Oocyte quality factors to think about after failed IVF

Jon Aizpurua, MD, PhD
Gyneacologist & Fertility Specialist

Failed IVF Cycles

Oocyte quality factor to think about after failed IVF
From this video you will find out:
  • how do specialists know if an oocyte is of good quality before fertilization?
  • what is the relationship between age and oocyte quality and aneuploidy rate?
  • can BMI index affect oocyte quality?
  • is PRP/ovarian rejuvenation something that could affect egg quality?
  • are there any procedures or solutions that may have a positive impact on egg quality?
  • can stimulation protocol enhance the quality of oocytes?


Egg quality factors to consider after unsuccessful IVF

If your IVF has failed, it is time to look closely at the quality of the oocytes and examine the reasons for the failure. Dr Jon Aizpurua, MD, PhD, gynaecologist, obstetrician, the founder, and president of IVF-Spain answered patients’ questions during the Online Patient Meeting.

Dr Jon Aizpurua started his talk by explaining how unique the shape of oocytes is. He explained that among all other somatic and germinal cells, the egg, the oocyte, is the most complex cell in the human body. It is also the biggest, it’s the only one that can be seen with bare eyes, it’s like one-tenth of 1 millimetre, so you don’t need a microscope to see an oocyte. In terms of predicting the IVF treatments success, the female factor is the most relevant and the oocyte singular cell is the most powerful predictive factor in terms of the quality and outcome of the treatments. It is a very complex cell, but it’s also very difficult to approach it and analyse it. Dr Aizpurua admitted that there are very few works and scientific evidence on the crucial factors of the viability of egg cells.

The most relevant factor related to the oocyte quality is the age of the oocyte. This is a take-home message that all should remember from this webinar. It is quite relevant in terms of the quality of the egg because time is a crucial factor in the decrease of the ovarian reserve, time in the fertility life of a woman. The older the woman is, the weaker the genetic background of the oocyte, which will later produce aneuploidies, embryos developing weekly, and at the end, implantation failures, abortions. Therefore, the most relevant factor in reproductive technologies and then assisted reproduction technologies is the age of the ovary and oocytes.

- Questions and Answers

How do specialists know if an oocyte is of good quality before fertilization?

This is a very interesting question which asks if we can assess the oocyte quality before fertilization. Obviously, an oocyte is a very valuable cell. We cannot manipulate it. If we manipulate it, we fall into a paradigm and a contradiction. Once an egg is manipulated, we can’t use it. Either we know about the molecular mechanisms of the oocyte and then we cannot follow up the development of the cell because we would need to kill the cell to know the molecular mechanisms or we can just assess, without any intervention, in order to be able to use this cell and to have information of the follow-up of its biological behaviour. This dilemma will always be there. All this information we have on egg quality is based on non-invasive technologies. Otherwise, we would not be able to follow up on the development of the cell. This is, obviously, a big restriction. We can only have indirect data. This is true that there are some attempts with artificial intelligence and big data involving screening the oocytes on different depths in 3D and taking high-resolution pictures. This procedure is non-invasive and preserves the viability of the cell. It also gives us a lot of information that we can cross-examine with the behaviour of these oocytes once fertilized. This is a very promising technology because we could identify some structures that are not visible to the human eye, advanced microscopes that use polarized light, or even fluorescence. This data, pictures of a cell, can predict if this cell can get fertilized properly or not if an embryo resulting from this cell will have a good chance to proceed to blastocyst or even if the clinical outcome of this embryo will be positive or not. Obviously, this research has just started and there are a couple of scientific studies that approach this topic but this looks very promising. This is nothing we are now using routinely at clinics but I hope this is a technology that will be available in a couple of years’ time. This is interesting only for countries where it is not allowed to fertilize all eggs, like in former times in Switzerland or Germany or other countries around the world where there are restrictions for generating embryos for each cycle. In Germany, for example, they fertilize the eggs and then freeze them in the pro-nuclear status before they can be defined as an embryo. But, in this case, it would be very useful to have a tool that can predict if an egg is competent or not and then we should rely on these artificial intelligence tools that will be coming in the next years. So far they are not ready. There are also some other approaches like analysing the follicular fluid of each oocyte or the cumulus cells that surround the oocyte inside the follicle that after aspiration we can also assess under the microscope. There are several scientific works regarding analysing these cumulus cells, factors that they extrude in the follicular fluid in order to have a molecular fingerprint of these oocytes that will tell us if it is a competent oocyte or not. This was done in France a couple of years ago, also there are some Canadian works on this that look very promising. To conclude, for most cases and most countries it is not that interesting to check the oocyte quality before fertilization because we will see the oocyte quality after fertilization through the embryo quality. This is the strongest factor. The oocyte quality contributes in more than 80% to the embryo quality and it drives and runs the first three days of embryo development, up to 8 cells until the embryo gets autonomous in the so-called zygotic activation. After that, the embryo takes control over the cell division itself. But before, everything is run by the oocyte. So that is why it is not interesting to look at the oocyte, not at the embryo in countries where it is allowed. But knowing this and knowing the restrictions we have in the molecular analysis of the oocyte, knowing that we can have high resolution images, knowing about the cumulus cells and follicular fluid can tell us something about the biological competence of cells is, for sure, interesting. In some countries it could really be a key to the selection of these oocytes before fertilization, oocytes that we would prefer to fertilize in order to generate the best possible embryos in the first run, not just by chance.

What is the relationship between age and oocyte quality and aneuploidy rate?

This is the strongest and most remarkable relationship that exists in reproductive medicine. I will go into a deeper explanation because I want patients to understand why this is so strictly strongly related and what implications there are for planning the treatment. There are studies across the world, in all ethnicities, among thousands of women of different ages who went through treatment that provided a blastocyst that could get analysed via PGT-A or PGS. These studies showed that the relationship between the age and the aneuploidy embryo is very strong. We could then discard the age of the male or a lot of factors regarding oocyte quality, morphology, treatment plan, schedule. All these factors were absolutely irrelevant and insignificant. The only thing that is extremely strongly correlated with aneuploidy rate was the age of the woman at the time of the pick-up. Comparing different ethnicities, different protocols always have given very low variability between cases. You can take it for sure that if you are 35, between 55-60% of your blastocysts will be aneuploidy. If you’re 40, this will be something about 65-70%. If you’re 42, this will be something between 75-80%. If you’re 44, this will be something between 90-95%. This is like a pill of wisdom. If you realise this, the implications are extreme because carrying out treatments without assessing the chromosomal competence of the embryos is like playing blind, ignoring the strongest factor for success. In 90% of cases, the aneuploid embryos do not implant. This is the strongest explanation for implantation failure. If they implant, they get miscarried or aborted in 90% of cases. This is the strongest explanation for recurrent abortions. And even if they pass through these two filters, the 10% that remain are Down’s syndrome cases and other very rare aneuploidy that are compatible with life. This is not the first aim of reproductive treatment. Since we have the Preimplantation Screening Technology, till now, we’ve always had to explain why we use this technology if we’re not necessarily damaging the embryos. Now there’s so much evidence that the damage to the embryos is so ridiculously low compared to the benefits. We’re now at the change of paradigms and possibly from now on the question will be completely different. It will not be “Why should we perform PGS on embryos?”. The questions should be “Why don’t we perform PGS on embryos?” if the evidence is so strong, our goal should be avoiding implantation failure, avoiding unnecessary transfers, avoiding losing more time, avoiding costs, loss of resources, energy and minding the psychological aspect. To sum up, the relationship is strongly proven, extremely strong and the implications of these findings should be part of our future practice.

Can BMI index affect oocyte quality?

Yes, the BMI parameter that measures also the metabolic competence and people with extremely high BMI suffer from a lot of collateral diseases and syndromes. This obviously affects oocytes. This can be measured through metabolic analysis and leptins in the blood. If they’re high, they affect the oocyte quality and also the implantation capabilities of the endometrium. You should know that with a BMI higher than 28, the risk of spontaneous abortion is threefold compared to normal BMI, which is a lot. But also in cases of a very low BMI index, we all know that the professional sportswomen miss their ovulation. Anorexia is also linked to ovulation failure. Obviously, BMI as a parameter of metabolic competence of the body is strongly linked to oocyte quality and quantity.

Is PRP/ovarian rejuvenation something that could affect egg quality and quantity?

Ovarian rejuvenation or regenerative medicine is an approach that has started in a couple of centres around the world and it looks very promising, I have to admit. At our clinic, we’re also running a clinical study. We haven’t had so much experience yet but relying on what has been published so far and our own experience, I am optimistic about this technology. What we have seen so far is both the egg quality and quantity can improve. Obviously, this is a quite complicated technology that is not available everywhere. For patients aged 42-45, I think there is space for this technology because rejuvenation could contribute in letting ovaries in a 43-year-old patient behave like ovaries of a 41-year-old patient which makes an absolute difference. And those patients who are 45 – their ovaries could start to behave like they’re 43. The difference is not so big but it could be useful. This applies, obviously, to younger women with a low ovarian reserve and all women that have difficulties in accepting egg donation as a solution. In those cases, I think, this is a very promising technology. We will follow it up rigorously with a scientific approach and clinical studies that, hopefully, will give us more evidence in the next years.

Are there any procedures or solutions that may have a positive impact on egg quality?

Other regenerative medicine/therapies – yes. There is stem cell research, for example, taking part of the ovary’s cap cell from the place where we know that there is a low concentration of stem cells but where there are some stem cells sitting that are capable of generating new follicles and have the capability of generating germinal cells, new follicles, and new eggs. So this is another approach which is even much less studied than PRP that we mentioned. There are others that are a little bit easier that rely on the presence of stem cells from bone marrow, therefore, you’d need an aspiration of your bone marrow for isolating some kind of cells that get cultivated. They are not the same as ovarian stem cells but are closely related and could then if injected back to the ovary, make the ovary behave younger. “Other techniques and procedures” are a very wide definition. In the area of supplements, there are some that are interesting. This started at the end of the 1990s in Australia. There were clinical studies using human growth hormones which, administered for the stimulation of ovaries showed not to improve the number of eggs but improve their quality. Also, 3-4 years ago we published a paper in the American Society of Reproductive Medicine where we showed this is not only the morphological quality that gets improved. This is also the euploidy rate. As we described before, there is a very precise prediction of how many of the embryos will be aneuploidy in relation to age. You can lower these figures and significantly improve the proportion of viable, euploid, healthy embryos if we use growth hormones in special cases, in patients of advanced age and so on. This is something we have to comment on because it is an established protocol. There are thousands of studies all around the world also meta-analysis – the evidence for that is quite high. This is routinely used in a lot of clinics. Regarding regenerative medicine, this is much more in an initial state of research.

Can stimulation protocol enhance the quality of oocytes? How can it be enhanced?

Yes, the stimulation protocol can affect the quality of oocytes. Not only the drugs we use matter but also the timing, when we use the drugs, when you start the cycle when you have the trigger shot and the ovulation. These are all the factors that affect the quality of the oocytes. How can it be enhanced? Through personalized approach. There have been studies and disputes between doctors if they should use agonists, if they should use antagonists, or recombinative gonadotropins if they should use HMG, if they should add LH or not. At the end of the day, it is all nonsense, because the studies were primarily to find the universal formula for everybody. There is no formula for everybody. What we have to do is to listen to the nature of each patient, to study the molecular profile if they have some kind of variance in gonadotropin receptors, if it is inborn. This belongs to the genetic variability of humans. Then we need to apply different protocols to them, different drugs, if they share some kind of molecular profile, sugar metabolism. We also know that they would profit from very specific approaches. In the end, how we can enhance the oocyte quality is treating every patient as an individual, studying their profile individually and applying our knowledge and experience of what protocols work better for those cases individually.

We have PGS/PGT-A to diagnose embryos before the transfer, do we have any options to test/diagnose oocytes before the fertilisation?

I already commented on this before in the first question but let’s deeper into the details of this question. Nothing is so accurate in genetic testing of a cell but if we assess the genome, the DNA of the oocyte, we can’t use it anymore. Here we have the dilemma between analysing or using. We can’t do both. Diagnosing oocytes indirectly will never be so accurate as a direct diagnosis. Having said that, the approaches we know, the artificial intelligence, big data photo, and indirect – the follicular fluid and cumulus cell study. There have been also other approaches like using polarized light under the microscope to see the miotic, this is the structure in the oocyte that later separates the chromosomes. But none of the findings can predict the genetic quality of eggs. So in countries where it is possible, we would always prefer to analyse the embryo at the stage when it has a hundred cells. Picking out 2-3 cells does not absolutely damage the embryo. Then we have representative information that is very reliable. We have a molecular profile of the whole embryo and also of the quality of the egg from which the embryo arose.

There are many patients 40+ still willing to try with their own eggs. What would you advise them?

There are many patients like this. Some of them are trying to have their first child. What we advise them is to fight for this possibility using all available technology, regenerative medicine, clinical trials, adjuvant therapies or even embryo banking always with genetic analysis because these patients have a higher risk of having aneuploidy embryos. We will strongly support them as long as nature allows us to go this way. If you’re over 40, with a low ovarian reserve and metabolically weaker oocyte quality and even a very low AMH and so on. Obviously, the time bomb is ticking and lowering the chances to zero in just a couple of years. It is also wise on the part of the physician to advise and inform patients about the chances, to be transparent in order to show them alternatives like egg donation for those cases where it is no longer possible to try with own eggs.

What about the future? Is there any research being done to have a greater impact on oocyte quality? Advanced testing, artificial gametes, cell programming, etc.?

Artificial gametes are something that has already passed many animal models and it looks manageable as it relies on technology like reprogramming stem cells which is a little bit difficult. We don’t know what effects this could have later on the quality and the safety of the pregnancies, health status and the life expectancy of the newborns. So we should approach this in a conservative manner. Until we have no strong evidence that this is safe, this is just science fiction but these are promising advances. Although I don’t expect they would be ready for use in humans earlier than in 10 or 20 years’ time. But you should know this exists and this will come. This also involves cell programming. In terms of advanced testing, what looks very promising, and this could be also managed earlier is to know all the metabolic mechanisms that allow oocyte to be mature and to be competent and to interfere in this process and support lack of some molecular pathways that could be impaired and that contribute then to the age-related, poorer quality of eggs. There are some promising approaches to how we could interfere in the maturation process of the eggs in vitro. This would be like IBM or so-called in vitro maturation. You take a piece of the ovaries out to the lab and then from the very crucial pre-antral follicular cells manage the whole maturation process in the lab, in vitro, taking care of all the steps of maturation so that the oocyte needs to be competent and to behave younger in a manipulative way. This is something that will come maybe in the next 5-10 years. There has been research around that since the 1990s. In some cases, for example, extreme PCOS, where there are strong maturation problems, there are already in vitro maturation technologies ready that can make these oocytes mature in the lab better than in the human body. This is quite promising and I think this will available very soon. The same now with taking big data taking massive sequencing of people into account where we could individualize the medicine, we can see which metabolic pathways are stronger or weaker in each person and we can also support them with nutrients, with behavioral recommendations towards better life quality and improving egg quality in a natural way.

What do you think about coenzyme Q10 in terms of quality?

Q10 is a very common and well-known antioxidant that interferes in several ways with the protection of many cells and contributes to the balance of oxidants and antioxidants. This is something we usually use with our patients and we recommend these and other antioxidants in order to have a good balance of the oxidative stress on cells. But this is nothing that improves egg quality. This is something that protects you against the interferences of our lifestyle like smoking, pollution, bad food, a sedentary lifestyle and a lot of things that contribute to the poisoning of our bodies. And this may protect from that. But this is nothing that improves the natural stage of a cell. Having said that, this is something we recommend in most cases.

Telomere length and oocyte quality?

Telomere length is related to lifespan expectancy. It is true and surprising that manipulating telomere length in animal models and in many cells the scientists could increase the life expectancy of cells and organisms, which is amazing. Such a simple thing could make us live longer but this applies to somatic cells. Somatic cells are the cells of the body excluding the germinal cells which in females, they’re oocytes and in males, they are sperm cells. The telomere length is not so relevant because the major factor for determining the age of the court of eggs is the first maturation stage of the precursor oocytes, the oogonia that have two copies of chromosomes before they make the first meiotic division and they start to prepare for a chromosomal formula that allows them to get fertilized. This happens interestingly at birth. The first reserve of precursor oocytes gets activated very early in our lives and from then on goes regular decrease that gets reactivated with the first menstruation where a lot of those cells get lost and then the fertility age of a woman starts. This time is the time that already sets the vulnerability of oocytes to time exposure and to the risk of aneuploidy later. So if the question suggests that enlarging the telomeres of oocytes could make them behave younger, I have to say that this is probably not what could happen, in my opinion. Despite there is other evidence so far and to the state of our knowledge this could apply to somatic cells but would not apply to germinal cells like oocytes.

Uses of DHEA and myo-inositol to increase quality of oocyte?

Yes, DHEA is a precursor to the growth hormone. This is a prohormone so this is a soft and cheap approach to improving the egg quality relying on the capability of the DHEA to activate the production of endogenous growth hormone. This is the right path as I explained before – growth hormones have shown that they work. Inositol is also a supplement that you can buy in all pharmacies and drugstores in the United States and is part of most of the compounds of the poly-beta and poly-supporting compounds that are available. The same is with vitamin D support and so on, antioxidants, the Q10 that was mentioned before. All this stuff is OK. I have to admit there is no serious scientific work that shows that the use of Q10 helps significantly to improve any parameter but the logic behind it is sustainable. The damage they produce is insignificant and so far there is no trouble and no fear about using it but there are, as I mentioned before, much stronger tools to improve the quality of eggs than this.

Is hyperbaric chamber session another option to improve egg quality but also superoxide dismutase molecular?

Yes, there are very interesting research results concerning the hyperbaric chamber. Also the use of ozone, also the freezing therapies. There are a lot of approaches. We are expectant regarding the results in the clinical trials that are seriously designed and that really could show that there is evidence for that. You can be sure that as long as there is strong evidence on any of these approaches, this will immediately spread around the world and everybody will use it. The fact that these approaches are now starting to get checked and contrasted is promising but we should not get too enthusiastic about it until there is proof that they do not damage the gametes and that they really help.

Any suggestions about egg donor age and gapping period for egg donation?

This is all very individual and very different. So this is a formula where not only the age is a predominant parameter, also the resource of the ovarian reserve. For example, a 36-year-old woman who already has absolutely no ovarian reserve should be orientated to egg donation earlier. Also, it is a matter of patients’ wishes. Some of them have, from the cultural or religious points of view, trouble in accepting egg donation as an option. We have to respect that. And others, even if they have a good ovarian reserve, they prefer the short and easier way to treatment and their success. So there is so much variability among IVF patients and humans so it’s quite difficult to suggest a time where this could be an alternative. But knowing the aneuploidy rates, knowing that ovarian reserve diminishes with age, I can give a concrete answer to this question – 43 is a good age to consider the option of egg donation.

Can you explain vacuolated oocyte quality?

This is a morphologic parameter of oocytes which has a lot of myths around it. It’s also not only the vacuolation but also the colour and shape which can be assessed through a microscope from a picture of an oocyte. They were the only parameters we had in the past to assess the quality and which have been strongly related to the quality of eggs and their results. And this is partially true. A vacuolated oocyte is an oocyte that, at least in the lipid metabolism, is insufficient or incompetent, otherwise, it would not build such kind of walls and also the pigmentation and many other parameters could give an impression of the viability of those oocytes. Some of the oocytes instead of being completely round are elongated like a pill [capsule] so this is also associated with a lesser quality of the embryos. So these indirect visual parameters that in the history of embryology have helped the embryologists to ascertain if an oocyte is normal or suspicious. But, honestly, this couldn’t contribute prognostically to improving anything. At the stage of fertilization, if the oocytes failed to fertilize, this evidence is much stronger than the appearance of an embryo. This is a biological fact: this egg couldn’t get fertilized so this is a non-competent egg.

How about if an older woman has cytoplasmic IVF i.e. using own eggs and cytoplasm from a younger woman?

This is forbidden in most countries because the cytoplasm has also the mitochondria. And the mitochondria contain DNA from the donor so if you create an embryo like this, you would have three genetic instances in one embryo. So three genetic parents are, first of all, not regulated in most countries. I think in the UK, a couple of years ago, there was a clinical study or an exceptional allowness to research in this area. But I don’t know how this ended. This was surprising for most of all other European clinicians who could never make things like that in our labs. The technology behind that is the same technology as the nuclear transfer that is used for cloning humans. Now you understand why this is forbidden. Having three genetic parts in an embryo is like a chimera. This is like mixing genomes from different origins so nothing really we should go for, I think.

What is your opinion on the 2-egg embryos using DNA of one woman and the mitochondria of another?

I think – safety first. The logic behind is easy to understand. The cytoplasm of the egg is like a universe. This is the most complex cell in the body. If you take all the parts of a younger, metabolically competent cell into the nucleus of an older woman, we could expect that the cell division will be then controlled by the competent and younger component of the cell, so this makes sense. Mitochondria are like the energy engines of the cell. When you’re young, you have a higher concentration of mitochondria in your cytoplasm. When you’re older, you lose it, but there are other approaches that work on the same aspect but avoid chimerazation and generation of embryos with three genetic parents. This is the autologous injection or accumulation of mitochondria in the own cytoplasm. This is like an autologous transplant of enriched mitochondria into the patient’s own cells which is like an autotransplant and thereby is ethically absolutely non-problematic and from any other point of view non-problematic. This also looks promising and there are a couple of studies already ran that showed some promising results.

Is it true that a very good laboratory makes a huge difference in the resulting embryos and their quality? Especially the medium/culture in which an embryo is helped to grow and develop?

Every good laboratory makes a huge difference. Let’s say a very good laboratory and a good laboratory make a huge difference compared to enriched or under average laboratory. As long as the standards are in the upper half or in the upper third, the differences are not so big. Obviously, the culture media are industrial products. They come from a couple of providers worldwide so there is not so much creativity left to improve this aspect. The way of work in our laboratory is essential; the technology in the laboratory, bench-top incubators, hypoxia in the incubation atmosphere, Time Lapse for all embryos so embryologists don’t need to take them in and out every day to assess them under the microscope – all this may contribute much more than the media to preserving the full potential of each embryo. To maintain them as much untouched as possible, keeping the environment as friendly as possible to the embryo. But there is not a super perfect environment that makes weak embryo stronger just like this, I hope you understand. The only thing that can be made in the culture and in the manipulation of embryos are mistakes or damaging them but nothing can be done to make them better than they are.

How about acupuncture? After still miscarriage I did 8 sessions of acupuncture and I noticed a tremendous change in the flow of my menstruation blood and the activity of my ovaries.

Acupuncture may help to improve some metabolic balances in the body and to restore some affected paths and I am happy that this helped but, for sure, the reason for miscarriages which is in 80% of cases of genetic origin cannot be treated with acupuncture. Your wellbeing can be treated with acupuncture, how you feel and how you process the whole treatment and we are open to acupuncture. We have acupuncture in our clinic, reiki and yoga specialists and everything is fine as long as this makes you feel better and more confident in the treatment, it relieves some pains and tensions. We are so thankful for having these approaches but seriously this will not be efficient against miscarriage risk if you have had one.

I want to have IVF with my own oocytes. How would you proceed in my case? How would you advise to start? I’m 39, AMH last year in April 1.5, slightly overweight, non-smoker, non-drinker. My husband: 59, sporty, non-smoker, non-drinker, diagnosed with varicocele last year. We’ve had one almost successful IVF with our own cells. We had 2 embryos: 5AB and 3BB. The first implantation with 5AB resulted in pregnancy with heartbeat on week 5, and miscarriage. Later frozen embryo transfer done with 3BB and resulted in pregnancy but pregnancy stopped to develop week 5. Miscarriage followed by aspiration. No PGD was done on the embryos. However, we were tested for over 700 genetic mutations – no significant genetic mutation diagnosed.

I think this exceeds a little the form of our event because this is such a specific question but I can tell you how we would approach that. You have a small ovarian reserve that does not fit so well with the AMH you have reported. Only two embryos resulting from a stimulation cycle is difficult to understand in a 39-year-old woman with such an AMH. The only explanation I could find you have very reduced ovarian volume; maybe you had surgeries before, some kind of cyst removed, or you lost ovarian tissue. Otherwise, this does not fit because I think with this age and this AMH you should be able to generate at least 6-8 embryos. As for the two implantations, this is very good news, you are a good implantator. All embryos seemed to be able to implant which is very good news but the reason for miscarrying both is very possible that they were aneuploidy. It is 80% of cases. We would propose for you to have an immunological assessment of your endometrial tissue in order to make sure that there is nothing additional in your neurologic going on. The treatment of choice for you would be if we cannot improve your stimulation results, embryo banking program with PGS with at least 2-3 stimulation cycles. As long as you are younger than 41, and if we could achieve higher stimulation results maybe 1-2 cycles would be enough. But with PGD, with freezing of the blastocyst, with the preparation of immunological rejection risks in advance and with a specific preparation in your endometrium to diminish the risk of repeated miscarriage. But with PGS the strongest risk would be definitely be removed.

What is your opinion on a large age gap between the egg donor the intended father in terms of the health of the resulting embryo? Especially autism as I’ve been told it relates to father’s age and a large age gap.

There is another option. To have treatment with both donated gametes. This is true that the increased age of the father is related to not only autism, possibly other epigenetic diseases where we don’t have so extensive records of follow-ups of the quality of life of these newborns across the world during the last decades. So there’s still a lot of work, analysis and epidemiologic follow-ups needed in order to assess properly this risk. This is then a question for the parents. I know a lot of cases where the woman is 40, the man is 50, and the woman has already diminished ovarian reserve so they need egg donation. The husband says “OK, if we go for egg donation, let’s go also for sperm donation and we make an embryo adoption” as a sign of solidarity. Patients should also consider how to avoid risks of epigenetic diseases if the husband is 60 or 70 is also an alternative. In the end, the assumption of that risk is something that the patients have to decide, our job is to inform them about those risks and that they can make the decision well-informed.

I’m 39. I’ve had 3 failed IUIs and 2 failed IVF treatments where I didn’t get any Day 5 blastocysts. I used donor sperm so that wasn’t an issue. Is egg donation my only hope?

I would need to see the profile of those two failed IVF treatments, which protocols were used, how many cells, why the embryos blocked their development. When using donor sperm, the male factor should be under control and the most reasonable explanation for embryos stopping development is the oocyte quality. This is exactly what the topic of this event is. Is there a possibility that a woman still has reproductive power to increase egg quality so she can avoid egg donation? This would need a very serious and deep study of this special case but, as we mentioned before, there are several technologies that are already available with hormones, adjuvant drugs, specific protocols, metabolism adapted protocols, regenerative medicine that could help exactly in those cases where the egg quality appears to be the main and crucial factor. But even after having checked these in an individual way then the egg donation is, for sure, an option and the shorter way and the easier way to success. This is then a decision that has to be taken in an informed and transparent way. These are exactly the cases where we see that the advice of a doctor is crucial.

Is it worth transferring mosaic embryos if they are the only ones left after PGD?

It depends on which chromosomes are affected by mosaicism. If these are chromosomes that are present in aneuploidy that is compatible with life, there is a recommendation by the European Society for Genetics not to transfer those embryos. For all others affecting big embryos that are absolutely incompatible with life or mixtures of embryos that have chromosomes misaligned that are incompatible with life, then there is nothing to lose transferring them. This is why, after the last revision of all the papers published, most European and American societies recommended transferring those embryos and this is routinely done in our clinic. We transfer those embryos. Here, you only can win but you cannot lose because if the mosaicism doesn’t get corrected, if it’s not an artifact of the technology, if it is not relevant because the healthy cells overtake the control and then you will have a healthy newborn. If it’s otherwise, if the mosaic cells are prominent, if they take control over the whole embryo, then you will have no implantation. That’s all, nothing to lose. It’s the same as transferring embryos without having tested them. It’s even less risky because we could avoid miscarriage and having a newborn with aneuploidy.

Would you recommend ovarian rejuvenation in women over 50 with AMH and LH of zero to be combined with an egg donor?

I don’t understand how to combine it with an egg donor but we usually do not recommend treatments for over 50-year-olds. If it’s difficult to have reasonable results with ovarian rejuvenation in women aged 43-45, imagine it in 50-year-olds. I don’t want to raise unrealistic expectations for anybody. 50 years old – this is unfortunately beyond the reasonable usefulness of these technologies. The only way for such a case is, after assessing the obstetric risks, having the compliance of the patient and all the doctors that will support the pregnancy, to have access to egg donation. There are clinics like ours that once a patient is already 51, we cannot help you anymore.

What kind of supplements do you recommend for a woman who wants to go ahead with her own cells in IVF treatment? Coenzyme Q? Myo-inositol?

Vitamin D, antioxidants, healthy lifestyle, healthy nutrition, sports, physical activity, yoga, meditation, and acupuncture. There are a lot of things that contribute to wellbeing and everything that contributes to wellbeing contributes to the expectations about the cycle.

What dosage of DHEA and coenzyme Q10 is recommended? What other supplements can help for non-PCOS patients?

I’ve just mentioned them. The doses of the DHEA and Q10 are 75 milligrams for DHEA and Q10 – 10 ml per day but this is not the question. It’s a more general approach as I mentioned in the last answer. Be healthy, enjoy life and this will help.

How about spirulina? I heard that women take it to get pregnant naturally as it is a very strong antioxidant.

I’m usually not against the use of such kind of supplementation but at this point where this is the fifth question regarding these supplements, I have to say that I am against taking those supplements. This is absolutely irrelevant which kind of antioxidant you take, what doses or combination. If you want to do something to feel better, go to your pharmacist, they will give you a formula for combining all possible antioxidants. However, believe me, this will not change your situation so much. If you feel better doing this, then do that but in terms of improving your chances, it is not so relevant as many people think. I understand that human psychology works the way that everybody is ready to do as much as they can and what is under their control. This is why I support this kind of supplements as long as they have shown no damage. But still, it’s also a wrong attitude to take it with serious expectations.

Can certain protocols (i.e. types of medication used of the dosage) negatively affect egg quality? In the USA, we seem to focus on quantity so more medicine is usually used.

Yes, this is true that protocols and the types of medicines affect egg quality because they have to get individualized and tailored to the metabolic shape of each patient. This is usually not done. Going to the second question, if higher doses have a negative impact, this is a very interesting question because some authors had a concern that overcooking the follicles may induce some kind of increase of their aneuploidy and this was believed by all of us for a lot of years. But recent data has shown this is not true – the aneuploidy rate is given by the quality of the eggs before you start the stimulation. You should know that even with higher doses you cannot go above a certain activation of follicles. If you need only 300 and you are giving 450, then possibly this supplementary 150 are not helping. Maybe they are contributing to damage, this is true. There is no relation between higher doses and aneuploidy but there is a relation between higher doses in unnecessary cases that could metabolically damage your embryos and they will damage your pocket.

I’ve had 5 operations for myomas. Does this change the quality of my oocytes? I am 41.

Absolutely not. You can relax – myomas and egg quality are absolutely not related. You may have problems with implantation, placentation, delivery method, you may have problems in another sense but not with the quality of the eggs. There is absolutely no relation. I would give a completely different answer if you ask me about endometriomas instead of myomas. Endometriomas or endometriosis is very closely related to huge impairment in the quality of oocytes despite endometriomas location, despite their grade, this is for sure a factor that will impair the quality of the oocytes but not the myomas.
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Jon Aizpurua, MD, PhD

Jon Aizpurua, MD, PhD

Dr Jon Aizpurua studied medicine at the Albert Ludwig University of Freiburg (Germany) and specialised in Gynaecology and Obstetrics at various clinics in Germany. He obtained his PhD in Oncology Research and graduated “Magna Cum Laude”. He graduated in Clinical Pharmacology and obtained an MBA in Public Health/Quality Control. He undertook additional scientific training in Germany in the fields of Oncology, Genetics and Fertility. Back in Spain, Dr Aizpurua led the implementation of IVI Bilbao clinic as well as several consulting services for various R&D initiatives, like the development of UPV and CIC bioGUNE collaboration. Since 2009, he is the Founder and President of IVF-Spain, Reproductive Medicine clinic based in Alicante. Since 2013, he is also the Director of the Human Fertility Chair at the University of Alicante. Dr Aizpurua speaks fluent English, German and Spanish.
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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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