How important are the implantation window and uterine lining quality in egg donation treatment? Meet Dr. Valentina Denisova, Obstetrician-Gynecologist, Fertility Specialist, PhD with 11 years of experience, who explains the importance of the quality of endometrium for implantation.
Actually, I do not know the correct answers to this question. The embryo quality is assessed based on several parameters like morphological, genetic, metabolic, and the quality of the embryo is dependant on the quality of oocytes or paternal factors and so on. We are observing that the transfer, even of euploid embryos result in implantation rate at approximately 60%, while 40% of euploid embryos remain unaccounted for, some of this loss is going to be accounted by endometria factors. Extended cultivation to the blastocyst stage has become a routine because it has been shown that it results in higher pregnancy rates and higher live birth rates than when we transfer in a cleavage stage embryos. The blastocyst in embryo culture is better to select the competent embryo, and we can reduce the number of embryos which we transfer in fresh cycles. Also, this extended embryo cultivation was enhanced by the application of the vitrification and PGT-A, now when we perform PGT-A we need to perform a biopsy of the trophectoderm, then the embryo will reach the blastocyst stage. A transfer of a single competent embryo in a frozen embryo transfer is becoming a normal procedure for undergoing ART.
The implantation failures in this concept have shifted the focus from the embryo quality to endometrium quality. So both embryo quality and endometrium are important. I suppose that embryo quality is more important than the endometrium quality because if we don’t have a good quality embryo, the implantation cannot occur. We know that not all the embryos are good, all the patients need to keep in mind that even in egg donation to receive one good quality embryo on average, we need at least 6 oocytes. If we are talking about good results in egg donation programs, we need at least 12 oocytes.
It was established that pregnancy rate was affected negatively by an individual thickness which is less than 7 millimetres and thin endometrium resulted in significantly lower implantation rate and lower pregnancy rate also it resulted in a higher risk of miscarriage. The definition and the cut off for thin endometrial differs between studies. Most of the studies used individual thickness of fewer than 7 millimetres or 8 millimetres on the day of starting progesterone treatment, in case of frozen embryo transfer or case of egg donation cycles. In our clinical practise, we decided that individual thickness should be at least 7 millimetres to start progesterone in frozen embryo transfer cycles or egg donation programs. Despite the fact, that some studies revealed better outcomes with more thick endometrium, some meta-analysis didn’t reveal any advantages of the endometrial thickness as a marker of IVF success rate, but as I have already told you, we try not to perform embryo transfer if they cannot reach the endometrial thickness of 7 millimetres.
To detect endometrial receptivity, we can use different tests, and one of the possible tests is ERA test, and there are some other tests as well. The endometrial receptivity array (ERA) is used to identify the window of implantation, and it changes based on more than 200 genes and first it was recommended for women with recurrent implantation failures. When they first recommended this test, they have found that in 25% of such patient with recurrent implantation failures, the window of implantation was shifted, and once the embryo transfer time was changed based on the personal data gathered from the ERA test, the rate of implantation increased to the rates of this receptive endometrium. That was their first studies. Now, there is a growing number of studies and conflicting data that has shown that this test is not very useful for every patient. I think they still need further studies with larger samples to identify the objectivity of this test and to choose the patients for whom it can be recommended. What we can use to detect endometrial receptivity in our everyday clinical practice, it’s the measurement of individual thickness by ultrasound examination, and we use it every day, and as I have told you in the previous question, we don’t perform embryo transfer when the endometrial thickness is less than 7 millimetres.
There are a lot of pathologists, which can lead to impaired endometrial receptivity. First of all, we need to identify the risk factors of endometrial pathology, and when we see a patient, we can ask about her case history, and we can determine these risk factors. I think there can be menstrual cycles disturbances, endocrine disorders, history of intrauterine interventions like abortions, curettage and pregnancy loss, usage of intrauterine contraception, chronic pelvic inflammatory diseases f.e. obstruction of the tubes, some of the gynaecological conditions like endometriosis, fibroids which also can influence the endometrial receptivity.
Sometimes when we know that patient has a risk factor, first, we recommend checking the uterine condition by hysteroscopy and the endometrial biopsy to reveal some pathology and to treat it if it is possible. We also can find endometrium that is not growing with normal doses of estrogens and in such cases, we have to prescribe higher doses of estrogens to prepare endometrium. Sometimes, we can also find endometrial polyps, they represent another endometrial growth disorder that may result from a hyperestrogenic state. If they find the polyps inside the uterine cavity, we need to remove it before the preparation is started. Also, we can find, endometrial lesions, and it can be another reason for implantation failures or pregnancy loss. We know that among infertile women, about 45% has chronic endometritis and in particular, these patients that have recurrent implantation failures. Chronic endometritis can be diagnosed during the histological examination, and in some cases, we can add immunohistochemistry to diagnose it, we can also try to find the bacteria which caused this pathology.
Sometimes we cannot find any bacteria, we can just find a proportion of normal bacteria in the reproductive tract, and this also can lead to this chronic inflammation. If you find chronic endometritis, we need to treat it before we start preparation. I also need to say a few words about a common gynaecological disease which is uterine fibroids, and if they find submucosal fibroid which is protruding the uterine cavity into the endometrium, it should be removed before they start endometrium preparation. If we’re talking about another type of fibroids, we can remove them or not, it depends on the size, its location, so not all of them need to be removed. Submucosal fibroids, on the other hand, should be removed in every case.
First of all, you can use some doses of estrogens which I already mentioned. If we have a thick endometrium, we recommend a higher dose. Considering our local Russian guidelines, we can use different forms, we can use a combination of forms of estrogen so we can use a higher dose. Also, we can use several medicines which can improve blood circulation in the cycle of stimulation if we are talking about fresh transfer or frozen embryo transfer. Some studies mention the usage of granulocyte-colony stimulating factor, and they have shown that it can improve endometrial thickness in cases of the intrauterine adhesions and especially in patients with Asherman’s syndrome in such type of synechiae inside the uterus. In our clinic, we also use autologous platelet-rich plasma injection (PRP) this is a safe method. This plasma can stimulate proliferation and regeneration by growth factors and cytokines that are inside this plasma. We usually perform 3 infusions, one infusion in one cycle before the embryo transfer, two infusions in the cycle of embryo transfer while we are preparing the endometrium, and it shows good results. This is not a painful procedure, so our patients like to use it.
When we find an inflammation we try to treat it. So usually, we prescribe some antibiotics and some medicine, and if we can find a viral infection we can add some antiviral medicine. Usually, the treatment lasts for two cycles, and after that, we are going to start endometrial preparation for embryo transfer. In regards to your history, I have a suggestion about the quality of embryo because at the age of 46 if you use your own eggs, unfortunately, the quality of embryos cannot be very good and probably the reason of failure is here, but if we are talking about egg donation programs, I think after the treatment of inflammation, you will have good chances.
It’s not absolutely necessary, but the patients who already had a few attempts with negative outcomes, sometimes they prefer to check. About 50-60% of embryos from donor eggs are euploid, so if you already had failures, I think it would be better to check.
About the IVF clinics and labs, it depends on the region in Russia, right now in St. Petersburg, we cannot work because of the situation with the coronavirus. You can bring the sperm across the border, and there is no problem, but you need to also show the documents and the examination of the sperm before it was frozen. If the examination, was performed according to our guidelines, there is no problem.
The EmbryoGlue is a special medium, and some studies have shown that it can improve implantation rate and pregnancy rate, but these studies are not done on a large number of cases, so I’m not sure about recommending this media for every patient.
No studies, when we just performed endometrial scratching shown that it works, but right now the data is controversial, so most of the investigators don’t recommend endometrial scratching. If you already had an embryo transfer of good quality embryos, you will need to do hysteroscopy if you didn’t do it, but I’m not sure about scratching.
I think running is good for your health, so if you used to run, you can go ahead and run, but I am not sure if that will impact negatively or positively on your endometrium.
In the cases of ovarian failure, of irregular cycles, we don’t perform embryo transfers in a natural cycle. In such cases, we perform embryo transfer while using hormone replacement therapy and we usually start with estrogens at the beginning of the cycle and then the endometrium reaches at least 7 or 8-millimetre, we prescribe progesterone, and then we perform embryo transfer. So the frozen embryo transfer will not depend on the day of your cycle, it will depend on the endometrial thickness.
The data on the ERA test was very promising, and first data about patients with recurrent implantation failures after the transfer of euploid embryos have shown that ERA test can improve pregnancy rate, in some patients, not in all patients. ERA test has revealed that only in one-quarter of patients, the window of implantation has shifted. Last data from about two years is not so clear. They don’t show that ERA test improves pregnancy rate and the live birth rate, so this new data conflicts with the previous data, so I think we need further studies to make an argument of this.
Right now, we don’t recommend endometrial scratch.
I didn’t see such data that the implantation window is changing by ageing or health issues. It is sometimes changing especially in women who had recurrent pregnancy loss because the embryo cannot implant and the establishment of pregnancy is not so good.
Unfortunately, miscarriage can negatively impact the endometrium due to inflammation. In such cases, we recommend performing hysteroscopy and an endometrial biopsy to determine if there is any inflammation in the endometrium.
At times, we can recommend a natural cycle for a frozen transfer, but the natural cycle can be recommended only in patients who have normal, regular cycles.
In such cases, we always recommend testing inflammation before the next embryo transfer, and in almost all such cases, we will see the inflammation, so it’s better to check and after that, to prescribe treatment. The time will depend on the results of the biopsy, so if there will be signs of chronic endometritis then the treatment usually lasts for 2 months. Sometimes we can prescribe only antibiotics for one cycle and then perform embryo transfer.
Yes, it can be later than day-5. In some patients ERA test shown that it can be later, but it can also be earlier.
We do not use those tests, so we don’t have clinical data about them.
Sometimes, such type of endometrium can be an indication for the surrogacy program. Especially, if you have tried all of our methods to prepare the endometrium. If you didn’t try anything, we should first try to prepare your endometrium.
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