By fertility experts from Spain.
It is an incredibly sad and frustrating fact of life but the age of a woman can and does play an important role in conception. Due to societal and cultural changes, the average age of motherhood is increasing – there are many different reasons as to why women start their families later on in life; career, meeting the right person and sometimes the struggle of previous unsuccessful and ongoing fertility treatments over the course of many years.
In this webinar, Dr Ulijana Dorofeyeva – the Medical Director at the Ukrainian Intersono IVF clinic examines the reasons behind female age-related infertility and discusses whether donor conception might be a solution for older couples who have experienced no success in their previous treatments.
In order to understand how a woman’s age can impact the chances of conception, we first need to look at the ovarian reserve. The term “ovarian reserve” describes the ovary’s capacity to produce viable egg cells. A low, or “diminished” ovarian reserve occurs when the ovaries start to lose their reproductive potential; this happens naturally with age, but it can also be caused by illness. A low ovarian reserve isn’t used to simply describe a lesser number of eggs – it also refers to the quality of the eggs. The level of AMH (Anti-Müllerian Hormone) in a woman’s blood is usually used as a benchmark for establishing ovarian reserve by medical professionals.
From what we know about the female reproductive system, it is easy to see how the number of eggs would decrease with age, but it is more difficult to understand why the quality would go down as well.
Findings from the Cochrane database show that the probability of a woman conceiving and then carrying a child to term reduces with age, significantly dropping past the age of 44. In over 18,000 reported IVF cycles in the study, it was discovered that on average, women over 40 needed to harvest between 90-100 oocytes in order to achieve a live birth via IVF. However, we should also remember that while statistical analysis can provide us with medical and scientific insights; each woman and each situation is completely individual and unique.
The elevated difficulty in conceiving and carrying a baby to term is, in part, due to increased rate of aneuploidies found in the embryos of older women. An aneuploidy is the presence of an abnormal number of chromosomes in a cell – this abnormal number is known to be a factor in embryonic developmental abnormalities. Aneuploidies are understood to increase with the age of the woman – it is estimated that in women over 42, over 85% of embryos will have aneuploidies.
Other factors are also thought to impact conception likelihood in women of advanced maternal age including less energetic mitochondrial function, and oxidative stress from lifestyle and environmental influences. Male factors also have an impact on embryo euploidy; Dr Dorofeyeva advises it’s important to test for DNA fragmentation and any other issues in the sperm being used.
While some problems encountered in conception will be due to embryonic factors, women failing to conceive should also have their endometrium checked. Implantation is a key component in IVF success and can be affected by uterine factors. Endometrium screening, biopsies, and scans are used to look for issues, which medical teams are then able to correct – in most cases – with surgical procedures or medication.
Screening of the immune system is also recommended and can be crucial, especially in cases of unexplained infertility and in IVF where the embryo quality has been good, yet treatments keep failing.
Dr Dorofeyeva concludes that when looking to conceive, naturally or with IVF, quality is key. It’s been well established that the conditions of both the sperm and the eggs have an impact on the quality of the embryo and its ability to implant. It’s therefore important to use high quality oocytes, either the patients’ own (if possible) or those of a donor for the best chances at success. The medical history of clients is also immensely important, and time should be spent by a reputable clinic to analyse the patient’s fertility journey in order to gain a full understanding about how best to proceed in each case.
You may be interested in reading more about:
Hydrosalpinx is really impacting the health status of the patient’s pelvis. We believe it should be laparoscopically taken out from the body because the tubes are not playing any role in the implantation in case we’re doing IVF. But by the presence of the hydrosalpinx, we’re keeping the influence in our ways, and also the changes with immune factors, and the influencing factors on the blood level, on the cell level, for the better implantation. Also all our pelvis organs are moving all the time, so if the tubes are not blocked, we’re not able to tell if they’re blocked for sure, if they are not connected with the cavity of the uterus, so we’re not going transfer embryos into the uterus until the hydrosalpinx is there. So the best recommendation is to have laparoscopy to remove hydrosalpinx and prepare for the embryo transfer.
Rheumatoid arthritis is not something that we call the main factor of playing a negative role. This is an additional category of the patient which needs immune investigation. I would say in 85%, even 90% of those, we find the additional immune suppression or unhealthy activity of the immune system. We perform immune treatment for those patients, but not for rheumatoid arthritis itself, but for the results of the additional investigation which treatment.
The somatic status – I haven’t mentioned it during my webinar. The somatic status of the patient is really important as well. For any kind of additional somatic or chronic diseases, we should be informed. There’s a list. For some specific cases, pregnancy is not allowed. It’s not the case of asthma. Also, for this patient (asking the question) we don’t know the level of asthma, how intense it is. If the treating physician allows the patient to have the IVF treatment and carry the pregnancy, so then we’re able to perform the treatment and we’re able, together with treating physician, with recommendations of our doctors to select those medications which could be used for the asthma treatment as well. We’ve had some patients before and we treated them very well but it all depends on good communication between the IVF doctor and the treating physician of the patient.
There are statistics of 3-10% for pregnancy and live birth for the patients over 40. But potentially miscarriages happen due to the quality of the embryo. We’re talking about the euploid embryo which has been implanted and grown for some period of time but didn’t really have the potential to be delivered as a healthy baby. We’re talking about the potential need for PGS testing in order to understand that we’re getting euploid embryos and the chances for the implantation and live birth are the highest possible and the chances for miscarriage are really low and this will not happen because of the embryo quality. If we still have the possibility to get some oocytes again, and the patient is willing to try again, so there is no medical contraindication not to try. But we need to be focused on the statistics and we need to realize what the real chances are. And maybe the next step would be egg donation after trying again with IVF or maybe we should do combined treatment with PGS in order to understand what the potential is, etc. So we need to have the AMH here. we need to have the antral follicle count, the number of the oocytes which are responding and growing to get the answer for gonadotropins, stimulation, etc.
I don’t see the age of the patient so it’s not easy to say – there’s no full clinical picture. But, yes, it’s true – if you have very low AMH and low antral follicle count, the natural stimulation, Clomid, or stimulation with a low dosage of FSH is really useful. But the question is: while doing the stimulation, we get just a few oocytes; what are the chances of these oocytes to be mature, to be well-fertilized and to turn into the high-quality embryo at least on day 3? We would more likely work with a blastocyst because the longer we are cultivating them, the more information we have about the potential of the embryos and if they are really not getting into the blastocyst stage, so the possibility of them being implanted is very low. It’s a debated issue – I know. We debate about this a lot at scientific meetings, but generally the natural stimulation is fine in this case. It’s good that the fertilization rate is 100%, so the question is: what is the patient’s age? How many oocytes is she producing and what is the quality of the embryo transferred? So we could continue trying with those low dosages of stimulation and the treatment regimen as it is, but also thinking about analysing previous attempts, embryological data and the quality of the embryos. IVF would be better in this case, because while doing IUI we only help the oocyte and the sperm to meet, but we don’t check if the fertilization occurred, what the quality of the fertilized embryo was if there was an embryo for sure, how it developed and if there is potential for implantation or not. So IVF is more recommended here.
Even though we have no statistical data for the own stimulation for such patients. Usually, the older patients who are included in the analysis are women who are 42, sometimes 44. Over 45 this is the age where we don’t recommend or try stimulation with own eggs and we start the treatment with donor eggs immediately to increase the chances and to have the best results.
The question is if there was embryo transfer on day 3 or on day 5. What was the quality? Because we also have the grading of the embryos, which is: the advanced blastocyst, blastocyst category A, B, or C. The genetics also plays a very important role. There is also no information regarding endometrium thickness and the absence of the immune disease of the patient and the full screening of the patient. That is why I really do not know what to advise here. If you could contact us and send more information, not only about the egg donation cycle itself but also about the medical condition of the patient in that case, so then we would be able to advise accordingly. And regarding the genetic screening, the data says that 30% of the embryos could be potentially aneuploid, even for the donor cycle. But even with transferring one embryo or transferring even two embryos, it is too much. Usually, we should get pregnant at the first or, maximum, at the second attempt with the egg donation treatment.
You should definitely continue your way into motherhood. Again, this question refers to question number 7. If you are screened really deeply if you did the investigation of your endometrium, your immune system and screening of the embryos, etc. as we already know which play a very important role. The question here is to get the medical history, to get the records of what has been done.
This is a really interesting question. I haven’t mentioned it here, but we are also working with the patients who are going to be treated for different kinds of tumours and we perform cryopreservation of the ovarian tissue before any kind of multi-chemotherapy or radiation treatment for the pelvis if they are needed. However, if this is an ovary tumour, it is not the usual practice we use. The question is how long ago the treatment was performed. Usually after two years of the period without recovery…we are able to send confirmation that the IVF treatment could take place. After receiving this conclusion from the treating physician, the oncologist, we are able to accept this patient for IVF. In that case, we would recommend IVF with egg donation and those patients get pregnant. They are not different from those who have different reasons for using IVF with donor eggs. The impact of the hormonal treatment prior to IVF, in the case where we are going to do the embryo transfer of the embryos created with donor eggs and the partner’s sperm, the preparation will be very minimal, just with low dosage of estrogen, we just need to follow the natural cycle even without ovaries. We have the ovarian cycle and the uterus cycle, so it can be predictable. We recommend very low dosage hormonal replacement therapy to perform the transfer. But, the question is, when can we start? And how long ago, in that case, was the treatment for the tumour performed? If the oncologist is already able to provide us with their conclusion regarding trying IVF.
Yes, we do have frozen oocytes. We have had a bank of vitrified donor eggs since 2008. At the moment we have about 5,000 oocytes or even more. You can select the donor in our online donor egg database by selecting vitrified oocytes. There are two options: fresh and vitrified. You can contact the coordinators and they will help you to understand how the database works. If we are talking about the risks of using vitrified oocytes or the statistical results with them, there is no statistically significant difference at all. The issue is more related to the fact that for a vitrified cycle, we recommend and perform those cycles with a limited number of the oocytes. More often, the basic package includes just 8 eggs. If we are talking about statistical data using 8 vitrified oocytes and compare it with at least 12 mature fresh eggs, the outcome is different and the selection of the embryos is different and the cumulative pregnancy rate is different as well. The statistical data, however, says, that for cycles with vitrified oocytes, the rate is 59%, compared to 64% with fresh oocytes. I believe the crucial role is the initial number of the oocytes per cycle and the difference is here, not in the difference in statistical data.
For a combined cycle we can use either fresh donor oocytes together with retrieved oocytes from the patient or vitrified oocytes. Vitrified eggs are more recommended for combined cycle because there is no need for synchronisation. Sometimes the older patients do not respond as we expect. The average longitude of the stimulation cycle should be 12 days. Patients with low ovarian reserve usually have shorter stimulation because the number of follicles that are retrieved is very small. It means sometimes we can have stimulation on 8-9 days if the donor is not ready after that time, so for those cases vitrified oocytes are beneficial so we can thaw them at any time. So this is a good option.
Statistically, we calculate this for women over 40, because the maturation level of the oocytes, fertilization level, etc. are lower. On average, we would need 6-8 fresh eggs from the patient in order to create one blastocyst, to be able to biopsy this blastocyst and perform genetic testing. Compared to egg donation, we would need on average 4 oocytes in order to have a blastocyst. For older patients, the number of oocytes needed for one blastocyst is also higher. If we are talking statistically again, if we have a very diminished ovarian reserve which means that by one stimulation we can provide likely 2-3 oocytes, in order to have at least 6 eggs, we need to have statistically 3 stimulations. And then, from those 6 oocytes, we could potentially have 1 blastocyst which can potentially be euploid only with only 15% being normal. Statistically, it is between 3-10%, but multiple stimulation cycles would be probably needed here and with the diminished ovarian reserve the chances are really low. But I’ve never said no to anybody, if this is the reason for the question, I think it is really reasonable to try at least one stimulation to see what we are going to get from there. Then, we would see how we should proceed further.
This is a very practical question. Thank you very much. Usually, we invite patients for an initial meeting in the clinic, meeting the doctors and getting an investigation done. But we can skip this if the patient has all the results in their home country. If the partner is going to come and provide the sperm sample, which is going to be frozen and later used for the fertilization of the retrieved oocytes, so the patient herself should come only for 3 days: for the embryo transfer. And these dates are always predictable, because we prescribe the stimulation protocol. Of course, the ultrasound scans would be required to be done in their home country and the results to be sent to us immediately. And we will correct the protocol, we will confirm the date of the embryo transfer, but the minimum timing is 3-4 days and just one visit. But the optimal solution is to come for an initial visit to get prepared the medical papers, sign the medical papers, do an evaluation, arrange tests to be performed which probably cannot be performed in their home country and then come again. During that visit, the partner can come as well and have his sperm sample frozen. Then the lady can come for the embryo transfer one and a half months later.
This is the data for the first half of 2017. The statistical data is 64% for a cycle with fresh donor oocytes, for one embryo transfer getting clinical pregnancy which means we get a heartbeat in week 6. In the case of frozen, vitrified oocytes used we have a clinical pregnancy rate 59% for the same period of time.
It depends on what type of diabetes the patient has and what would be the recommendation from the treating doctor. As I said before, any somatic status or chronic diseases should be discussed between the IVF doctor and the treating physician of the patient. Only with a confirmation letter from the physician that this patient, if we potentially perform IVF, can carry the pregnancy, we can create a supportive medical treatment plan. And only after this confirmation we can perform the treatment itself.
Yes for both questions. We cooperate with agencies in South Africa, Asia, China, in different parts of the world, because our patients come from all over the world. We need to have those options available. Mostly those donors are called travelling donors. We do not have them available immediately in Ukraine, but by communicating with the agencies we plan the treatment cycles for them and they come for fresh stimulation. They start the stimulation in their home country and then they come for the egg collection, and the patient comes as well. The final step of the IVF treatment takes place in our clinic. We also do sperm donation as well, from Ukrainian and international donors as well.
Yes. I should mention that even if the age is a negative predictor, but while we get high-quality embryos or euploid embryos, so then the chances for different age categories of the patients are the same. So it means that even if you are 47, but you get high-quality euploid embryos, the percentage of the implantation for you would be the same as for younger women with high-quality embryos. Implantation does not play such a crucial role for patients of different ages. We are able to implant the embryo until the woman has her menstruation or even after that, in case we have the hormonal replacement therapy and we prepare the uterus for the implantation. With donor eggs at that age, the chances are really high, as high as 64% with fresh eggs or 49% with vitrified eggs.
I can also see a question about single women. By law, we can accept single women for IVF treatment and there are no contraindications. We can treat the official couples, couples who are not married but live together or single women. It refers to regular IVF treatment and egg donation treatment.
Yes, if Hashimoto is confirmed and the level of the antibodies’ thyroid gland is high, the additional test for immune activity is recommended to be done. Usually, for those patients, the levels will be evaluated. This is also the point that we should do the immune treatment for that patient. Yes, this patient could have IVF or egg donation procedure but with the immune treatment. It would increase the chances for the implantation and is really needed for that case.
As we have been a part of the Medicover group since 2013. Medicover is a private health care provider in central and eastern Europe, and not only Europe. There are three branches: medical health care and Medicover fertility. Medicover fertility has a clinic which is called Reproductive House Group in Manchester and we are in one group by now. They also get vitrified oocytes from Ukraine. We are able to export oocytes into the UK according to patients’ needs and you may have the treatment with the vitrified donor oocytes in the UK, in that clinic in Manchester.
Yes, we help with the process. We can send letters which you can present at the consulate or other authority you require in order to get the visa. How long does it take? From our side, to prepare the documents it doesn’t take long. You just need to have your passport and the dates of the treatment scheduled, and we will send it immediately. But how long it takes from the other side we don’t know and we have no influence over that. You need to find out from your country’s institution or the consulate.
A very nice question. The fibroid, depending on where it is located, may be a cause for miscarriage, but they couldn’t be or shouldn’t be. If the doctor says it shouldn’t be a problem, it probably shouldn’t be. If it’s not the fibroid which impacts the endometrium cavity. But two failed IVF attempts without implantation mean that there is probably an issue with implantation, not the issue related to the quality of the embryo because it was perfect grade and blastocyst day 5. You should analyse your implantation potential. Maybe the window of implantation, maybe the IVF treatment (you’ve mentioned here intralipids) so this is what we would probably recommend as well, but also your endometrium should be investigated further. We also recommend vitamins and low dosage of aspirin and sometimes prednisolone as well for patients who are preparing themselves for the treatment cycle. In that case IVF ED treatment I would really recommend. What are the other medications? It’s up to the dose which you’ve mentioned before. It’s only prednisolone. How many embryos should we transfer? We transfer one or two. We’re not able to transfer three embryos except in the case of failed negative multiple cycles before (by multiple I mean more than three) or if we have a very low quality of embryos. However, we do this very rarely. Mostly we transfer two embryos if they are not screened genetically, but in many cases, we transfer just one in order to avoid multiple pregnancies because the implantation rate is high, so the success rate is also high. For the last 6 months, we’ve had 6% of twins which is really high. We started to think about transferring one embryo per transfer.
No, arterial hypertension is not a contraindication for IVF, only in cases with really high blood pressure. This all can be treated. Again we’re talking about the somatic status and the chronic diseases. The preeclampsia risk could be and should be treated during the pregnancy care and the control by the physician during the pregnancy itself. You should be treated by both doctors: the IVF doctor and the physician treating your hypertension status.
Yes, both. If the genetic failure is confirmed here, so probably the main issue was the genetic failure. But such a low success rate for 7 IVFs and just one implantation probably is connected to Hashimoto and the level of the antibodies. The additional treatment and the IVF LG treatment would be recommended here. This would have a great impact on the success. And I need to mention that sometimes we recommend the IVF LG treatment not only for the implantation on the day of the embryo transfer but also after initial infusion – it’s valid for 28 days. But for some patients with really significant immune issues, we recommend doing this even until 12 weeks of the pregnancy. We have patients who are successfully pregnant but they fly again every month at least three times until they reach the end of the first trimester in order to overcome the issues of early miscarriages in those cases.
No, probably not. But the question is: how old is the patient? Potentially if there is high AMH, this is just the question of selecting the best stimulation protocol. In such a case, the recommended protocol would be the step-up protocol starting from a little bit lower dosage of the FSH or the stimulation drugs in the beginning, not to recruit so many follicles at once. Then, increase the dosage in order to allow those follicles which are already recruited to grow. Then, the number of mature eggs can be much higher. We want to have a good number of oocytes. If the potential of the ovaries is so high, that we could expect the OHSS (the syndrome of the hyperstimulation), we always have the possibility to select, and to freeze the oocytes or the embryos and transfer them in the next cycle in order not to have the risk of the OHSS, but to have a good number of the oocytes that further create embryos. So no egg donation is needed, but the right treatment regimen for the female patient.