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Failed fertilization after ICSI: how can we overcome this?

Björn Heindryckx, PhD
Principle Investigator, Ghent-Fertility and Stem cell Team (G-FaST), Ghent University Hospital, Ghent University Hospital

Failed IVF Cycles, Male Factor

What can we do when fertilisation fails after ICSI?
From this video you will find out:
  • How is IVF different from ICSI?
  • What is the oocyte activation mechanism?
  • What are the crucial ingredients for successful fertilization?
  • What is the role of the oocyte in fertilization?
  • How efficient is ICSI?

How to approach failed IVF-ICSI?

In this session, Björn Heindryckx, PhD, Principle Investigator, Ghent-Fertility and Stem cell Team (G-FaST), Department for Reproductive Medicine, Ghent University Hospital in Belgium has been talking about the role of sperm vs. oocytes in fertilization, and explained how to diagnose and treat failed fertilization after ICSI.

How to approach failed IVF-ICSI? - Questions and Answers

When would you recommend ICSI, or is it always indicated?

It depends on the sperm quality, so we have some minimum parameters, the motility should be at least so much percentage, the concentration should be at least so many millions. We have criteria that almost every IVF clinic is Rusing, and if a sperm sample does not meet the minimum criteria, we will do ICSI in the first cycle. Nowadays, ICSI is a little bit overused, sperm quality has decreased during the last decades, that’s for sure. The reason for this is that most people say it’s environment-related or the lifestyle of the patients. We know it’s a fact that sperm quality has decreased immensely during the last decades, so we are using a lot of ICSI. For example, in Belgium, 70 to 80% of all the cycles use ICSI, and only 20 to a maximum of 30% use IVF. It’s because the sperm quality is not good enough to be sure that IVF will work, that’s why we prefer to do ICSI in the first cycle to prevent fertilization failure after IVF because of bad sperm quality. We have our criteria that everyone is using in all the IVF labs worldwide, and then we decide if it’s IVF or ICSI depends on the sperm quality. I’m quite sure that in a lot of ICSI cases, where the sperm is like on the edge of not being good enough for IVF and if we would do IVF with this couple that it would also work, but we try to avoid failed fertilization after IVF, that’s why we go ahead with ICSI a bit quicker.

Are there any other lab techniques, apart from ICSI, that can help with fertilization? I had a failure each time.

If no fertilization happens after ICSI, it’s mostly due to the oocyte activation problem. We do artificially induced calcium rises, and in the majority of the patients, it works. It’s only in less than 10% of the oocytes that we still don’t have fertilization yet. There is no other technique at the moment next to ICSI because that’s the last resort technique that is now existing, but if it’s an oocyte problem, we are quite sure that we could maybe rescue it with this nuclear transfer technology, but it’s too premature to use it in the clinic. We still have to do a lot more experiments and research to know if this nuclear transfer technique would be the next step after ICSI to overcome some fertilization problems. It will only help if it’s an oocyte, probably because we are transferring the nucleus from bad quality oocytes to donor oocytes, and then we have to fertilize it with sperm, so it would only be beneficial for patients with oocytes problem. In most cases, when we identify a sperm problem, this assisted activation always works, that’s a fact, and it’s working very efficiently.

I have 3 fertilized embryos. Would you go for blastocysts transfer or transfer day-2, or day-3?

In our clinic, we shifted to day-5 transfer, and our success rates have improved. We are doing day-5 transfer for 5-6 years already. I would go to day-5 because when the embryos don’t make it to day-5, it’s very likely that they won’t make it. It’s a good natural selection when you culture your embryos to day-5. We know in human embryology that the first 3 days of development are very much directed from the oocyte. It has all the proteins present in the oocyte that ensure embryo development until day-3. It’s only from day-3 onwards that the embryo awakes those new proteins, which are produced by the embryo itself. It’s also good if you culture until day-5, that way you know that the last two days, so from day-3 to day-5 that they are working. If they are not working from day-3 to day-5, if you have failed blastocyst development, failed embryo development, we suspect that there is something wrong with the paternal DNA, so with the father.

What about PICSI? When is it recommended?

PICSI, it’s a kind of selection technology to select sperm with normal DNA, without DNA fragmentation, but I’m not a believer in the technique. The studies that have been published are not convincing to me and the experts in the field. If it would be promising, everyone would do PICSI. I don’t see a lot of publications anymore on PICSI outcomes, so I think it was hype for a certain time. People thought that if you select sperm, which contains less DNA fragmentation that you have a higher success rate resulting in pregnancy, but all the studies that have been published are not reassuring, not convincing. We also did some studies, on PICSI and we didn’t see any benefit of using this technology, so I would not recommend it. The literature is now quite sure that it doesn’t give any benefits for any indication of any sperm abnormality.

What is your opinion on trying to improve egg quality, e.g., via PRP? Do you do PRP at your clinic?

We don’t use it in our clinic, it’s a technique to increase the maturation status of the oocytes. When we have this failed fertilization after ICSI, and we see that the mouse tests point to an oocyte factor, we wait longer to do the ICSI with assisted oocytes activation (AOA). We know that the maturation stage of the oocytes is very crucial. If you suspect an oocyte factor, the cytoplasm can be a little bit too immature, so we wait for a very long time to remove the cumulus cells around the oocytes. The oocyte is getting matured after collection even longer than what we normally, do in other normal patients. When we then denuded the oocytes, we also wait an extra time before we do this assisted activation, so it might not be a bad idea to start the upper study to increase the maturation stage of the oocytes, but we don’t do it in our clinic, and we have done a study, but it has not been done in the context of failed fertilization, it might be a good suggestion to dig into further.

Can I double-check if what you have explained the same as Calcium Ionophore? I have seen this listed in my clinic’s price list.

Different calcium ionophores are being used as a technique to induce this calcium raises. In the UK, as far as I know, they are only allowed to use this commercial one, it’s called Cult-Active, well the product is called calcimycin. Because of the regulations in the UK, they can only use this commercial one, which is EU approved, but in our hands, it’s not working. When we exposed oocytes to this calcium ionophore that is used in the UK, we didn’t see any activation happening. We only saw as I showed you in the picture a very small calcium raise. This is not enough to activate an oocyte. I’m not in favor of this commercial calcium, and I know the company is shifting. They will start producing this commercial calcium ionophore that we are using shortly, the ionomycin. It is much more powerful and gives a very big calcium raise, and is very efficient in our hands. I heard it’s already 2 or 3 years that the company is doing this since we published our study and showed that this Cult-Active is not very efficient and not activating human oocytes. The company has developed a commercial version of the ionophore that we are using, however, it’s still not on the market, unfortunately. In Belgium, all the labs use ionomycin, and they all use the protocol to induce efficient calcium rises to overcome failed fertilization.

If you say the UK only uses commercial calcium ionophore, then it is not worth adding it in?

It gives some calcium raise, as we have seen in our study, but it doesn’t activate the oocyte. I think it has to do with the stability of the product, so maybe because some publications mention that they can rescue failed fertilization with this Cult-Active, but the efficiency rate is always much lower than the efficiency rate. If you use it quite freshly, you have to keep it in the refrigerator, this commercial one and it’s ready to use, so I think if you buy it, and you use it immediately, it still has some power to work efficiently. We used it after several weeks of being in the refrigerator. It doesn’t expire so fast, so you can use it whenever you want, and we didn’t see any activation, any fertilization with this product. It might work if you use it when it is very fresh, and that’s why some clinics get some activation and success but with less efficiency than the protocol that we are using. I heard a lot of complaints about this commercial Cult-Active and a lot of labs contacted us to ask why this Cult-Active is not working, but in our hands, it also was not working. We didn’t do a big study on that yet, for example, study when it expires or when the activity is losing its effects. I do think it has to do with the stability of the ready-to-use-product. The ionomycin that we are using, we make it fresh for each patient. We make it just before the treatments, we make the solution, and we apply it on the day for one patient, and then we throw it away, so we make it fresh for every patient that has to undergo AOA because the ionophores we know are very unstable so if you keep it for a long time, it will lose its activity, and it will lose its efficiency. I would not recommend using this commercial Cult-Active that is used in the UK.

Can it happen that sometimes not all the sperm chosen for ICSI is correct?

We always use motile sperm to inject because it’s a sign that the sperm is alive, you should never select immotile sperm because if it’s immotile, it can already be dead for a long time, and then you have DNA degradation, which will affect your embryonic developmental potential. We have to base on the morphology, the head if there are no gross abnormalities that we see but we cannot see, the DNA inside, so the DNA might be more damaged in one sperm than the other. There are no techniques to examine this or no selection procedures like this magnetic sorting that can help to increase the efficiency of selecting sperm. Not all the embryos that we produce make it to day-5, so it could happen that some sperm is not capable of supporting embryo development, and then it’s the wrong sperm, but we cannot avoid it, there are no techniques or microscopes at the moment to choose the perfect sperm, that’s not possible.

When you are preparing for IVF is there any food that is required for the couple?

This is a little bit out of my expertise field, but I know a lot is going on with nutrition and antioxidants for sperm quality now, as well as, other stuff. For me, there is no concrete evidence that there is something magic to improve your sperm or egg quality because if there would be, then we would recommend it for every patient, so it’s also a commercial angle. There are some companies specialized in all these antioxidants and healthy foods for IVF people, so like I said, if there would be something magical again, we would be obligated to mention it to patients and give the advice of eating some kinds of food or some supplements in their food to increase their pregnancy chances. Some things are very detrimental for the egg or sperm quality like smoking, smoking will reduce 50% of your pregnancy chances, especially, in female but also male, too much alcohol will also decrease your sperm quality and your egg quality, so that’s the obvious things that we know that are reducing your success rates immensely but apart from smoking and drinking, I would not say there is concrete evidence that there is something magic that can improve your fertility apart from your lifestyle, a healthy BMI is also important.

Björn Heindryckx, PhD

Björn Heindryckx, PhD

Björn Heindryckx, PhD is a Principle Investigator, Ghent-Fertility and Stem cell Team (G-FaST), Department for Reproductive Medicine, Ghent University Hospital in Belgium. Currently, he's also a promoter of 10 PhD students, 1 post-doc. Directly supervised 16 finished PhDs. He's a National Representative of Belgium for ESHRE / Co-founder of the Belgian Society for Stem Cell Research (BeSSCR)/ Board Member of the Belgian Society for Reproductive Medicine. Author and co-author of 103 A1 publications. His main topics of research are: Lineage segregation during early embryo development in mouse and human / Investigating different pluripotency states of embryonic stem cells in mouse and human / Failed fertilisation after ICSI & the oocyte activation mechanism / Nuclear Transfer to overcome mitochondrial diseases and Infertility/ Gene editing in the mouse and human germline.
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