scratching, PGT-A, time-lapse imaging, IMSI and PICSI.

Dr Daphnis said that there has been a lot of controversy regarding the subject of IVF-add-ons. Scientists, embryologists and doctors opinions vary as many people view it as a way to increase their income within an IVF clinic. Other people believe them scientifically and try to help patients by acting upon them.

Dr Daphnis started with very crucial information that ART (Assisted Reproductive Technology) is going to reach 50 billion $ as a market by 2026, so people are looking at IVF in the wrong way. IVF is meant to help patients, it’s not to make money, it’s not to try and find ways of getting money out of patients.

What is an add-on?

An add-on, in simple terms, is a technique derived from standard IVF, it’s something that is not included in the routine IVF. Usually, it’s a diagnostic technique, which might or might not have a benefit. This can include laboratory clinical and complementary treatment. However, it’s quite controversial if there is evidence that they improve the live birth rate. Therefore, Dr Daphnis always advises patients that whenever they choose an add-on, it has to be after solid information from the doctor.

Dr Daphnis also mentioned that The UK HFEA (Human Fertilization and Embryology Authority) has been quite involved in these add-ons and has this specific traffic light rating. It lists some add-ons, and if you go to their website at hfea.org.uk, you will find out what each light means, for example, if it’s red, it means that there’s no scientific evidence. If it’s yellow, it means that it’s controversial, so there is some scientific evidence, but it’s not 100% backed up from analysis and randomized controlled trials. If it’s double red, then you should be able to look at it differently, so Dr Daphnis always urges that if you want to have more information about add-ons, you can visit the HFEA website. It’s quite informative.

Laser-assisted hatching (LAH)

It’s a technique where a small hole is created in the outer membrane of the embryo. It is supposed to make it easier for it to hatch. When the embryos get to day-5 or day-6 of development, they will start hatching and come out completely out of their outer membrane called zona pellucida. There are some situations where the outer membrane is abnormally thick, in some women of advanced maternal age, we can see this effect or if it’s hardened after a freezing procedure.

If you do want to do it, it’s quite easy, however, there has not been scientific evidence that it does improve pregnancy rates and especially live birth rates.

EmbryoGlue

It’s a specific media from a specific company. It’s enriched with hyaluronan, and this specific media has been told that it aids the implantation of the embryos, therefore, it might improve in vitro fertilization. It is hypothesized that it’s best suited for blastocyst transfer rather than cleavage-stage embryos.

However, the beneficial effect of this media is found in advanced age patients, and after recurrent IVF failures, it has been demonstrated by several studies.
Recently, there’s been an analysis regarding EmbryoGlue saying that it is helpful, but only in specific groups of patients. Therefore, it should be always very carefully selected for patients.

Endometrial scratching

It is quite controversial. It’s not an embryological technique, it’s a gynaecological technique. It’s supposed to increase the chances of implantation. How is it done? A gynaecologist will usually superficially wound the lining of your womb to improve the receptivity.

The theory behind that is that the procedure triggers the body to repair the site of the scratch. That releases chemicals as well as hormones, which is similar to what happens during embryo implantation. 
Supposedly, by scratching your endometrium, they try to mimic the implantation factors that arise. Some suggest that it also can activate genes to make the lining more receptive.

However, endometrial scratching has not been conclusively supported by evidence that it increases live birth rates, which is what we would like.

Time-lapse Imaging

This is one of the new tools for embryology. There has been a surge of companies that are making incubators, which are big cupboards that the embryologists culture embryos in. They’ve put cameras inside the incubators, these cameras can monitor each embryo by itself and look at how the embryo develops. 

What everybody is doing at the moment, in the last four or five years, is trying to create a logarithm that shows if development is specific, then you might have higher chances of implantation. When an embryologist looks down at the microscope, as it has been for so many years, they assess embryos morphologically, they assess embryos on how they look, so good-looking embryos have a higher chance of implanting, worse quality embryos have lower chances of implantation. With time-lapse imaging, we can see, and we can try and assess the embryos better.

 It has shown some promising results by trying to see the developmental milestones, especially after blastocyst formation, which has been helpful to select and perform a single embryo transfer.

The other good thing about time-lapse is that it’s non-invasive, so you don’t do anything to the embryo. You expose them much less to light or outside incubator conditions, so it provides a safe environment to observe the embryos. Hopefully, it will be possible to select the best embryos or mostly blastocyst to transfer to patients.

Time-lapse at the moment is still in its infancy, the data is still being gathered. They still are trying to make a hypothesis on what is best.  Dr Daphnis emphasizes that the embryos are still graded according to their looks, even though it is possible to look at how they develop.

IMSI & PICSI

These are two techniques, which are correlated with ICSI.

IMSI (Intracytoplasmic Morphologically Selected Sperm Injection) gives the possibility to see sperm more clearly through a microscope with a higher magnification.  
When you do IMSI, you see it much bigger, and you’re able to have a better view of the sperm, the head, the neck as well as its tail, you can look at cytoplasmic droplets and be able to assess the sperm morphologically better.
This is usually used for men with high numbers of abnormal sperm, or if they’ve done previous ICSI failed attempts, it might enhance fertilization results and hopefully better embryo development.
Again, it is not proven scientifically by any randomized controlled trials, so we’re still waiting to see its effectiveness.

PICSI (Physiological Intracytoplasmic Sperm Injection)also uses hyaluronic acid (HA) as EmbryoGlue does. There is a specific dish that is coated in hyaluronic acid. This specific compound helps sperm to be selected better for treatment. What does hyaluronic acid does in sperm? It shows sperm that is less DNA fragmented and more mature, therefore, by doing PICSI supposedly, you are selecting better quality sperm.

It is again not proven scientifically, but it has shown higher fertilization rates, higher embryo development rates, but not increased live birth rates.

PGT-A (Pre-implantation Genetic Screening for aneuploidies)

Three large randomized control trials are the most important ones and the most effective ones. And the conclusion is as follows:

  • it has been found that only when you do a biopsy on the cleavage stage, it can improve the live birth rate. Most IVF centres lately have been doing blastocyst biopsy and not cleavage-stage biopsies
  • everyone was expecting that at least it will reduce miscarriages, but in the STAR trial, it hasn’t, so that also has been a problem
  • it does help patients, but only those of advanced maternal age. Although, only if you look at the cumulative live birth rate, not per embryo transfer

These 3 large randomized control trials have not been so helpful in assessing and confirming that PGT-A does help patients.

Dr Daphnis also showed the status of Pre-implantation Genetic Testing in the UK and the USA. From 200 000 IVF cycles in the UK, only 3 000 were performed with PGT-A, so that’s less than 1.5%. Whereas in the US, from 458 000, 94 000 are with PGT-A, that’s 20%, that’s almost 10 to 15 times more PGT-A cycles per IVF, it’s quite a dramatic increase, so we have to be quite careful to whom we offer, what we offer.
If you speak to US groups, usually they would advise going through PGT-A testing however, there is no scientific evidence, at the moment, that it does help.

Types of studies

Dr Daphnis also presented how, in general, we should check if the evidence is there. Initially, whatever comes out, it starts with an editorial, then a case report, then case-control studies, cohort studies, randomized control studies and then systematic reviews. That means that all the above add-ons that Dr Daphnis mentioned should have this pyramid of papers of scientific journals until we get the systematic reviews to see if they do help.

This is the scientific way of doing it, that is why we need to be able to accept good quality studies and especially either randomized control trials or systematic reviews.

Dr Daphnis also emphasized:

‘We have to responsibly use the treatment add-ons in a fertility service. Patients must be informed fully, they must know exactly why they’re doing a specific add-on, not just for the financial aspect. Patients do deserve consistent and evidence-based treatments. Doctors should always declare any financial interest and always refer to the scientific aspects. It is extremely important because that way, we will be able to increase live birth rates by looking into more advanced treatments, better treatments and not just something that patients have looked up on different sites. We have to look at it scientifically to help patients achieve a much better quality of treatment.’

IVF add-ons in the laboratory - are they always helpful? - Questions and Answers

What are your thoughts on sperm diagnostic testing before IVF to look at varicocele stages that the doctors cannot detect via an exam? Also, do you look at DNA fragmentation levels in your lab?

When there is a problem like a varicocele, it’s always best to speak to a urologist, not any urologist, I would suggest a urologist who deals with infertility or a very good surgeon urologist. It would be good to do a scrotum or testicular ultrasound, have a set of blood hormones checked, do a semen assessment as well as semen culture. As you did mention, either perform sperm DNA fragmentation or even test the oxidative stress. 

The answer to your question is simple, I would advise going ahead and test all the parameters, especially if there is a varicocele present.

What about mosaicism after PGT-A on day-5 versus day-3?

That is a huge conversation between scientists on that. We know that on day-3 it exists, and it’s more difficult to assess it because, on day-3, the embryos are of eight cells, therefore it means that when we take one cell out, we only take one out of eight, we don’t know if it’s representative,  we do know that it’s present on day-3. When we do day-5 because we do take part of the trophectoderm, not the inner cell mass of the blastocyst, not to affect the embryo proper. There is a low level of mosaicism as well on day-5, however, you always must remember that when you take a chunk of cells from a trophectoderm of a blastocyst, you do get better quality results.  

Mosaicism is present on both. However, the big controversy is that we’re not sure, and this is what we’re trying to find out if mosaicism is a normal phenomenon. The fact that we have different cell lines is not something abnormal as long as it is low level.

Have you had a patient who after, many IVF failures with their own eggs had success after using an additional procedure?

The answer is yes. The difficult aspect is that we cannot be sure if the add-on helped or it was just the patient’s or the couple’s time to get pregnant. Even if you try an add-on, which I haven’t mentioned because this talk would take ages, it’s called PRP (Plasma Rich Platelet) infusion either in the ovaries or the endometrium. Some patients after PRP have had pregnancies, however, we are we cannot know for sure if the add-on was responsible for the pregnancy or the patient would have got pregnant anyway.

In your experience, do you think PGT-A increases success rates?

It increases the success rate of a very specific group of patients. It is important to do PGT-A when you have repeated implantation failures because chromosomal abnormalities can affect, or you should do it when you are of advanced maternal age.

Lately, I have had patients doing an egg donation cycle, and they asked if we should do PGT-A, which might affect chances of implantation. In advanced maternal age and repeated IVF failures, it does have a benefit, in my experience.

What do you think about immunological tests and therapies like intralipid infusions?

You can go to immunologists or haematologists, each one of them will subscribe to your own set of tests and subsequently give you specific regimes like Prednisolone. They should give you low-molecular-weight heparin (LMWH), they will do intralipid infusions, they might even ask you to do vaccines and stuff with anti-paternal antibodies. 

The basic fact, unfortunately, is that none of this is scientifically proven.  There are no randomized controlled trials or studies that have been performed by reputable laboratories that have been able to prove it.  The scientific aspect is that they’re not adding to your chances of getting pregnant at all.

We have seen in many fertility centres information in U.S. and Europe that PGT-A improves pregnancy from 20 to 60% for women over 38. After this presentation, I suppose that this information is not the truth?

In our lab, we have seen that in advanced maternal age patients, there is a benefit. If that increases pregnancy rates from 20 to 60%, I would not say it increases threefold. There is an increase in chances of getting pregnant, however, I doubt that it’s from 20 to 60%.

I would not want to quote that centres are lying because that’s not correct. If you go back to the trials, the randomized control trials, you will see that there’s no such big increase in the percentage of getting pregnant after PGT-A.

What is EmbryoGlue? Does it work?

EmbryoGlue is a specific media, it contains hyaluronic acid, which supposedly increases implantation, and any lab can use it. It’s fairly easy, it’s not that expensive, it’s one of the least expensive add-ons. You just utilize it to culture the blastocyst and use it to do the actual embryo transfer with EmbryoGlue. To increase the chances of the blastocyst attaching to your womb, it’s as simple as that. 

No specific data is out on whether it works. Some studies say yes, some studies say no. It’s not an expensive add-on, so I think it’s one of the add-ons that you can use.

Which sperm test do you recommend to prevent a fertilization failure in IVF?

There’s no way to know if you have an FDF, as we call it a failure to fertilize following conventional IVF, not ICSI. Unfortunately, 10 to 12 of normal parameter sperm, even if you’ve done DNA fragmentation, even if you’ve done FISH sperm DNA, there’s no way to determine that the sperm is going to fail to fertilize. 

Remember, it might not be the sperm’s fault, it might be that the eggs have a hardened zona pellucida, the outer membrane, and it’s not permeable to the sperm. You always have to consider that as well, so the sperm might be of very good quality, but it’s the egg’s fault for not allowing the sperm to go in.

Is it better to transfer 3 or 4 embryos at 38 without testing knowing that there will be no viable embryo because of the age?

I would start with the second part of your sentence, you do not know that there is no viable embryo because of age. Transferring 3 or 4 embryos depends if you’re talking about blastocysts, I would say it’s quite a risk to transfer 4 blastocysts, it’s a little bit too much. However, it depends on how many IVFs you’ve done, how many attempts you’ve done, it depends on the quality of those blastocysts or day-3 embryos that you’re going to transfer. If you have done it quite many times and it’s not working, then I would advise you to do PGT-A because you’re above 38 years of age, it might have a positive effect.

To answer the question properly, I would require more data and give you the correct response.

Do you do frozen embryos transfers or fresh?

We do both. There is no reason to choose one or the other. It depends on each patient, on the way you want to treat the patient, but you do both. With vitrification, it’s quite good to perform it, and you don’t lose embryo quality as long as the vitrified embryos are of good quality to start with. I’ve seen it many times if I vitrify medium quality or not good quality embryos, they tend not to survive, whereas good quality embryos or blastocysts almost have 95-98% chances of surviving.

The answer to the question is we do both, and I think most centres do both.

MitoScore – what is your opinion on that? Have you ever used it?

It’s quite new, it uses time-lapse imaging to do the mitochondrial score. I’ve used it only three times, and the reason behind that is there’s not enough evidence, or let me say, there’s not enough data at the moment to know what is best to look for.

Therefore, at the moment, everybody’s keeping at bay. Some big laboratories in the U.S. and Belgium are looking more into it.  My answer to this is that it’s quite new, we have no good or bad data to support it at the moment.

Wouldn’t it be better to do the PGT-A testing knowing that at an advanced age, we don’t have so many possible attempts because of the dropping number of good eggs? Trying many times is also a waste of time and money at this age.

In my experience, patients of advanced maternal age might have a beneficial effect of PGT-A however it also has to depend on each patient’s parameters because there are ladies who are above 39-40 years of age who make good quality blastocysts, you can have 3-4 or 5-6 good quality blastocysts. On the other hand, we have some ladies who are not able to get 1 or 2 blastocysts. 

As you can imagine, doing PGT-A testing on these 2 blastocysts is also a little of a waste of money. Your doctor should always take into consideration your specific requirements. If the couple produces good quality blastocysts and a good number of quality blastocysts, then yes, I would advise them to do PGT-A testing just to make sure.

Is it worth doing ICSI when there is no male factor?

If you look at conventional IVF rates and live birth rates, and ICSI rates for patients who don’t have a problem with a male factor, you do see that the rates are comparable. The answer would be no, it’s not worth it. However, we always have to take into consideration specific problems.

Let’s say that you have a patient who is coming from overseas, they’re coming from Australia to do an egg donation cycle. When you have egg donation, you tend to do ICSI. Why is that? If there is this chance of 10 to 12 failure to fertilize because the eggs were hardened or the sperm’s capacity to fertilize is not good, then you can imagine it’s a waste of time, money, and of course, the psychology of the couple.

If you’re looking at it on simple base terms, the answer to your question, it’s not worth doing ICSI if there’s no male factor, however, there are cases in which you should consider doing ICSI for the sake and benefit of the patient.

Wouldn’t the MitoScrore be more beneficial for older age patients? In conjunction with PGT-A?

I would probably agree with you when there is enough data to be able to assess MitoScore. That is the point of the MitoScrore, to help advance the maternal age of the patient and select embryos, which can become babies. I want to stress that there’s not enough data out yet to make this assessment.

If you hear me being hesitant, it’s not because I don’t agree with it, it’s because I always come back to the fact that it has to be evidence-based, not just something that 2 or 3 laboratories have come up with. Let us get more data, and that would be able to help you at that point.

What do you think about the cumulus cell test to select the right embryo for a single transfer?

It was a very good idea to test the cumulus cells that came out from the egg as a non-invasive technique. People thought that whatever covers the egg before we strip them to do ICSI, you can test them, you can do DNA fragmentation.

However, there’s no way to know that because cumulus cells are damaged, or not, that’s the egg being damaged or not damaged, it’s not directly linked to the egg quality, it was a very good idea, but it was abandoned quite quickly.

What number of mature eggs are needed for a live birth at 38, in your experience?

Mature eggs would not signify a specific number, you can have 2 mature eggs to be of spectacular quality and get a baby at the end of the day.  There’s no correlation if you have many mature eggs, then you will get pregnant. 

There was one study that said that the more eggs you have, the more chances you get to get pregnant. However, nobody has stipulated a specific number of mature eggs to get a live birth at 38. 

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. 
Event Moderator
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 traveling, biking, learning new things, or spending time outdoors.

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