Have you had an unsuccessful IVF attempt? What next? Juliya Voznesenskaya, MD, Gynecologist Reproductologist and Head of Clinic of reproductive and prenatal medicine at European Medical Centre in Moscow, Russia, answered patients’ questions during the Online Patient Meeting. Watch the recording.
The second one is the quality of the lining or maybe the quality of endometrium. During the stimulation and before the IVF cycle, we should know whether the thickness of the lining is enough for implantation, or is too thick, too thin or maybe abnormal and so on. There is a lot of question now about fresh cycles and frozen ones. I know that a lot of clinics prefer to do an embryo transfer in a frozen cycle but, I don’t think that it works in all cases. Of course, the most important thing is the embryo quality, but you see embryo quality is a very questionable thing. Because all of us want to have strong blastocyst with good quality, but we know that in some cases you receive a good healthy baby after the transfer of embryos which are not so good. That’s why to estimate and to predict implantation rate and pregnancy rate for these embryos is very difficult for a couple. Generally, it’s easy to a lot of patients, but it also can be a lot more difficult for a lot of couples anyhow.
We have a huge amount of different protocols for stimulations. It means that we have no ideal protocol. Generally, there are some strong rules for stimulation. As I showed you in my previous slide, pregnancy rate strongly depends on how many oocytes I receive from patients. It doesn’t mean that I should receive 100 oocytes per cycle, but we should receive approximately 10-20 oocytes, which is enough to get good embryos that will lead to a pregnancy. That’s why the first important thing is to choose the initial dose of the gonadotropins. Our antral follicles, which is the number of oocytes we have, we need to count them and then decide how many units of gonadotropins we should offer. If she has a large number of follicles, we can decrease the dosage if she doesn’t have so many follicles, we can increase it. The second one is very important to keep these doses during the stimulation, it’s not good to change with the medication because it can lead to the growth of abnormal follicles and receiving oocytes that are not of good quality. The third thing is how to choose a day for egg retrieval and how to choose trigger which is a special medication which we prescribe to patients 24 hours before egg retrieval to get those oocytes. We can have a different type of trigger, and in some cases, we can f.e. prescribe double trigger etc.
Any transfer process is really easy to perform. I should put an embryo in a very strong position in the uterus, and we always hope that this embryo will stay there. We should go inside the cervix, and we should go to the uterus and put it in the middle of the uterus. If a woman has no cervix abnormalities usually, it is very easy. We prefer to control our movement with the scan and our nurse stays and take a probe, and we can go inside in the uterus. We should press the syringe, and we should do it very slowly because there is a lot of data that says that if we press quickly we can destroy the embryos, that’s why we do it very slowly and then wait about 10-20 seconds, then we go outside also very slowly.
After we remove this catheter, we give it to the embryologist, and he or she will check if there are embryos left there, in some cases the embryos can be stuck in the catheter, and we would need to repeat the procedure. After embryo transfer, generally, bed rest is not recommended. We recommend our patients to go to the toilet and just to have a rest for 10 minutes, and the patient can leave the clinic. Some patients may have so-called difficult embryo transfer which is when we try to go inside but we cannot, for this kind of embryo transfer we have a special catheter which will help us to go inside and in this case we can have some bleeding, or it may be painful. Of course, we have some medicine to decrease this feeling, but if you don’t get pregnant after such embryo transfer, we try to find the solution and perhaps perform hysteroscopy etc.
After the IVF program, whether it’s successful or not, every patient should receive two papers. First one is a paper from a reproductive endocrinologist about the type of treatment, type of stimulation, medicine etc. and the second one is much more important for the patient as it’s about the embryos. As you can see here, from these patients we receive 6 oocytes, we perform ICSI on all oocytes, and we receive 5 oocytes which were fertilized correctly. Then we will have the history of all embryos, how they develop day by the day and on day-6 we get blastocysts, and we biopsy them. We can see all the special characteristic of the quality, how many cells they have etc. The patients also receive a document from the doctor where you can find the information on how many embryos the patient has and of what grade they are. There is also information on the concentration and quality of sperm which is used for fertilization.
It depends on the situation, but generally after the estimation of the previous cycle, protocol and embryos we will and try to understand what to do next. First of all, all additional tests depend on how many tests were done before the first cycle. Usually, if we do not receive pregnancy, we prescribe karyotype tests for both men and women, we want to avoid some rare but very serious condition which can lead to miscarriages or abnormal pregnancy development. In some cases, we need to evaluate the lining of the endometrium. If we find that during stimulation there is some abnormality in the endometrium, it is too thick or too thin – we prescribe hysteroscopy. Also, PGT-A so genetic investigation can allow us to know the karyotype of embryos. Generally, the pregnancy rate of these embryos is a little bit higher but, if the woman is older than 40 or 41, usually we don’t have enough embryos, and we don’t have a good quality of these embryos to perform the biopsy. That’s why this is an open question for our patients. We discuss the situation with them after IVF attempt. There are some other tests like ERA test for the lining of endometrium, sometimes we prescribe laparoscopy, but it really depends on previous patients history.
The tests for endometrial receptivity, f.e. ERA test was developed in Spain. When we have 1 or 2-3 embryos which are of good quality, and we transfer them, but no pregnancy occurs, we can investigate the window of implantation. Some doctors agree with this, some of them don’t, but it can be suggested. Sometimes, after embryo transfer, we can lose some embryos even if we see them on the scan and we believe that it’s right in the middle the uterus, but we don’t know exactly what is going on later on. That’s why there is a lot of research which showed that it can be useful for patients who already had 2-3 failed IVF attempts to prescribe oxytocin inhibitor. It is a medicine which we can use in intravenous therapy during the embryo transfer. It blocks all oxytocin receptors in the uterus for five days. I cannot say that we have a great effect of this treatment, but in some cases, the patients feel much more comfortable after embryo transfer, and they don’t feel any pain or any discomfort which can occur after embryo transfer, especially in a fresh cycle. There are also some other therapies, but a lot of them have no proof that they work.
It was popular a maybe five-six years ago, we controlled our patients because we prescribed some progesterone to support the pregnancy, and we prescribe some blood tests for progesterone level, estradiol level. Generally, we didn’t receive any correlation between these patients, that’s why we control this one only in one case when we have a high risk of OHSS syndrome. If you receive a lot of eggs, we prefer to do embryo transfer, in this case, we perform blood tests to see if there is any danger for the patient.
ERA test is a useful test indeed. If we don’t understand why we don’t receive pregnancy f.e., we have a young woman and a lot of embryos and even these embryos went through the PTT PGT-A, so I know that I transferred 1,2,3 or 4 times excellent embryos, but there is no pregnancy, that’s why we try to find the problem in the lining. Possibly, during embryo transfer, the embryos cannot find the right place in the endometrium. In this investigation ERA test or some other one, we will choose the right time, the right day for embryo transfer. Some research shows that pregnancy rate is higher after this test, but there are also a lot of trials which showed us that it is the same. That’s why in some cases we advise it, but if a woman had a previous pregnancy, has a child already before, we know that the implantation window was normal, so there is no need for it. If this woman never had any previous pregnancy, we might be able to suggest an ERA test. Generally, I cannot say that we have a great effect when it comes to this test.
When we are born we have about 300,000 follicles, and when we are let’s say 20 years old, nobody thinks about the pregnancy, but we lose almost half of these oocytes, so that is why at the age of 30 or 40 we have about 65,000 and then you see the number is decreasing very fast. It’s a natural process, and we cannot change this. That’s why it’s important for us to have patients for IVF as early as possible. A lot of patients come to the clinic too late, and we cannot help them. The patients that we have are usually 40, and we usually call such patients poor responders, we stimulate them, and we receive only 2, 3,4 or 5 eggs, and that’s all. And this is repeating in all cycles. So before starting, we try to increase the number and increase the quality of the eggs. There are some special types of stimulations, like double-stimulation in the second phrase, some protocols that should help us to receive eggs of better quality. We can prescribe some special therapy before the IVF cycle, it can be hormone replacement quality. There are a lot of methods which are not used routinely f.e., the use of stem cells although, it’s not allowed to offer for the general population. When a woman is young, even if we receive 1 or 2 more eggs it will increase pregnancy rate, but if I receive 1-3 additional eggs from a woman who is 40 we will have the same pregnancy rates.
It’s important to keep track on the progesterone level because we can predict estradiol level, we know that approximately in one follicle we have about 300 picograms of estradiol. Progesterone elevation before egg retrieval is much more interesting. When and if you have such problem the fresh embryo transfer should be stopped. We used to control the estradiol level during stimulation and after egg retrieval, in case of OHSS syndrome, but now we understand that there is no correlation with estradiol level and the severity of OHSS. That’s why routinely we don’t do this. We always control progesterone level during the stimulation.
Normally, you shouldn’t have this problem, in normal embryo transfers we don’t see any bleeding. Usually, when I have a consultation and after embryo transfer, I advise them that they can have some discomfort in the abdomen. Just because of the speculum. At the day of embryo transfer, there can be some spotting, very light brown spotting, it’s just because of their catheter. If we have very difficult embryo transfer, we should use a strong catheter and in this case, we can disturb the cervix or the lining so the embryologist will show us a drop of blood inside, but other than that, the answer is no.
With AMH level of 0.02, it’s possible of course, but it’s not a good level, but it will depend on the age. If you are 45 and the AMH is only 0.02, the chance for the pregnancy is very low, but if you are 30 are 35, we can definitely try. If a patient never had a previous cycle and she came to a reproductive endocrinologist for the first time, and she asked about this, we always discuss it and we can try to Wake Her ovaries up. We can offer maybe 2, 3 types of stimulation and we try, and if she receives the follicles growing and we receive eggs etc., we can wait for the pregnancy. But if we don’t receive eggs after the egg retrieval or we don’t receive embryos because of the wrong fertilization, we should stop the treatment. We always try to discuss it with the patients, and we often tell them that we can try Whiting those 3 cycles and then we choose what to do next. If we have embryos, we do every transfer, if not, we will discuss egg donation.
It is oxytocin inhibitor, and it’s called atosiban, there is a strong protocol on how to use it. The patients come for embryo transfer 2 hours in advance, and we put the first sample in intravenous, then she receives only 25 millilitres approximately 12 hours before the embryo transfer, during transfer and about 1-2 hours after embryo transfer. According to some data, we can prescribe this therapy for patients who already had two or three embryo transfers, with the embryos of excellent quality. So it works only in case if you don’t have any problems with embryos and we do embryo transfer, and we don’t receive implantation, we check everything, the uterus, the karyotype and so on but we don’t receive pregnancy. A lot of clinics offer this sort of therapy in such cases.
There are two things, the first one is to stimulate the patient to receive as many eggs as possible then cultivate them until blastocyst, then do PGT-A, and then try to do the embryo transfer. Normally, only 7-10% per cent of our patients who are older than 40 reach the embryo transfer. That’s why we prefer to use another way to do embryo transfer, we stimulate patients, and we receive maybe 2-3 eggs, we fertilize them, and if you don’t have any contraindication for fresh embryo transfer, we can do embryo transfer on Day-2 or Day-3. If we do embryo transfer, we will have the chance for the pregnancy, even if I don’t like the quality of the embryos, even if they are not blastocyst. If embryos are inside the uterus, they will receive the chance. I know that this is used by many other clinics in different countries, to receive eggs, fertilize them and transfer them as soon as possible. For me, it’s very important to give you pregnancy, for patients it’s much more important to have their own baby, but we should find the best solution in our fight against infertility.
Yes, you do and it is very easy in fact. We can wake up our uterus for our periods and we had a lot of patients who already had menopause, and they are 50 or 55 and even 60 and 65. We perform hormone replacement therapy, usually, it takes about 3-4 months to wake up the lining and to grow the uterus, and then we start the cycle, we fertilize oocytes from the egg donor with the husband’s sperm and do the embryo transfer. The pregnancy rate, in this case, will depend on the donor’s age, not the uterus age. The pregnancy rate is approximately 50-55% per embryo transfer.
In Russia, we don’t have an age limit. My eldest patient was 64 years old, it was said story that’s why we did it. And now she has a 3-year-old. We try not to offer this treatment for patients who are over 50, but we can do it.
I don’t think it’s too low, but it depends on which units it has been measured. The most important things are that you are only 33 years old, and even if you have only 1 or 2 oocytes, the chance for the pregnancy is high. When we have a young woman, but the ovary is not so good, in this case, the preparation for the IVF cycle is very important, in our clinic we prescribe some special therapy 1-3 months before the stimulation, I mean the testosterone therapy etc. We can also prescribe so-called Duo-Stim, which means that we prescribe 2 stimulations in one menstrual cycle. So you have two egg retrieval in one cycles, and we try to bank oocytes or embryos, it depends if you have a partner or not. When we receive approximately 6,7 or 8 eggs, we can fertilize them together and then perform embryo transfer, so you can have a longer period to reach pregnancy because of oocytes amount.
Ten years ago, when I did the protocols it was a strong rule to have three months break before the stimulation. Now, we have a rule that after a failed attempt, if we have embryos which were preserved, you can do embryo transfer even during next cycle so in one month. It depends on different conditions like if we need to do any investigations etc. If we’re talking about Dual-Stim, now we have Tri-Stim we prescribe stimulation 3 days after egg retrieval, we can start again after 3 days. It’s not easy for patients, that’s why we don’t offer more than two cycles. If you have time if you are not 43 years old, and if you have the normal amount of your eggs 5- 8 or maybe more, I think you should have rest for minimum 2 months between the treatment.
I see it’s a good idea, but I don’t know if it works. It’s an experimental method, and only some clinics can offer it for patients. Generally, in Russia, we can use this inside the uterus and inside the ovary. We use the material from the patients, it works better when the patient is young, if the patient is older than 40 years the results will be worse. That’s why routinely, we don’t use this method and we had only a few patients that had done it. We didn’t see any improvement of the function of the ovary, and we prefer to use methods which went through the randomized, controlled trial. Possibly, in a few years time, it will be thoroughly checked, and we’ll be using this.
We have a lot of articles and a lot of studies about our babies. There are two very important point s which are very seriously investigated during the last 40 years. The first one is the health of our women who went through the IVF cycles, about cancer etc. And the second one is about the health of our babies. We know that the health and the age of the woman who comes to an IVF clinic are around 40 years old, so we should be aware that we are not as healthy when we are 40. That’s why we should compare our babies, our pregnancies and deliveries with the same patients but after natural fertilization. So when we compare it, we don’t have any problems with the children, in some cases, we can have some obstetrician abnormalities f.e. we have more premature deliveries, we get different weights of the babies, in some cases, it was lower, in other it was higher. But the studies showed that IVF is not the cause, it could be the age because the same condition we receive from patients who received only stimulation, without IVF, so just the stimulation for follicle growth and that’s all.
In general, we have fewer types of Duo-Stim. The first one, we call Chinese protocol, the second one is the Spanish protocol. They differ from each other, but generally, we start 3 -4 days after egg retrieval and in Spanish version we should prescribe the same therapy as in the previous cycle. In the Chinese version, it’s much more interesting, because we combine three types of medicine during the simulation. There are tablets and injections. In the second cycle, we prefer to prescribe more units of gonadotropins than in previous cycles, but you see it depends on how many follicles we see after three days after egg retrieval. Normally, we offer this one only for poor responders, when you receive only 2,3,4 maximum 5 eggs, so we use all these types in our clinic and we don’t receive any differences concerning the amount and quality of eggs, but the Chinese version is much cheaper. That’s why we try to use this.
Here, in our clinic, we do have some oocytes from women who are brown so we could find a donor for you. Concerning, your daughter. In Russia we have very strong legislation concerning who can become a donor, it should be a woman from 20 to 35 years old, and she should be very healthy, so normally when we decide to use a relative as a donor, we invite them for estimation, maybe we’ll receive some information about the menstrual cycle and so and if we don’t have any problem with genera health, she can do it.
We have a law here in Russia about the information which we can provide to the patients concerning donors. Normally, it’s a precise description, about nationality, weight, height and education. The photos are possible if the donor will allow it. When we ask donors some of them give us their photos, some of them don’t, so it depends on the donors.
We mostly have Caucasian egg donors, but we always try to have donors from different nationalities. If we have some patients and we don’t have eggs that would match the patient, we try to find these oocytes in other clinics or bank. I don’t remember the situation where we never found them.