ICSI or not to ICSI: should it be considered in every IVF cycle?

Victor Montalvo Pallés, Institut Marquès, Spain: My name is Victor. I was born in Barcelona, and I’ve worked as an embryologist for the past 9 years, mainly in Spain. Nowadays, I’m the Lab Director for the Institut Marquès group. We have a lab in Rome and another in Barcelona, and I’m managing both.

We’re part of the FutureLife group, which has many clinics around Europe, so we have a lot of international access. Many of our patients in Barcelona are international—French, Italian, even Australian—so we’re used to working with a variety of cultures and languages. I’m just happy to be here and to discuss ICSI. I think it’s an interesting topic.

In our clinic, we’ve been doing 100% ICSI probably since 2018. Before that, we used to do maybe 10% conventional IVF, and all of those cases were split cases—half of the eggs with ICSI, half with IVF. That gave us a lot of data. For us, the results were better, not necessarily in fertilization rate or blastocyst rate, but in avoiding fertilization failures.

We also found that it was easier for doctors to explain to patients that we were doing everything we could from the beginning. From the first treatment, we used ICSI to avoid the emotional and financial cost of fertilization failure and having to repeat the treatment. That’s the reasoning behind our move to 100%.

Natalia Kondakova, IVF International, UAE: My name is Natalia Kondakova. I’m originally from Moscow, Russia, but I’m now based in the UAE. I’m a senior embryologist at IVF International Fertility Center in Dubai. I started my career about 15 years ago. Since then, I have worked as a clinical embryologist in Moscow, Kazakhstan, and now in the UAE.

We also do 100% ICSI. We’re quite new on the market in the UAE, we opened just 6 months ago. For us, the main reason is also to avoid bad experiences for our patients, fertilization failure or even low fertilization rates. We try to avoid that entirely. So ICSI is our method of choice for that reason.

Natalia Kondakova, IVF International, UAE: Well, generally, ICSI is not a strict requirement for genetic testing nowadays. Conventional IVF can also be used for PGT. As I mentioned, to increase fertilization rates and the number of viable embryos suitable for biopsy, and to avoid any failure, we use ICSI as our preferred method.

Victor Montalvo Pallés, Institut Marquès, Spain: Usually, when you have a case like this, where embryos stop developing at day 3, we think that it could be a male factor. Obviously, we cannot guarantee that, but we tend to think that way because day 3 is when the genetic material of the male activates, and it can give rise to this stoppage of cell division.

On the other hand, today we just saw a case in the clinic—a 31-year-old woman—who was having exactly this issue. They decided to split the eggs: half with a sperm donor and half with the husband. We saw that all the embryos did exactly the same—they stopped developing. That’s proof that it’s not only a male factor; it can also be egg-related. So yes, we tend to think that way. Honestly, you could do another test to complement the spermogram, and I think it’s a good idea.

Natalia Kondakova, IVF International, UAE: Generally, we try to evaluate the history of the patient, always. If a patient has undergone a previous cycle with us, we always review that information and see what we can change, what other options we can offer.

So yes, it’s definitely good to see the DNA fragmentation. But also, there’s a lack of information in this question. Cases like this need to be evaluated in general. As Victor said, it can be egg-related. Also, if the patient has PCOS, what was the maturation? How many actually got fertilized? How many reached day 3? If only one reached the blastocyst stage, what quality was it? Has it been tested or not?

All of this can be evaluated to understand what it’s related to, generally.

Victor Montalvo Pallés, Institut Marquès, Spain: There are a lot of studies, a lot of papers, that speak about the safety of ICSI—or the safety of IVF in general. Nowadays, there’s no difference. There’s no higher risk from using ICSI. The only thing that could be damaged during ICSI is the egg itself—if it’s not performed properly, or if the egg is a bit damaged or sensitive. That could be an age-related factor or a morphological factor.

Yes, a small percentage of eggs could be damaged during ICSI. That KPI is usually below 5%. If your lab is performing well, you should have a low degeneration rate after ICSI. That’s the only thing that could be damaged—not the future baby, not the future adult. That’s not proven.

Natalia Kondakova, IVF International, UAE:  First, it needs to be mentioned that ICSI is a method of overcoming male factor infertility. Many research papers state that some patients, some groups of patients, can benefit from conventional IVF.

In terms of overusing ICSI: yes, it is being used wider and wider all over the world. And actually, in my opinion, we need to be reconsidering it, because it is already stated that it’s not giving some couples a better chance to have a baby sooner. It’s not increasing our fertilization, it’s not increasing the pregnancy rates, but it is definitely preventing us from fertilization failure.

The success rates of fertilization are quite high. As Victor said, if the lab performs well, the degeneration rate should be less than 5%, and the fertilization rate should be above 80%.

Regarding the ethical question, I’m not sure how it is in Spain or in London, whether it’s charged extra for ICSI or not. Generally, in the UAE, it comes as a package. So in terms of money, the patient pays for the package, and it’s already included. Well, in terms of creating, as we say, an artificial human, using a not very natural method, I think what we try to do in the lab is to mimic nature.

Victor Montalvo Pallés, Institut Marquès, Spain: In our clinic, we are very evidence-based. PICSI, IMSI, and even ZyMot have not been strongly proven to give an advantage. I’ll explain the difference:

ICSI, we choose a sperm, and we just put it inside the egg.

PICSI would be a more physiological solution, because we are trying to find the sperm that can fertilize, the protein that’s on the surface of the sperm, and through a process, we choose that sperm.

IMSI is just higher magnification that allows us to see it way closer and choose better which sperm we’re going to use.

In our clinic, we are offering IMSI, but we don’t see any benefits. Together with all the research, we don’t see any benefits of IMSI. That being said, it’s the same with ZyMot or any microfluidics—they are really trendy right now. A lot of clinics, including ourselves, are offering it. We’re collecting a lot of data to try to prove whether we see any benefits or not. But for now, there is no strong evidence to support it. Every clinic has its own results, and that’s what we’re trying to do as a scientific community—to aggregate all this data to come up with an answer for all of you. Every clinic has its preference.

For me, my preference is just plain old ICSI and doing it properly.

Natalia Kondakova, IVF International, UAE: No, we just use classic ICSI. We are not offering IMSI or PICSI at all.

Recently, we switched to ZyMot totally. We stopped using centrifuge, except for very severe cases. So we are using ZyMot for all our cases, for all patients. I’m still collecting data, but the aneuploidy rate, I already see from the data, is increasing after starting to use ZyMot.

I definitely like it because it really helps us to focus mostly on the advanced techniques, not on working in andrology too much.

From my point of view, subjectively, when doing ICSI, morphology is much better after ZyMot than after the conventional preparation, like a gradient. We have the opportunity to do DNA fragmentation tests because we have CASA. So far, we didn’t start this research, like before and after ZyMot, what is the DNA fragmentation level. If the DNA fragmentation is high, then even after, it will be high. Let us see—we will continue research and collecting data. So far, results are promising.

Victor Montalvo Pallés, Institut Marquès, Spain: Basically, to choose the sperm, we choose the one that moves forward, motility and that looks good.

With sperm, we are strict. Only around 4% of sperm are normal. That just shows that humans are not great natural reproducers; we’re not really great at that. ICSI helps in cases of:

• oligospermia (low sperm count),

• teratospermia (when morphology is not as it should be),

• and asthenospermia (when motility is not as it should be).

In all these cases, it has been proven that ICSI can help over IVF. That’s the point of this conversation, whether it’s proven or not. But yes, it doesn’t overcome anything like DNA fragmentation, because that is unfortunately not something we can visualize through the microscopes themselves.

Natalia Kondakova, IVF International, UAE: If I knew the answer to this question… There are a lot of reasons for implantation failure—a lot of reasons—because it’s multifactorial.

Generally, if PGT-A is not performed, the first reason for implantation failure can be embryo aneuploidy. If it is a tested embryo, then it is even more unclear. It can be the uterus, factors like the different microenvironment in the uterus. Generally, we don’t know exactly what is going on if implantation fails.

We just try to do our best to transfer the most viable embryo in terms of morphology. If we are not performing PGT-A, we transfer the most beautiful, good-looking embryo. If it is PGT-A-tested, then it is also a morphology and a PGT-A-normal euploid embryo. Nowadays, we also have time-lapse technology to evaluate morphokinetics, which is the specific timings of embryo development. This can also be a tool to select the best one.

Victor Montalvo Pallés, Institut Marquès, Spain: Focusing on grading blastocysts now, which is a day 5, 6, or 7 embryo. The most common grading system is the Gardner score. There are several systems. That’s the most common. In Spain, for example, we have our own, which is the ASEBIR score.

All of the scores look at the same: the number of cells that we have in the embryo. We divide the blastocyst, which you should imagine as a 3D sphere, into two areas:

The inner area that you can see, like a ball inside, is called the inner cell mass, and this is what will develop into the baby. What we check is the number of cells that this inner cell mass has. When you see it by size, if it’s bigger, it’s a higher grade, usually an A. If it’s a bit smaller, or it’s degenerated, or you cannot see it clearly, then it’s a C or D grade, depending on the grading score that you’re using.

Then we have the trophectoderm, which is the remainder of the cells surrounding the embryo. This is also checked for the number of cells—if we have a lot, then it’s an A. If we don’t have a lot, then it might be a C or a D. The last thing we check is expansion, how big this embryo is.

If it’s really, really big and it’s hatching from the zona pellucida, then we can consider it a 5, depending on the score. It might have a number or a letter, depending on the grading system. We check these three parameters: expansion, inner cell mass, and trophectoderm.

Natalia Kondakova, IVF International, UAE: The first benefit of transferring a day 5 embryo is actually better embryo selection. We can see, if the embryo develops into a blastocyst, that it has potential. If we do the embryo transfer early, we cannot predict which one, even if it looks good, will form the blastocyst.

Here in the UAE, as far as I know, the majority of clinics perform single euploid blastocyst transfer, because generally our aim is the live birth of one singleton. However, I know some clinics transfer early, and maybe still there are groups of patients who can benefit from transfer on day 3, for example, some patients whose embryos are not developing.

Many professionals still believe that the best incubator is the uterus. So, if there is a chance, it still can be a chance.

Victor Montalvo Pallés, Institut Marquès, Spain: Unfortunately, using the microscope, we cannot see the genetic content—otherwise, our lives would be much easier in the lab.

That said, it has not been proven that ICSI either selects positively or negatively for genetically abnormal sperm. So, we’re not choosing more abnormal sperm using ICSI than we would be using IVF. Having said that, what we could do is try to use FISH testing on the sperm sample to see if we have an abnormal proportion of genetically abnormal sperm cells.

That’s a diagnostic technique that not a lot of clinics use. I think in the UK it’s not that common, but in Spain, it’s really, really common. We use it just to diagnose—to know if we should use PGT or not, or if we need to switch the sperm or not. So, that’s another diagnostic tool that we have.

Natalia Kondakova, IVF International, UAE: To be evidence-based, I would not recommend any additional add-ons to the cycle. In my current practice, we are not using it.

Definitely, if there was a history of degeneration after ICSI, because some patients have more sensitive eggs, and there could be some reasons, I would do the split, 50/50. I would try to do that. But, as Victor said, there is no such method that can help us to decrease the level of DNA fragmentation during the procedure.

A specialist urologist—a consultant urologist—can help in terms of this, to decrease or change lifestyle, or use some medication to decrease the levels of DNA fragmentation before treatment.

Victor Montalvo Pallés, Institut Marquès, Spain: We’ve been trying to implement ZyMot since 2018, I think it was. We did several studies to validate it—we had higher oocyte rates, higher fertilization, higher blastocyst rates, higher everything. We didn’t see any difference.

The only difference for us in our clinic was in the lab—we were faster and more efficient with sperm preparation. We also have to consider the costs. Here in Spain, at least in our clinic, if we use ZyMot, we have to charge it to patients, and that’s an extra cost. If we don’t see any benefits, that’s not always what we want to do. What we selected is a population of patients that do benefit from ZyMot, which is higher fragmentation: double-stranded and single-stranded fragmentation.

In these cases, we saw an improvement. It’s only in these cases that we consider using ZyMot. Otherwise, we use the classical version of sperm preparation, that’s density gradients, just using a centrifuge and doing different density gradients to see which sperm is capable of arriving to the end of the gradient.

Only in a selected number of cases do we use ZyMot.

Natalia Kondakova, IVF International, UAE: We have a time-lapse incubator available for all our patients.  I have a time-lapse incubator for 12 chambers. So far, all of my patients’ fit in a time-lapse. Sometimes I split also in between bench top incubator and time-lapse incubator.

It’s quite useful for us because we can check the fertilization, check embryo development remotely, 24 hours, seven days a week. This really makes our life easier and, as for the patients, it doesn’t cost anything for them. We are just offering it as a part of the package. For the sperm preparation also, Zymot is included.

I know that the cost of the IVF cycle in the UAE is much higher than in other countries. We try to offer as much as possible, as much as we can.
So far, we don’t have any artificial intelligence linked to our incubator, but I hope soon we will have one. This is something that we offer for all our patients.

Sandy Christiansen, MSc, Clinical Embryologist & Fertility Educator and Advocate: In the UK, we have our regulatory body, which is the HFEA—that’s the Human Fertilisation and Embryology Authority—and they have a code of practice. It is often recommended by the code of practice that ICSI is something that should be offered as either a medical necessity for male factor issues or in cases where there has been a failed fertilization with IVF. So, essentially, it is almost a requirement to have a medical indication. It is that way as well, I would say, with a small caveat—because it comes at a cost. You’re looking at paying an additional £1,000 to about £1,200, maybe even more in some clinics these days, to have that fee on top of your IVF cycle.

I think that is the case in the majority of clinics. We very rarely see full package deals here that include everything—from your consultations, your scans, your egg collection, and even medication. You rarely see anything that encompasses everything with things like time-lapse and ICSI. So, it’s a really good question. But I think, you know, there are definite cultural differences, there are clinical differences, and of course, regulatory bodies in different countries have different levels of what they can actually regulate, if that makes sense. So again, we all try to do our best with best practices to ensure the best chances of pregnancy for our patients within what we can do, what we can control. I hope that answers your question.

Victor Montalvo Pallés, Institut Marquès, Spain: We’ve been using time-lapse since the very beginning—I think it was 2012, 2013. We culture, I would say, almost 99% of our patients in a time-lapse. Unfortunately, in the clinic, it is still considered an add-on. I would like to offer, as Natalia was mentioning before, a rounded package that includes everything, but no. The economic reality is that it’s an expensive machine to have in the lab, so we have to offer it like this.

We didn’t see an increase in pregnancy rates overall when you’re looking at thousands of patients. But when you see certain cases—where you would miss fertilization in an egg, or you would miss reverse cleavage (which is an abnormal development that otherwise you would not see)—in those cases, yes, for that patient, it made a difference. Maybe looking at thousands of cases, it doesn’t increase the pregnancy rate by 5%, but for just that one patient, it was really important. And that’s what we try to convey in the consultation with the patients—that’s a powerful message. That’s why almost every patient decides to use time-lapse in our clinic.

Also, for us, it’s a transparency effort. We give access to the time-lapse imaging to patients live. That’s a lot of work for the whole clinic, because patients obviously do not understand what they’re seeing. There are a lot of questions asked. But that’s a full transparency mode for us—like, you can see the embryos. We’re not going to lie to you about what happened. You’re going to see what happened. You can go to another clinic, and they’re going to tell you, “No, that’s the grading. This one is good, this one is not.” So I think patients trust us because of that. That’s also a powerful message.