By fertility experts from Spain.
Dr. Valentina Denisova, Fertility Specialist at International Centre for Reproductive Medicine (ICRM), Russia, discusses IVF with donor eggs failure, the reasons and prospects for successful treatment and birth.
This is the most common question because every time a patient comes to the office we are interested in what we can do. First of all, I need to say it works about an embryo because the preliminary step of ART, assisted reproductive technology, is the factorization of the oocytes and then transformations into a zygote which is monitored by the laboratory in the clinic. We try to determine the embryo quality which is assessed based on several parameters – morphological developmental, genetic and metabolic. The quality of the embryo is dependent on the quality of the oocyte that created it. Some parameters can also be increased by paternal factors. We observe that the transfer of an employed embryo results in implantation rate of approximately 60% while almost 40% of embryos remain unaccounted for. Some loss can be accounted for by endometrial factors, but the residual loss could be partly accounted for by paternal factors. What factors can be changed by the patient to improve the chances? I think the first factor is weight and obesity. We know that being overweight and obesity are associated with increased risks of some kind of complications like gestational diabetes hypertensive disorders, preeclampsia, or preterm birth. We realized that for these women, it can be very hard to lose enough weight to achieve normal BMI categories. We suggest for these women to lose weight to achieve 10 or 15% reduction of their current BMI and that earth could be useful to reduce these risks. For an overweight patient, even 5 of reduction of BMI can be helpful. Surprisingly, male obesity can also influence the result. We know that obesity is associated with a higher risk of infertility in male, and it is regulated on the epigenetic level in sperms. It can influence the embryogenesis and even health of offspring. Animal studies have shown that male obesity can lead to the risk of metabolic and reproductive disorders in the offspring. It is then good for both male and female patient to lose weight before the planned program. Another risk factor for the male is smoking which can be responsible for decreasing fertility. We know that sperm concentration can be lower, and smoking can be negatively associated with sperm count, motility and morphology. The same goes for alcohol intake in males. It can have a detrimental effect on the semen volume and sperm morphology. This is seen in chronic alcohol intake. What can be changed in the lifestyle of the female? First of all, we can change smoking and alcohol intake because both are associated with miscarriage during the early stage of fetal development, and there is no safe dose of alcohol during pregnancy. It can lead to some form of pathology in the child. Stress factors may also impact the result. We know that elevated cortisol levels lead to free time greater chance of miscarriage during the first three weeks after conception in comparison to the patients with normal cortisol levels. We suggest avoiding the stress factors before planning a pregnancy.
When we are talking about the gynaecological condition, the first problem is fibroids. This is the most common benign uterine tumour and evaluation by ultrasound reveals the incidence of fibroids in about 40 per cent of women at the age of 35, and the numbers go up to almost 80 per cent at the age of 50. These myomas or fibroids can influence fertility in different ways like distortion of the uterine cavity and endometrial contractility which can lead to a chronic inflammatory reaction. This can influence implantation. Operation is not always needed, but it is necessary in case of submucosal fibroid and all cases when the fibroid can influence the womb. In some other cases, we can use therapeutic options like a new generation of analogue selective modulators of progesterone receptors and some other options.
Another gynaecological disorder which can also influence the result and this disease are called adenomyosis. It is also a benign uterus disorder, and it is characterized by invasion of the endometrium into the myometrium. Identifying all this may impact fertility by increased uterine contractility, impaired endometrial receptivity and some alterations in the expression of cytokines and growth factors within the endometrium. There are several other conditions which can also lead to implantation failures, like autoimmune antibodies, antiphospholipid syndrome, hereditary thrombophilia, some kinds of infections. There are a lot of disorders which can lead to failures. I suppose, that before planning IVF, a patient needs to try to find out this possible reason and to correct it. We need to eliminate intrauterine pathology like all these polyps, lesions, fibroids, endometrial hyperplasia. In some cases, we suggest our patients should perform laparoscopy especially if we can find some other pathologies in the tubes. We also suggest the correction of any concomitant diseases. All that can be very important for planning a pregnancy or planning an IVF.
This is a very important question because, for many years, I used to think that only oocytes quality can influence the success rate. Our attention was paid mostly to females’ health. Right now, we realized that the male factor matters. We know abnormalities in sperm from chromatin correlate with the chromosomal abnormalities within the embryos. Increased sperm chromatin may impact the result. We know that an increased percentage of immature chromatin in the sperm is associated with a lower fertilization rate and a slower embryo development so it can influence the result. Right now a very popular topic is DNA fragmentation of the sperm. It can be caused by the environment, radiotherapy, chemotherapy reactive oxygen species and so on. We know that current methods of detection and correction of DNA fragmentation or attempts to find the best sperm are varied, and the results are controversial, so we need to have more studies on this topic. Another important point is chromosome Y microdeletions. They affect spermatogenesis, and they affect IVF results. I have to say a few words about paternal age because we used to think that father’s age does not matter. In recent years, however, we realized the importance of paternal age. Paternal age of more than 50 years old is associated with a high percentage of epigenetic changes, higher percentage of DNA mutations within the sperms, and impaired spermatogenesis. It decreases the success rate of our program. We can find the risk of some kind of diseases in offspring like autism, psychological disorders, like bipolar disorders. Advanced age is murder.
We know that not all the embryos are euploid. Aneuploidy is the most common reason for failures. Actually, to receive one euploid embryo, we need at least 6 oocytes at the age of 35 years. So one of the questions is how many donor eggs should I choose. Patients are always interested in it, and this can be very important when we’re talking about frozen eggs. Several studies revealed that pregnancy rate from fresh and frozen eggs is similar if we use the same number of eggs. From a fresh donor cycle, we usually retrieve about 15 and sometimes up to 20 eggs and clinical pregnancy rate is more than 50 per cent, about 52%. To achieve such a good clinical pregnancy rate around 50% while using frozen eggs we need about 15 eggs, and our suggestion for patients is to use at least 12 eggs. When we choose more eggs so it is much easier to find a healthy embryo and the chances will be higher. Another option is PGT-A, pre-implantation genetic testing and especially pre-implantation genetic testing for aneuploidy because PGT-M is for patients with chromosomal disorders. Here we are talking about PGT-A. When we use donor eggs PGT-A is not necessary but, in some cases, especially when the patient has already had a few unsuccessful IVF attempts, PGT-A can be a solution, and they can choose this option in our clinic. We perform the PGT-A by NGS, and in my opinion, the most common genetic testing is NGS. It is important to understand that none of these methods can give a hundred per cent guarantee to have a healthy child. Some mutations may happen after we have tested the embryo, and even after the transfer of the embryo into the uterine cavity. We cannot deny the influence of pregnancy and its complications on the health of offspring. In some cases, PGT can be a solution, but in some cases, the patient can just choose more eggs.
Implantation relies on the crosstalk between the embryo and the endometrium, the facilitation of many different factors such as growth factor or cytokine cell adhesion, molecules transcription factors and so on. This is a very complicated process, and the implantation window depends on the optimal environment and the balance of these factors. It usually lasts only a few days and begins around six days after ovulation. One of the possible mechanisms which are involved in implantation failures, and especially in recurrent implantation failures, is the change of individual receptivity or the possibility of the endometrium to attract the embryo. One of the changes of this receptivity might involve the shift of timing of the implantation window. This previously was assumed to be the same in all women. Regulation and dysregulation of many different genes are indicated in these changes in the endometrium, and the window of implantation. One of the options can be the endometrial receptivity test or ERA test, which is used to identify the window of implantation changes. It is based on 200 genes. The first study in this field revealed that the window of implantation is shifted to almost 25 per cent of patients with recurrent implantation failures. After the personalized embryo transfer planned on the basis of ERA test, the rates of successful implantation climbed to match the rates of patients with receptive endometrium with a normal window of implantation. In the last few years, the results of new studies bring some controversy to these results, so I think we need further studies on larger groups to identify the effectivity of this test. In some cases, we can still use these tests. Another reason for implantation failures can be chronic inflammation within the endometrium, chronic endometritis. This is the pathology that is traditionally diagnosed by histological examination. There is also a hysteroscopy and bacterial culture. In some cases, we can add some additional tests like immunohistochemistry for diagnosis, so we can reveal the bacteria, which can lead to this process. In this case, we can add antibiotics before the embryo transfer or a cycle before the embryo transfer. It will depend on each clinical case.
There are a lot of studies, meta-analysis and clinical trials and in fact, we don’t know which is the best form of progesterone and estrogen for gestation. If you are interested in which is better to use, progesterone or estrogen, we can use both these forms. We use progesterone in all cases in all IVF cycles because progesterone is needed. After all, it eliminates phase defect in IVF cycles. Estrogen is not always needed. We can add estrogen in some cases, especially when we are talking about thin endometrium or when we use frozen embryo transfer.
In most cases, I recommend hysteroscopy if a patient has already had a few failed IVF attempts. We can find some pathology, as I’ve already said, for example, chronic endometritis, we can improve our chances. It is recommended, especially if a patient has tried at the age of over 45. The most common reason for failures in such an advanced age is the quality of eggs. It’s not necessary in all cases, but it is recommended in case of a few failed attempts at that age.
The Trilaminar line can be it can be important, but actually, we evaluate the thickness of the endometrium. This is not the only option to determine if they can do the transfer in this cycle, or we can do the transfer in another cycle. I think the endometrial thickness will be more helpful than the Trilaminar line.
In the 20th century and 21st century we consume a lot of sugar, much more than we need. The problem is the high incidence of diabetes mellitus, and if a patient has some problems with the sugar level, we need to exclude sugar. If a patient has no problem, I think she doesn’t need to exclude sugar.
There is no data that COVID19 can be transmitted through the eggs, so there is no reason to find out COVID19 in the donor in the donor. But COVID19 can influence pregnancy and IVF results, so as you know, right now most of the international societies suggested stopping all the new cycles. We are waiting for the end of this epidemic to continue our programmes.
This is a question for a urologist or an embryologist, but I will try to answer that. Age can influence sperm quality, and it can influence epigenetic changes, ploidy of sperm. If we compare the prognosis while using the same norms, the sperm from the younger male will be better, and the results will be better.
It is a really rare case to retrieve 50 eggs and as we can see from clinical practice when retrieving such a large number of eggs not all of them will be very good, and some of them will be immature. I don’t think you have to choose an egg donor with a history of 50 eggs. 20 to 25 eggs is a very good response, and that will be enough with the pregnancy rate of about 50 to 52 per cent. I will repeat that 20 eggs are usually enough to have one or two embryos to day five for the transfer, and in this case, we can usually freeze a few good embryos after the transfer.
A blocked tube is not a problem with IVF. There is a problem when we can see the tubes that look like bags, we call this problem hydrosalpinx. We suggest removing such tubes because this is the source of inflammation and the implantation can fail when we have a lot of inflammatory environment.
Since I’m not an immunologist, I’m gynaecologist and fertility expert, I cannot give any suggestions if the specialist in the field recommends that. If they know the relative studies in this field and some of them have shown good results. The immunoglobulin in some cases really works so if your immunologist recommends this and if you really have problems with recurrent pregnancy loss.
We have photos of donors, and we have photos of donors at the childhood age. Some photos at adult age, so you can choose better.
Menopause itself doesn’t influence the possibility of implantation because, in clinical practice, we have examples of pregnancies even after 10 years of menopause. In such cases, we use hormone replacement treatment to prepare the uterus for the implantation, and the endometrium thickness will grow to the optimal level, so this is not a problem. If we are talking about age and especially advanced age, we need to remember about the pregnancy and possible complications during pregnancy. We have to think about what will happen with this patient after pregnancy. If the patient is of very advanced age, we will discuss if we need to do this pregnancy, if she needs to carry the baby herself.
Considering the meta-analysis, considering different studies all these forms have similar efficacy, but in different countries, we have different forms of progesterone which we can use. For example, we don’t have subcutaneous injections of progesterone in Russia. We have vaginal forms, both pessaries and gel. We have an oral form of progesterone, we also have intramuscular injections. Each form works with similar effectiveness. As for the usual dose, 600 milligrams is the usual dose, but sometimes we can prescribe more. Concerning estrogens for frozen embryo transfer, I think the oral form is more comfortable for the patients, but in some cases, I prescribe a transdermal form. We don’t have a vaginal form of estrogens in Russia, but we have a transdermal form in gel, so we use both of these. As for the daily dose, we can use up to 10 milligrams per day, so we can even combine these forms for the more comfortable use in a different patient.
If that was your second attempt, that depends on your age and the results of your partner’s examination. In advanced age, I would recommend donor eggs, but if we are talking about a young patient, probably we will try to find another reason. We will try to examine the male and try to find out the reason there. After the third unsuccessful IVF attempt, probably I will recommend egg donation. No matter what the age of the patient.
I think the incidence of cesareans is rising because of the psychological well-being of our patients. Especially when we are talking about patients who conceived through the IVF and when this is not the first attempt. Of course, when the patient is afraid of something not going well during the natural delivery, in such cases, probably doctors will perform caesareans but, IVF itself is not an indication for cesarean section. If there are no other problems, if there is no problem then with the somatic health, with pregnancy managing you’re after the IVF, if there are no obstetrical complications, there is no need to avoid natural delivery.
In the patient with irregular cycles, who has some problems with ovaries function before planning the IVF we prepare for the embryo transfer by prescribing hormone treatment to regulate the cycle. That would induce a cycle, not a natural cycle but a cycle of replacement treatment. We prescribe estrogens, and when the endometrium thickness is of at least eight millimetres (think that optimal thickness is from 10 to 12 millimetres) then we prescribe progesterone. The duration of progesterone treatment will depend on the stage of freezing all stage of embryo development.
The religion is not a part of the background which we check. That’s not necessary in Russia.
Yes, we can provide online consultations in our clinic through different types of services. First of all, you can contact our doctors by mails, and you can contact our manager of international programmes and also you can contact us and get this consultation through online services.
If we are talking about the same number of eggs, so there is no advantage of fresh donor eggs. When the patient chooses a small number of frozen eggs, the pregnancy rate can be lower than when we use fresh donor eggs because we usually retrieve about 15 fresh donor eggs. It’s 15 or 20 fresh donor eggs, and when we fertilize all of the eggs we have a wider choice of embryos to transfer. Just to compare if a patient chooses only six frozen eggs, we will not have such a wide choice of embryos, and that’s why the pregnancy rate can be lower. But if you choose about 12 or 15 frozen donor eggs, the pregnancy rate will be the same, about 50%.
There are a lot of studies and evidence about the role of NK cells on implementation failures and some even suggest some treatment options but, the test group samples sizes are small, so we cannot give any suggestions for our patients. These are just experimental studies, so that’s not for everyday clinical practice.
If there is not any pathology, probably you can try to do PGT for these embryos and try once again. With such a story we can suggest using a surrogate. As for other tests, I’m sure that you need to do all these testing again. In our clinical practice, if you have done hysteroscopy, laparoscopy, karyotyping and so on you can just follow the examination list and all the examinations which are mentioned in our guidelines. Sometimes patients need to repeat some tests, but as for the whole story, I suppose be PGT-A and probably surrogacy.
Usually, two weeks is enough. Usually, we start estrogens at the beginning of the cycle, on the second or third day of the cycle, and by day twelve or fourteen of the cycle endometrial thickness is enough, and we can prescribe the progesterone.
You can choose your own donor, but if you are going to do the egg donation programme here in Russia, this egg donor should be younger than thirty-five years old. She should have a normal karyotype, and she should have all the examinations mentioned in our guidelines. She should be in good somatic health.
In fact, at this age the chances with own eggs are low, and I always prefer to tell the truth to my patients. The chances are very low, and I will recommend donor eggs. If you have no contraindications for ovarian stimulation and if you really have antral follicles we can try to do the stimulation but, I think patient always have to know the real chances and consider them while making a decision.
Well, for estrogen in menopause, if patients that didn’t take hormonal replacement treatment for menopause, two weeks will not be enough in such cases. We need to evaluate the uterine condition – to measure the size of the uterus and decide how to prepare. In menopause and especially post-menopausal women we usually prescribe hormone replacement treatment for a minimum duration of four or six months before the IVF and only after that we can prescribe estrogens for endometrial preparation.
We always test the sperm before the fertilization, but we suggest to examine husband sperm before we start the programme, as we have to plan everything. Sometimes we can find some abnormalities, and we will need to do some additional test, so it’s better to check it before you come. You can check it, not only in our clinic. You can check it everywhere and send us the results. Then we will decide about the proper approach and the embryologist we’ll check it before the fertilization.
That depends on your condition. Patients who have abnormalities in their ovaries function usually take some hormones before starting the IVF. Even in the donor programme, for patients who have no abnormalities in the ovaries function, I choose the donor program for other reasons, they can use hormone treatment before. It depends on each clinical case, and you are welcome to ask a question and send her some kind of history, and probably I can answer better.
Unfortunately, it’s very hard to find colour donors in Russia, we don’t have black donors.
Yes, surrogacy is legal in Russia. Under medical indications, not by request of patients. If there are medical indications, we do service in surrogacy.
We would usually do a uterus examination first. We can check out your ultrasound and then we can check with hysteroscopy. In some cases, we can also suggest laparoscopy and then decide if there are any abnormalities in your uterus and other organs of the reproductive system. Contractions are not pathology by themselves.
Well, I usually prescribe vitamins at least for two months before planning a pregnancy, but if you have taken them for more than one year, you can have a break.