Dr Esther Marbán, Gynaecologist & Fertility Specialist at Clínica Tambre discussed the latest advancements and shared practical tips to help you navigate challenges, understand the complexities of recurrent failures in IVF.
The endometrium is the innermost layer of the uterus where embryo implantation and fetal development take place. Due to ovarian hormone changes every month, estrogens produce thickening of the lining to prepare for potential pregnancy, and finally, progesterone prepares the endometrium for pregnancy by supplying the lining and stimulating gland growth to nourish the early embryo.
Why is the endometrium so important in fertility treatments? It is the place where the embryo implants, so we need a good endometrium to give you the highest pregnancy rates. We need a good endometrium in terms of thickness and also a triple-line aspect, which means that the endometrium has 3 distinct lines before we plan the embryo transfer. This aspect and good endometrial thickness are necessary to achieve better chances of implantation.
This stage can be achieved in different kinds of treatments:
Apart from the endometrium’s appearance, it is also important to have a receptive endometrium. When we talk about endometrial receptivity, we focus on what we call the “window of implantation.”
The window of implantation is the period when the endometrium has the best conditions for embryo implantation, and we refer to it as a receptive endometrium.
This is the moment when the endometrium is most receptive to implantation, meaning that if we do the embryo transfer at that time, there should be a higher chance of implantation.This period is short and depends on the effects of estrogen and progesterone on the uterine lining, which may vary between women.
Between 25 to 30% of patients might have a displaced window of implantation, meaning that if the embryo transfer is performed at the same time for all patients, not all of their endometria will be receptive. By checking the window of implantation, it’s possible to personalize the embryo transfer much better. This means some patients may need more hours of progesterone to make the endometrium receptive, or even fewer hours, therefore, it’s possible to calculate the best moment for each patient.
In addition, it’s also really important to focus on the endometrial microbiome and the potential for chronic endometritis. The endometrial microbiome is the totality of microorganisms present in the endometrium. The normal microbiome of the endometrium is dominated by a bacteria called Lactobacillus species. We know that deviations from the normal Lactobacillus species can play a role in implantation failure and infertility. An abnormal endometrial microbiome has been associated with implantation failure, pregnancy loss, and adverse obstetrical outcomes.
In recent years, we have become much more aware of the importance of the endometrial microbiome. In the past, we didn’t know much about it and weren’t paying enough attention to that part of the endometrial lining. It’s quite important to focus on that, to examine it when needed, and to find the proper treatment if any abnormalities are found.
It is necessary to do a biopsy of the endometrium to properly examine the endometrium. How is it done? Some part of the endometrial tissue is taken, it’s not performed at the same time as the embryo transfer—it will be done at a separate moment. Normally it is best to perform it as close to the embryo transfer as possible, with the idea of having an updated understanding of how the endometrium is doing before the embryo transfer. Biopsy will give the information about the window of implantation.
It’s also possible to diagnose the endometrial microbiome by checking the bacteria that the endometrium contains. This allows us to find potential chronic infections that are often completely asymptomatic. If needed, we can find the best treatment for those infections. The idea is to check first if there is any chronic infection and then determine if the bacteria the patient has in the endometrium is the one we recommend, which is Lactobacillus species. If there is a chronic infection, the Lactobacillus may be reduced, and non-beneficial bacteria may grow, leading to a disbalance between species. Sometimes, a proper antibiotic is needed to remove the infection first, and then restore the endometrial environment with probiotics, either oral or vaginal, depending on the case.
Apart from the endometrium’s condition, which is one of the most important parts, we also need to:
One reason the endometrium might not grow as it should could be a potential uterine malformation, which can also increase the risk of implantation failure and miscarriage. Therefore, when talking about reproductive patients, especially those with implantation failure, it is crucial to focus on the uterine factor. It is essential to provide a thorough uterine assessment to maximize the chance of implantation.
Implantation failure is defined as the failure to achieve pregnancy in women younger than 40 years old after transferring at least 4 good-quality embryos, considering both fresh and frozen embryo transfers. Currently, when high-quality embryos are transferred and at least 1 or 2 of those embryos fail, it’s safe to assume that we are dealing with implantation failure. Although this is not the exact definition, it reflects the reality of the techniques used in the laboratory and the high potential implantation rates of embryos, especially in patients undergoing egg donation treatments.
When we talk about embryo implantation, we need to consider that this is the procedure by which the embryo, at the blastocyst stage (on day 5 or 6 of developement), joins the maternal endometrium to continue its development. There are different stages of implantation:
All these steps must be followed from the beginning to the end for successful implantation. It’s not as simple as just performing the embryo transfer and leaving the embryo there; many steps need to be followed before implantation happens.
Tthe implantation procedure involves both the endometrium and the embryo. Therefore, we need to have a good endometrium and also a good quality embryo is crucial for implantation. If we do not have a high-quality embryo, even if the patient has the best implantation conditions possible, the chances of implantation will be reduced. Embryo quality is related to the quality of the gametes—both egg and sperm. We also need to consider the technique and timing of the embryo transfer and ensure a proper dialogue between the embryo and the endometrium. Additionally, suitable luteal phase support is necessary.
Another important aspect to consider is what is not considered implantation failure. For women older than 40 years old, if the embryos have not been tested for chromosomal abnormalities, the potential chance of implantation with those embryos is quite low. Even if the embryos have optimal quality, the potential implantation rate remains reduced. Therefore, such a patient should not be considered as having an implantation failure. If a patient has medical conditions such as hydrosalpinges (fluid-filled tubes) or endometriosis, they may have a decreased implantation rate. Endometriosis can affect egg quality and quantity and, in some cases, particularly with adenomyosis (a type of endometriosis affecting the uterus), it may play a significant role in implantation failure. Patients with these conditions might experience reduced chances of pregnancy. As previously mentioned, low embryo quality is related to implantation failure; transferring low-quality embryos results in a low chance of pregnancy and is not considered an implantation failure. Similarly, issues in the uterine cavity, such as polyps, fibroids, or scars, may affect implantation. If a patient has such problems, likely, the embryo will not implant due to these issues.
Finally, if the endometrium has not grown as expected or does not have a good aspect or thickness, it is not suitable for implantation. In this case, the patient is not experiencing implantation failure because the endometrium is not adequate to allow implantation.
There are different strategies for recurrent implantation failure related to the uterine factor that should be considered. Those include:
In recent years, a new treatment called Platelet-Rich Plasma (PRP) has been used. PRP has been used for patients with recurrent implantation failure and those with thin endometrium. PRP involves an infusion using a sample of the patient’s blood. The blood is extracted, the platelets are isolated from the serum, and we obtain a concentrate, which is then used. Three different infusions are used before the embryo transfer at various cycle stages and endometrial thickness is measured to assess effectiveness. This procedure is not painful; it involves infusions similar to an intrauterine insemination (IUI) technique, and the results are quite promising.
Despite these advances, challenges remain. In some patients, we may not detect uterine malformations, and it can be difficult to understand why some patients do not achieve a good endometrium. We strive to improve outcomes with new techniques, but achieving the ideal endometrial condition can still be challenging.
In conclusion, an accurate diagnosis and specific tests are essential for correct assessment and proper treatment of implantation failure. A multidisciplinary approach is important; while we focus on the uterus today, a comprehensive assessment of the endometrium is crucial. This includes conducting a thorough examination with a 3D scan or MRI when indicated. It is also necessary to perform further tests to identify chronic endometritis or other issues affecting implantation.
A good endometrium significantly increases the chances of implantation. If the endometrium does not meet the required standards, the implantation rate may decrease. Therefore, precise assessment and tailored treatment are key to improving implantation rates and personalizing the embryo transfer protocol. In summary, finding the best treatment for patients with endometrial issues is crucial to enhancing their chances of successful implantation.
Adenomyosis is normally diagnosed with an MRI or a 3D scan. While sometimes hysteroscopy can reveal signs of adenomyosis, in our experience, the 3D scan provides a better diagnosis. When a patient is diagnosed with adenomyosis, we know that it may increase the failure of implantation rate and also the miscarriage rate. Because of this, we always try to reduce those complications when possible. In our case, we typically use Decapeptyl for at least 3 months to try to lower the impact of adenomyosis. Other protocols also use medication like Letrozole to reduce the activity of adenomyosis, minimizing its potential negative effects on implantation.
The only reason I would suggest undergoing a substituted cycle is if the patient is not having regular periods. If the patient is having regular periods, we can do a natural or modified natural cycle, which is quite comfortable for the patient. The results are the same in both cases. So, if the patient is having regular periods and is willing to come in for maybe 2 to 3 scans for monitoring, either option would be fine.
Considering the focus on immune factors today, I would suggest at least doing a 3D scan or even hysteroscopy to check the uterus cavity. Given that the patient has undergone egg donation, I assume the embryos had good quality. However, if there are issues with high NK cells, it might be advisable to consult an immunologist who specializes in reproductive issues to ensure proper treatment in this case.
Implantation may be achieved, but the chances are quite reduced. The same applies to the thickness of the endometrium. We always aim for a thickness of 7 millimetres, but it doesn’t mean that if the patient has 5 millimetres, she won’t get pregnant. Pregnancy can still occur if the endometrium has a good triple-line aspect. Our goal is to achieve a triple-line aspect and a thickness greater than 7 millimetres. If the endometrium has a good aspect but is not trilaminar, the chances are reduced. We always strive to achieve that triple-line aspect, which is the most important part.
Yes, because in the end, when you’re having menopause, it doesn’t mean that you can get pregnant naturally, because, of course, you can’t use a natural cycle. We are using a substitute cycle, so with that substitute cycle, due to the hormonal effect and also the progesterone intake, that window of implantation will be there. So in the end, it’s not a matter of having a regular period or not. Of course, this patient, without having a regular period, can get pregnant, but with treatment. So we are giving her the hormones in a controlled way with the idea of making the endometrium receptive. So because of that, of course, she can get pregnant and will have a receptive endometrium for sure.
The most important information for me in this case is knowing the patient’s age. If the patient, of course, is older than 37 or 38 years old, the main reason could be the embryo. So even though the uterus seems to be fine, the quality of the embryos is fine, and the male factor has also been excluded, if the embryo is not healthy because of age and the potential risk of having some chromosomal abnormalities, the risk of having another miscarriage is high. The main step should be knowing the age of the patient and, of course, doing the PGT-A. I think it may help you.
Even though in Spain it is not possible, it’s true that some patients may have a clear indication for surrogacy. Especially patients with, for instance, really thin endometrium that are completely unresponsive to any medication, maybe patients with a very small uterus, or also patients with many fibroids that are making the endometrium completely abnormal in terms of shape and volume. These could be the main indications for surrogacy, even though in Spain it is not possible.
The ERA test and similar tests indeed are, let’s say, controversial. That’s completely true. According to the research, it’s supposed that if we follow the same protocol to prepare the uterus, the window of implantation should not change so much. However, it may indeed change. What our data suggests is that we have been using the ERA test and similar ones for years, and we are getting pretty good results. In the end, when a patient gets pregnant, it’s very difficult to know the main reason. We know that the window of implantation may help, but it’s not the only factor we should focus on.
There is much research that says it’s completely useless, and some others say it can be quite useful for a certain group of patients. In our opinion, it may help, but it’s not the only factor. According to the data, the implantation window shouldn’t change so much in the following months after performing the ERA test.
It’s true that because of the techniques we use, we are diagnosing adenomyosis more frequently. The number of patients suffering from adenomyosis is increasing. Not all adenomyosis may affect the uterus the same way. In mild adenomyosis, where the junction between the endometrium and the myometrium is not affected, the potential risk of having any issues because of that is not very high.
At the same time, we need to consider the patient’s background. If it’s the first embryo transfer, maybe we don’t need to treat it, but if the patient has failed several times, sometimes we need to consider that it may be a potential factor to consider. It doesn’t mean that it’s going to be the main one, but it may affect the outcome for sure. So in that way, it’s important not just to focus on whether the patient has adenomyosis or not. We need to have a different approach or at least a broader perspective, taking into account the patient’s medical history and putting everything together to find the best solution for those patients.
This is not a test that we normally perform. The same happens with the question about lymphocyte immunization therapy. As I mentioned, it’s something related to immunology, and apart from that, our immunologist is not doing those tests. I can’t add anything more because we’re not using those tests currently.
I think it’s a really good idea. As we mentioned, it’s really important to have a good assessment of the uterine factors. Apart from other factors, as I mentioned, we are not talking about the embryos now. We are discussing the potential uterine factors. I think undergoing a hysteroscopy is a really good idea to have a good diagnosis of the endometrium and also the uterine cavity.
Actually, I would say both. It’s true that when a patient comes to the consultation suffering from infertility problems, we need to make a proper diagnosis. Sometimes, it’s true that they can be completely asymptomatic, and there could be very small signs of adenomyosis or endometriosis in the scan. It’s a good way to start and to suspect that there might be slight endometriosis that can also affect fertility.
In the end, we need to find the best strategy for those patients. As I mentioned, some patients didn’t know that they had that issue before until we did a high-resolution scan or a 3D scan in which we could see both conditions. If a patient suffers from failed implantation, it’s really important to do some tests on the uterus to exclude those factors that, in the end, we know may play a role.
The main factor affecting implantation success for women in their 40s is the embryo itself, aside from other factors. It is crucial to test the embryos first to maximize the chances of selecting a healthy embryo. Once healthy embryos are identified, other factors can be considered, but the embryo’s health is the most critical aspect.
If the embryos are being tested, 99% of the time, we freeze the embryos and then perform the embryo transfer after receiving the genetic results. Therefore, if they are planning to use this technique, they will most likely be using frozen embryos.
The effectiveness of endometrial scratching is controversial. Some research has found a slight increase in implantation rates, while other studies have found no benefit. It depends on the protocols each clinic follows. We do not perform endometrial scratching routinely, but we offer it to patients who request it. However, it’s not a standard practice.
No, EmbryoGlue does not increase the implantation rate. While the name might be appealing, studies have shown that it does not improve implantation success. Some patients still choose to use it, which is fine, but we always explain that no data is suggesting it will enhance implantation rates.
We typically perform PRP in the same preparation cycle when the embryo transfer takes place. After starting endometrial preparation, the first infusion is done between 5 to 7 days later, followed by a second infusion 2 days after the first, and a 3rd infusion 2 days after the second. The embryo transfer is then planned according to this protocol within the same cycle.
Vitamin E has been shown to increase endometrial thickness, similar to aspirin and pentoxifylline. Some data also suggest that sildenafil may increase blood flow in the uterus, which is why it is sometimes used. However, it shouldn’t be used in all patients due to potential side effects. These supplements aim to increase blood flow in the uterus and improve the appearance and thickness of the endometrium. However the effect may not be dramatic; for instance, a patient with 4mm endometrium might not reach 10mm, but there could be a slight improvement, perhaps by 1-2mm, which could be beneficial for implantation.
The endometrium shouldn’t be significantly affected by age. While the ovaries have a limited period when they function optimally, the endometrium is more flexible. For example, even women who have been in menopause for years can still grow their endometrium to a good thickness and have a chance of implantation with hormone therapy. The main reason why egg donation treatments work is due to the uterus’s ability to respond to medication, even if a patient is older and not having regular periods. The chance of implantation is the same if the embryo transfer involves a healthy, good-quality embryo.
If a patient consistently has a thin endometrium, the first step is to diagnose any potential factors affecting that patient. If the endometrium, uterine cavity, and uterus appear fine and there’s no infection, a change in strategy may be needed, such as trying a natural or modified cycle. Different strategies can be used to improve endometrial thickness.
Submucosal fibroids are typically the ones that affect implantation and should be removed. Intramural fibroids are more controversial and depend on their location and size. Often, we decide not to remove them because opening the uterus can impact timing and implantation. If the fibroid isn’t large and the patient has only had one embryo transfer, it may be best to keep trying. However, if the fibroid grows or affects the uterine cavity, surgery might be considered.
Apart from endometrial tests, a thorough assessment with hysteroscopy or a 3D scan should be considered. Assuming the embryos are fine, further tests on the embryos and a complete examination of the immune and clotting systems might be needed. Implantation requires all factors to work together, and if one part fails, it can impact the others.
I would suggest doing an ERA test and checking the uterus thoroughly, even if it seems fine from ultrasounds. This could include an MRI or 3D scan. Additionally, considering further tests, such as immunological or clotting tests, could be beneficial.
The main reason could be the embryos themselves. Although the patient was 36, which isn’t considered old, embryos can stop growing due to potential chromosomal abnormalities. While we can’t be 100% sure, this could be the primary reason.
Not really. If the surgery was done on the cervix, which is separate from the endometrium, it shouldn’t affect implantation. However, cervical surgery can make the cervix narrower, which might affect the ease of embryo transfer. But in terms of implantation, if the embryo transfer goes well, it shouldn’t affect it at all.
I would say around 14 millimetres or over. If it’s a perfect triple-line endometrium and it’s around 14 points or something, we should discuss if it could still be good enough. But I would say a maximum of 14 millimetres is acceptable. More than 14 is generally not good.
There aren’t specific “best” or “worst” probiotics; it depends on the bacteria that need to be restored. Depending on the bacteria a patient lacks, different species of lactobacillus may be recommended. Probiotics, both oral and vaginal, contain various species of lactobacillus. Usually, 2 to 3 weeks of treatment should be enough to restore the lactobacillus in the endometrium. If an infection is present, it should be treated first, and then probiotics can be used. In some cases, antibiotics may also be recommended if an infection has been found.
CoQ10 is supposed to help with egg quality and may also help the endometrium. It’s not something we use routinely, but like other supplements, it may help. However, I wouldn’t say it’s a major factor in making the endometrium grow.
The infusions we do in the consultation are less invasive. Hysteroscopic PRP injection is more like surgery, often done in an operating theatre, and it can be more painful since it involves inserting a camera into the uterus. Some protocols recommend PRP infusions behind the endometrium, but in our clinic, we use the simpler, less painful infusion method without hysteroscopy, and we get good results. There’s no major difference between the techniques, so it depends on the protocol each clinic follows.
The latest data suggests that N-acetyl cysteine doesn’t have a significant effect on implantation failure and recurrent miscarriages. As with many new molecules, there are claims about potential benefits, but it hasn’t been proven to play an important role.
