In this session, Dr Uliana Dorofeyeva, Director of International Cooperation sat IVMED, Kiev, Ukraine & Medical Director at OVOGENE Egg Donor Bank has been talking about age and its impact on IVF success as well as provided information on some new techniques like PRP that can increase your chances.
All women are born with a certain number of follicles. The maximum number of follicles in a woman’s ovaries is during the antenatal growth when she’s 7 months of development until puberty, there are around 400,000 follicles, and during the fertile period, which is between 11 and 45 years old, there are about 400-500 ovulated cycles, meaning only a tiny percent of the oocytes are used during a woman’s whole life, 99.9% of oocytes are lost. Nowadays, we have options to preserve oocytes or embryos, however, those alternatives were not possible several years ago, even 5-10 years ago. Therefore, we need to focus on opportunities given to those patients who are considering getting pregnant now, and because of their age and having fewer follicles, they need to look for some other options.
When a patient who is over 35 years old is coming to visit the clinic, her chances are already lower, and they are getting lower as her age progresses. Therefore, there is an alternative option available that has high success rates in the case of using oocyte donation or cryopreserved oocytes from before when she was younger.
The average baby delivery age in the world is increasing, the trend is that every decade a woman’s age delivering her first baby increases per two years, so by 2100, the first delivery would take place at 51. One in 25 UK births is to women over 40.
Another thing we need to remember is that the rate of genetic abnormalities also increases with age. Even in young patients, some percentage of the quality of the oocyte or embryos will be aneuploid, even in the case of egg donation. Up to 30% of oocytes donated by the egg donor will be aneuploid. The older a woman is, the higher percentage of aneuploidy will occur. This is also the reason for the unsuccessful treatment cycle.
The first factor is age, AMH (Anti-Müllerian Hormone), which helps to predict your outcomes based on these, Antral Follicle Count (AFC), which changes from cycle to cycle. During one cycle, you can have 2 follicles that are seen on the ultrasound, and in another cycle, you can see 4 or 5, etc. Once you start your IVF treatment, proper medication and type of stimulation protocol are crucial. There are also some additions like supplements and vitamins or testosterone, growth factor, etc. as well as some experimental treatments.
One of the unique techniques is the ovarian rejuvenation of the oocytes and endometrium by using platelet-rich plasma, which is injected into the ovaries and endometrium. It works well for patients with very low ovarian reserve but still have several follicles or even a few follicles, and a low AMH level. The platelet-rich plasma gives the possibility to awake those small antral follicles or pre-antral follicles to make them grow in the next cycle in order to perform the stimulation. This method is recommended for patients with primary ovarian insufficiency, advanced maternal age, premature ovarian failure (POF), and loss of ovarian functions due to surgeries or chemotherapy or ovarian dysfunctions. How it is performed?
First, the PRP plasma is prepared. Around 20 millilitres of your blood will be drawn, it will be centrifugated to separate the plasma and platelet from white and red cells. The procedure will take around 1–2 hours, and about 2 to 1 millilitre will be injected into the ovaries. The procedure will be scheduled immediately as soon as the material is ready, and the injection will be done the same. The doctor will use a tiny needle and under the ultrasound guidance, he will inject the PRP distributing the material across the ovary. This procedure is done under anaesthesia. It’s safe because this is the patient’s own blood, so there is no risk of infections or allergic reactions.
This procedure is still an experimental treatment, it is allowed in Ukraine, and it works for patients with a low ovarian reserve, but who are not ready for oocyte donation yet and would like to increase their chances to use their own eggs.
Once the oocyte is retrieved, it is very important to check the genetic status of the material. It’s also possible to check the oocyte status by performing NGS testing of the oocyte, it’s possible to check it with Polar body diagnosis (PBD), which is a method for the indirect genetic analysis of oocytes. It is also recommended to do the embryo biopsy, as soon as the blastocyst is developed, the biopsy can be performed and it’s possible to check the genetic status of this embryo, and it is always best to transfer 1 euploid embryo to increase the chances of success.
It’s not only about a healthy embryo, another significant aspect is well-prepared endometrium, it should have a proper structure and proper thickness. You also need to remember about the endocrine status, the initial tests should include testing the thyroid function. Sometimes immunological status might need to be checked, as the potential for implantation by accessing the window of implantation and many tests based on the medical status and the previous outcomes.
In oocyte donation, it’s possible to use fresh or vitrified oocytes. In Ukraine, there is a wide variety of phenotypes, there are over 3000 available immediately. You will have a wide variety of donors according to your phenotype. All donors in Ukraine are with proven fertility and are genetically tested.
In some cases, when a woman produces 1–2 oocytes, there is a high chance of not being able to create embryos, and in order not to lose the possibility to have embryo transfer, there is another option available so-called combined oocyte donation. This is for patients with a low ovarian reserve who are not ready for conventional oocyte donation and for those who are most likely to have canceled embryo transfers. This is almost 100% guarantee, there will be 2 dishes, in one dish, your oocytes will be put, and in the other dish, the donor’s oocytes. Both will be fertilized with the sperm of your male partner, and on the day of the embryo transfer, we will check the quality of the materials, and the doctor together with a patient will decide which materials should be transferred.
In Ukraine, there are alternative possibilities for oocyte donation, so-called spindle transfer or nuclear transfer. It’s still an experimental treatment. Starting with mitochondria, which are like a battery of the cell, 90% of the cellular energy is produced by the mitochondria. It also has a genome, it’s about 37 genes. The young oocyte has a lot of mitochondria and their potential is high, but with the increased age of the patient, the levels of the mitochondrial’s DNA are morphologically changed and have increased deletions.
By getting mitochondrial dysfunction, we have lower IVF success rates, lower fertilization and higher aneuploidy rates. Transferring the mitochondria and the pronuclear, we can receive mitochondria from the young oocyte, and we can use nuclear mitochondria from the mother’s oocyte and the sperm from the father. This is a unique technique, it’s done only in a few centres in the world, it requires specific equipment and the knowledge of the embryologist, but this might be done.
Data from the UK demonstrated that in over 150 000 cycles and over 257 treatment cycles in 9 treatment cycles performed in patients at 40–42 years old with own oocytes, the cumulative live birth rate got up to 30%. In IVF treatments with own eggs up to the age of 40 within 6 IVF cycles, the rate was over 60% up to 75%. In egg donation cycles within 5 treatment cycles, it was already over 80% up to 95%. Therefore, this is something you should ask yourself, how many cycles have you already had and how different they were? Getting a second opinion from another doctor or another centre from another country might be beneficial because the way they treat patients can be different.
Another publication showed no big increase after the 3rd attempt in cumulative pregnancy and live birth rates in women at 44–45 years. You can try for the 1st and then the 2nd time, but the cumulative live birth rate would not be higher than 7%. This might something you need to consider, and probably think about alternative options.
There are various treatment options available for IVF to help you become a parent. Below are some important factors and choices to consider for IVF treatment, taking into account your age and personal situation.
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According to Fertility Clinics Abroad’s guide to IVF age limits, “a few countries write the limit into law: 49 in the Czech Republic, 54 in Greece, 50 in Estonia, 46 in Denmark and 47 in Belgium.” Most clinics stop IVF with a woman’s own eggs at about 45 and treat with donor eggs up to about 50.
Let’s go step by step with this question. I just would like to say once again that in Ukraine, there is no upper age limit. There are no recommendations, every clinic needs to decide by the medical committee what would be the best option for the patient who was referred to that clinic. A very important fact is the semantic status of the patient and the histories of the previous outcomes, and we are always in communication with the treating person from the home country, and we would never proceed with the treatment if we are not in touch with such a specialist.
If you are talking about specific treatments like PRP therapy or ovarian rejuvenation until we can see some levels of AMH like I would say we’ve been trying even 0.1, but the question is we can try once again, and if we can see the follicle, which is growing, we would proceed with the stimulation, but in such cases, the outcomes are really different. Sometimes, we are not getting follicle growth, the best outcomes with the ovarian rejuvenation, we are getting with the level of 0.3 AMH and higher, so I would say that all patients for whom we did PRP therapy, we have several indications that we’ve seen AMH being increased, FSH being decreased, and new follicles have been growing, and as soon as we see this, we are starting the stimulation. If we are talking about mitochondrial donation or pronuclear transfer, the maximum recommended age is 43, but again, it’s based on each cycle evaluation. Usually, if we still can see some levels of the AMH and positive outcomes for the treatments in the past, meaning receiving at least 1 oocyte, we would proceed with the treatment because we need to be sure that we are receiving oocytes in this treatment. If we are talking about egg donation and surrogacy again, as I said, it is based on the somatic status and the general health of the patient.
I would like to get an answer to my question. If you have been trying IVF before and what were the outcomes in terms of how many oocytes were produced? What was the quality of the embryos etc.? Statistically, I think still with 4 antral follicles and being 42, your chances of receiving 2 to 3 oocytes should be quite high, but the question would be of blastocyst formation probably and the euploidy of your embryos. The second question would be how much time you are giving yourself until you will get pregnant. If you would like to get pregnant within several months, definitely oocytes donation is best for you. If you are not ready for the oocytes donation and you would like to try for the last time, you need to keep in mind that your chances definitely would be lower in comparison to the oocytes donation.
Some patients with PCOS, at their younger age, still at the age of over 40-43, we can see AMH level like this. The potential to receive more oocytes at this age is higher, compared to, let’s say even at the previous case, but still, the percentage of aneuploidy, unfortunately, would be the same, so if you would like to try, I would say that you should try. We would consider you as a low prognosis, but still with some prognosis in about 3 to 5% or up to 10%. If this is something that you would expect, and if you would consider yes, go ahead.
If considering just case by case, I would say that this case is the most optimistic one because the level of the AMH and FSH is absolutely fine, antral follicle count is great, so I would say that your chances would be even between 20 to 30 or even over 30%, but again to improve the egg quality we have different recommendations, but they are not as a clinically approved. This is not something which is given as a recommendation by any society, this is just from our experience like the complex of the vitamins, testosterone, etc.
If you would send us a mail, we will send you the scheme, but and usually, we recommend this to improve the oocyte quality and to take these supplements 2 to 3 months before the treatment cycle, this is what I would just recommend doing prior to the IVF treatment, but also I would like to recommend starting treatment as soon as possible because with every month we are just getting older and older and the chances are getting lower, so to prepare best is just to start the IVF.
All the measurements like the AMH, AFC, TSH is also absolutely fine. This edge is within the range being normal, it’s just a recommendation to have it below 2, and if you are already taking medications to regulate your thyroid function, you just should follow the changes, but I think that within 2 to 3 weeks, even the changes will be already there, so the most important is the age. As you are already 42, again I would recommend starting as soon as possible. What you just need to consider is that for all patients over 38 years old, we are recommending medications such as FSH + LH. Just consult with your doctor and double-check because LH is really important for women in the advanced maternal age, and this would be the best stimulation regimen. If you don’t have endometriosis, if your cycles are still regular, it could be short stimulated protocols with the antagonist and probably RCG (human chorionic gonadotrophin) triggering.
Not to avoid freeze all and maximize the fresh embryo transfers in the end, but maybe you should also consider PGD for the embryos because if you will get several oocytes, it’s very important to know which embryos would be euploid, so here are the recommendations and again just start as soon as possible.
Yes, I moved to Kyiv, and I am working together with the team of the IVMED in Kyiv now. This is a great clinic, a great team of really fast and developing embryology with all those potentials of the mitochondrial prenuclear transfers, etc ., and NGS testing. As I said, the maximum age for the treatment is considered during the clinical decision of all doctors. After we have received the medical documents related to the patient and all the history. Also, if the decision is positive or we need to consider something else, we are asking the patient to connect through Zoom or Skype. Yes, we have clinics in Canada, but due to the changed regulations recently, they will not accept absolutely anonymous donation right now, and also all materials which are shipped to Canada, they need to be FDA tested, very similar how it is for the USA, so I think it will not be possible to transfer those embryos. The maximum age for pronuclear transfer is 43, that is the recommendation, but again it can be different from case to case, we need to consider previous outcomes and age, and potential to produce oocytes, and if the menopause is reached already probably, there is no possibility because we will not be able to get follicles. The probability of getting oocytes will be really low.
The decrease in the follicle count could not be a reason for the cesarean section, only in case, it was laparoscopy, and something was done to the ovaries, but usually, the cesarean section has nothing to do with the ovaries, so it’s not connected to one to another. Being 43 and having 4 follicles, probably you will be able to produce 1 to 2 oocytes, again the question is: Have you tried, and what is your experience on reacting to the medications? 14.2 pmol/l, it’s into our levels, it’s between like 2 point something, it’s still quite good AMH, so I think there is still a reason to try it with own eggs. Also, you can try ovarian rejuvenation if this possible in your country or you should travel somewhere.
The opportunities to travel right now are really limited, but if you would like to travel to Ukraine for treatment, they are able to do this, even during this strict quarantine that we have right now, we sent the documents confirming the patients are coming for medical treatment and there were no questions in the borders. The only issues are with flights etc., but our international department will be happy to help you with that and to accommodate and to help to answer all the questions regarding the flights, etc., as well.
In our clinic, we do not recommend for the surrogate to have another attempt either surrogacy or having a transfer after the birth of a baby within 2 years. But if you will postpone a little bit and, again we need to check the status of the surrogate like if she’s healthy, if the pregnancy was without complications, if she is not breastfeeding, etc. There is a list of the tests which are needed to be done for the surrogate mother. After checking that, I would be able to confirm or not if she’s a good candidate. With the information I have here, I would just only say what I have just recommended. In general, everything looks fine in terms of the blood type, it’s absolutely fine.
The pregnancy itself is the status of the body of every woman independently, whether it is a patient or a surrogate mother. Surrogacy is a very important procedure and a very responsible one, so just from the clinical side, we would like to be sure that we have the best conditions and depending again on how was the delivery of that previous pregnancy, how was the pregnancy itself, what is the status of the patient, of a surrogate mother today, we are recommending to have embryo transfers within 2 years and later after the previous delivery, but every case can be different, and we just need to get more information in order to confirm this or to say we still need to wait.
I would say that this would depend on the quality of the sperm sample, but if your clinic decided to freeze it, and there was no recommendation that the quality of the material is low or that could be any risks here like that, it’s still recommended to fly and to produce fresh over, so it should be absolutely fine. It’s better to understand the status and the sperm quality to answer this properly, but in many cases, we recommend the same. So if patients would like to avoid staying longer in Ukraine, for example, or if the male partner cannot travel, we are just recommending to free the sperm somewhere, and we are sending the courier, and we bring materials over to Ukraine. Usually, a sperm sample has millions of motile sperm, and even if there is cryotolerance, in normal sperm samples, it’s only up to 30% that we are losing, and we still have enough for the fertilization. In general, it should be fine.
The technique is in place, but because the results were not really high. Usually, IVM was done for oncological patients in order not to stimulate them because of the risk of the high level of estrogens, and by avoiding this, we did IVM, we do not have really many of those patients. It’s not really common, but the technique is there, and because there were not really good results, I cannot provide you with proper data, but I will be able to find out more and will be able to provide more information if needed.
It would be testosterone, Coq10, and vitamin D.
I would like to know what would be the FSH level, but if still there is a possibility to try with your own eggs, I would try to perform ovarian rejuvenation. Potentially, we would decrease the FSH and increase the AMH a little bit, but we need to check if we will get more follicles to grow. I think egg donation for your age and the parameters and also the previous outcome is the most reliable and the right procedure.
It is very similar to the previous patient, and what is the most negative here, unfortunately, this is the age. I think that both of you also can try combined egg donation.
Once you are receiving IVF treatment and gonadotropins, even if you are ending up with no follicular growth or if you’re ending up with the follicular growth, but no oocyte, this still also can happen, anyhow your endometrium is growing and you shouldn’t stop treatment, you can just proceed with the egg donation starting from the time of your OPU (oocytes pick-up) and OPU is day zero , this is a day when your egg donor also should be punctured or in this case, the synchronization sometimes can be complicated because you need to postpone or to get faster someone and this is not always optimal in timing, that’s why the vitified occyte donation would be recommended because as you are getting materials from the egg bank, you should thaw them exactly, on a day when you are having your oocyte retrieval and the oocytes vitrification thawing is absolutely a great technique like survival rate is over 95%, we are not losing materials, fertilizationrate and the clinical outcomes are the same, so still, more publication and more beliefs even between the doctors are for fresh oocytes donation, but my experience shows that the vitrified oocytes donation has much more benefits in comparison to fresh.
There is no synchronization, you can predict how many oocytes you need in order to produce embryos, we’re usually calculating oocyte for one healthy blastocyst, also in the fresh egg donation, there a possibility but also there is a risk to create surplus embryos meaning if you are in your older age and you stimulated one donor per patient, and you received 5 to 6 blastocyst, but you need only 1 or 2 so you will have additional embryos, which will never be used and someone could potentially have been using part of those oocytes from the donors, so vitrified oocytes donation has many, many benefits. I would recommend trying combined treatment if you would consider this as well.
Yes, absolutely. If you would consider oocyte donation, I would recommend probably for the successful treatment of having 2,3 babies, you would need to have either full fresh egg donation or receiving between 12 to 15 or 18 vitrified donor oocytes, you should expect with the good quality sperm of getting 4 to 5 or even 6 blastocysts out of this. With egg donation, it’s not usually recommended to perform PGS testing, but you can do this as well, and this would be like a full material to be used in advance or in the future and, also you can order some vitrified oocytes. If still in a bank, you have more materials being available. Let’s say you can do the first trial of 12 oocytes, warm them, fertilize them, cultivate until blastocyst, understand how many blastocysts you received and if this is enough for 3 or 4 embryo transfers, and then you can order the materials from the same donor. Usually, donors are donating several times, so it’s a very common thing that you still can contact the oocytes bank and get the same donor materials.
Statistically, it’s between 15 to 20%.
The question is: What is the starting point, but if the starting point is already, let’s say 1, it would be individual, but the average it’s 50% less every year. If you are already on the low levels, today you have 1, and in one year, it will be 0.5, in 2 years, it will be up to almost zero, so it’s quite fast.
I think that during all these trials of 8 IUI and % or 6 IVF attempts and such a male factor probably the reason of failed attempts was more connected to the malefactor than to the oocytes, but because today you are 43, I think that it’s already too late to try donor sperm, but maybe it’s still reasonable. We need to consider the fact that at 43, the percentage of success would be about 10% if you will use donor sperm or double donation, but this is something that you are just not considering. There are still some options. I would say that the donation would be definitely recommended, either your eggs and the sperm donation, as getting no implantation and miscarriage in the previous treatments, and this can be connected to the male factor in this situation or double-donation.
Yes, IVM is recommended as a technique to grow immature oocytes or if the previous maturation rates of the oocytes were poor and it needs to do it up to MII oocyte, but again it should be a clear medical indication for this. If the reason for getting MI oocytes is not a proper stimulation protocol, we should just change the protocol or understand what is not working properly in the stimulation protocol. There is no other reason to receive M1 oocytes. If the stimulation is proper, it should be M2.
If we are puncturing follicles with the size of between 10 to 12, 13, 14 millimeters, we are expecting to receive immature oocytes, then we can grow them up to M2 in the laboratory conditions, but what is the reason not to stimulate a patient up to M2 in the ovaries, so then chances in comparison to IVM at least in our experience would be definitely much higher, so it should be a proper medical indication for IVM.
There are so many producers of those supplements, we are not really recommending any brands because worldwide, they are so so much different. The folic acid is recommended, of course, and the probiotics, but there is no one recommendation for all. There is something general, but again we need to consider different factors, so it’s better to have individual recommendations for this.
Yes, in Portugal, oocyte donation is legal and officially performed, we are collaborating with clinics there, I will be happy to provide you with some data. In Germany, oocyte donation is not allowed, so we can only transfer embryos if those are embryos from your oocytes and your partner’s sperm. This is the only possibility there, that’s why the options are really limited. From Germany, we would recommend traveling somewhere that is close to you like Poland or even Ukraine or somewhere around.
When it comes to Assisted hatching, we have a very positive experience by using this, and we the assisted hatching for all embryos, which were vitrified and warmed, and also for the embryos created from the vitrified oocytes. I would say yes, but once we would prepare this embryo for the embryo transfer from 2AA, we would give the opportunity for this embryo to grow until 3, like 3AA, and then we will see what is the development, how fast it is developing, and then decide regarding should the hatching be done here or not because like if the development is absolutely proper, maybe we should avoid helping this embryo and just leave it. It’s a decision made by the embryologist together with the doctor and the patient.
The CoQ10 is on the list, but I would need to double-check the dosage. I am not able to provide this right now.
There are huge differences between those morphological grading of embryos, this is an invasive, but very important information we can get from the embryos. There are different machines like timelapse technologies and some others which are helping using artificial intelligence to tell us in advance what would be the potential of these embryos to be implanted. By grading embryos between A, B, and C, I would say that A is the great embryo, B is the embryo with some morphological disorders, which is equal to the medium quality, and C is a very low-quality embryo with very low implantation potential. There are many, many publications, and we also follow this in our practice that the implantation potential for AA or AB, which are considered good quality embryos is high. BB is already lower, and BC is the lowest still, we have implantations, but the potential is very low.
According to Fertility Clinics Abroad’s guide to IVF age limits, a few countries write the limit into law: 49 in the Czech Republic, 54 in Greece, 50 in Estonia, 46 in Denmark and 47 in Belgium. In the UK, the US, Spain and Poland the law sets no maximum and clinics decide, usually stopping own-egg IVF at about 45 and donor-egg IVF at about 50.
