During this event, Dr Esther Marbán, Gynaecologist & Fertility Specialist at Clínica Tambre, Madrid, Spain, discussed the reasons why IVF sometimes fails and what can be done differently to improve success rates.
Dr Marbán explored the common causes of IVF failure, shared effective strategies to enhance your chances, and provided insights into the latest advancements in IVF treatments.
Dr Marbán starts with the most common cases of IVF failure. The first and most important one is the factors related to the embryo. Embryonic abnormalities may be caused by a low ovarian response or low implantation rates, with no embryo obtained, which would be one of the main factors—also related to poor egg quality. The most important are poor embryo morphology and poor embryo quality.
The way the embryos are classified will also give us information about what we may expect from that embryo transfer. Good-quality embryos might potentially have an increased implantation rate, and, the low-quality embryos will have a different and lower potential implantation rate.
Apart from quality, it’s crucial to mention potential chromosomal abnormalities. That factor is the most common cause of implantation failure. If the embryo we are transferring is not healthy, and if we haven’t done any tests to check whether the embryo was healthy or not, the chance of implantation with that embryo will be potentially lower.
The second factor is the uterus and the endometrium. Some problems related to uterine structures, such as fibroids, polyps, adhesions, or some kind of malformation in the uterus, can also lead to implantation failure. Additionally, some potential alterations in the endometrium can also contribute to implantation failure. Apart from the window of implantation, which is the moment when the endometrium is most receptive to implantation, sometimes chronic endometritis can also result in this kind of issue.
Finally, apart from uterine and embryo-related factors, there could be also clotting and immunological disorders, which are also known to contribute to implantation failure. The embryo is the most important factor that has to be checked and examined when discussing implantation failure. It could account for around 70% of implantation failure. If we are talking about good-quality embryos that have not been tested, the chance of having an ongoing pregnancy with untested embryos, if they are not healthy, would be quite reduced. Apart from that, uterine abnormalities and immunological factors also play a role.
One of the factors could be a male factor, so we need to examine the sperm in the best and most accurate way possible. Apart from doing a normal and basic sperm test, we always prescribe a test called a SpermComet test, which is designed to check single- and double-stranded DNA fragmentation.
Sometimes, there are some alterations and problems related to DNA fragmentation in the sperm, which can be treated. It’s possible to select sperm differently than normal to try to lower the risk of selecting fragmented sperm to fertilize the egg. When we find certain alterations in DNA fragmentation, depending on what alteration we find, we use different techniques to select sperm at the time of fertilization. Apart from a normal and general sperm test, it is also important to conduct a more extended test to gain more information about sperm quality and find the best way to select sperm if needed.
Egg quality and implantation failureOne of the main factors linked to implantation failure is egg quality. Some patients, even though they are young, might have problems with egg quality. We can try different strategies to improve egg quality. The first one is using supplements such as melatonin, inositol, or CoQ10. These supplements are supposed to increase or improve egg quality. Apart from that, when a patient comes to the clinic after previous treatments in other clinics, it is possible to change the stimulation protocol to try to achieve a better response and, if possible, better egg quality.
Sometimes, in cases of a low ovarian reserve, when we want to maximize the options of having a higher number of embryos to be PGT-A tested, different strategies can be used, such as the dual stim, in which a back-to-back stimulation is performed. The first one would be done in the normal way, with a proliferative phase starting with menstruation, and the second stimulation would be started some days after having done the first one, in what is called the luteal phase. Two simulations are performed at two different moments of the cycle, with the idea of also knowing how the ovaries work at different moments of the cycle and giving the chance of having better outcomes.
It’s important to have a good quality embryo and also transfer a healthy embryo.
In the past, it was recommended to transfer embryos on day 2 or day 3, however nowadays blastocyst transfer (day 5 embryo) maximizes the chances of pregnancy. Apart from that, it’s the best moment to do the biopsy on the embryos if we want to have them tested for chromosomal abnormalities. Single embryo transfer on day 5 is the best option to reduce risk during pregnancy such as prematurity, preeclampsia, or diabetes.
Clínica Tambre offers GERI Time-Lapse incubator, which is designed to take pictures every 5 minutes of the embryo, which means that the embryo doesn’t have to be taken out of the incubator to be checked under the microscope. With that incubator, the embryos remain inside for the whole procedure, so they have constant, stable conditions in terms of temperature, oxygen, and light exposure. These conditions do not change at all. Apart from that, more information about those embryos will be provided, as the camera takes pictures every 5 minutes. This means it could be a really good way to have more information about when the embryo divides and when the cells start compacting. That information can also be very helpful for the embryologist to select the best embryo to transfer and also the embryos that should be frozen if there is more than one.
In addition to that, the most important part of the implantation procedure is the embryo and then the other factors mentioned above. If there is a good-quality embryo, it doesn’t mean that the embryo will have no abnormalities in the chromosomes. When the embryo has certain problems in the chromosomes, the chances of implantation with that embryo are much lower. Therefore, normally preimplantation genetic screening is indicated in patients who, for instance, might have problems with the karyotype. Sometimes, some alterations such as deletions or translocations in the karyotype can be found that should also be tested in the embryos. Also, if a patient has experienced repeated miscarriages or implantation failures, it is a very good indication. Finally, patients who might have certain genetic diseases that need to be diagnosed before transfer can also benefit from this testing to avoid having a baby affected by that genetic disease.
PGT-A and all genetic diagnosis techniques are designed to lower the risk of transferring a non-healthy embryo, which could lead to miscarriage or implantation failure. In many cases, the only problem is advanced maternal age, so in that group of patients, it is a good option and technique that can help in achieving pregnancy.
As shown in the slide above, you might see how the rates of getting healthy embryos change depending on age. As a woman gets older, the number of potential healthy embryos starts decreasing. That is why it is normally suggested to use these techniques in patients older than 37–38 years, as this is the moment when the risk of miscarriage and repeated implantation failure starts increasing due to the higher number of non-healthy embryos expected with age.
Various tests are designed to learn more about the endometrium. One of the reasons for failure of implantation or also repeated miscarriages could be chronic infections, which could be chronic endometritis. Chronic infections in the uterine cavity can lead to these problems. There is a test called ES-META that gives us the chance to check for potential chronic endometritis in the uterus, so we can know if there is any infection first, and we can also check the microbiome to know more about the environment in the uterus. Sometimes we need to find a good balance between the good bacteria and the non-good bacteria in the uterus to find the best treatment for those patients if needed.
In addition to that, it’s also possible to check what we call the window of implantation, the window of implantation is the moment when the endometrium is most receptive to implantation. This means that we would have a higher chance of implantation if we transferred the embryo during that window. Indeed, this test is not indicated for everyone, and it can also be controversial, but it’s useful in certain groups of patients. The test is called ES-TIME. This test is not offered for all patients, but we should have a clear idea in our mind about which patients could benefit from using it. This test can also help to personalize the embryo transfer, doing it at the best moment for the patient’s endometrium.
Sometimes, we may detect issues that are visible on a standard ultrasound, such as fibroids or certain uterine malformations. Therefore, we typically recommend performing a specialized test called a 3D ultrasound scan, which allows us to identify any potential abnormalities in the uterus. This scan also enables us to assess the uterine cavity to ensure its size and shape are suitable for implantation, while also ruling out conditions like adenomyosis, which is relatively common. If we discover any factors that could negatively affect implantation rates, these should be addressed before proceeding with the next embryo transfer. The same approach applies to other issues, such as abnormalities in the isthmus, which should also be treated beforehand.
In addition to the 3D scan, hysteroscopy is a really good technique to check the uterine cavity and make sure that everything is fine. The hysteroscopy won’t let us know everything about adenomyosis because sometimes we can’t see the muscle of the uterus with it, but at least we have a good option to take samples if needed. We can also check the uterine cavity, and if we find any kind of polyp or fibroid, we can remove those during the same procedure.
Sometimes, it is also recommended to perform tests that are usually done using blood samples to determine if there is any form of genetic thrombophilia or markers associated with antiphospholipid syndrome. These conditions should be treated, as they have been shown to lower implantation rates and are linked to an increased risk of complications during pregnancy. Some patients may require treatment with heparin, aspirin, or a combination of both. The same approach applies to the immune system. When aiming for a comprehensive evaluation of the issue, it is quite common to assess the immune system to determine if any additional treatments are necessary, such as corticosteroids or, in some cases, intralipids.
In addition to heparin and aspirin, maintaining the immune system in optimal balance is crucial to maximizing the chances of success.
When the standard procedures fail, other options are available. If a patient with poor egg quality or a low ovarian reserve has tried IVF several times, sometimes we need to consider other techniques, such as egg donation. Having a severe male factor can also be the main reason for low-quality embryos. In such cases, patients might also need to consider the option of using donor sperm.
According to the Spanish reproduction law, donor selection includes criteria such as age, and exclusion of certain problems in the family and the donors themselves. Rigorous selection is performed and follows the necessary tests and instructions provided by the law. more than 90% of donors are younger than 30 years old, and many of them are already fertile. We also exclude familial diseases, and we perform many tests before donating to ensure the treatment is done in the best conditions with the lowest possible risks. Apart from the way donors are selected, the physical appearance of the donor and the patient is considered.
We use a technology called Fenomatch, which does facial biometry to analyze the distance between the eyes, nose, etc., to maximize the chances of selecting the best donor for each patient. Additionally, we can do genetic matching to reduce the risk of having a baby affected by a genetic disease.
The most common indications for egg donation are low ovarian reserve, advanced maternal age, low egg quality, certain hereditary diseases detected through genetic tests, poor response to stimulation, and of course, repeated miscarriages or failed IVF cycles.
In the field of assisted reproduction, artificial intelligence is also being used to assist in embryo selection. At Clínica Tambre, a program called CHLOE supports embryologists by assigning a score to each embryo, which is taken into account during the selection process. It is specifically designed to help identify the best embryos for transfer. Similarly, the MATRIS project analyzes endometrial thickness and other factors to improve the chances of successful implantation with the transferred embryo.
Finally, to summarize, in cases of previous implantation failure, it’s really important to have an experienced and multidisciplinary team to go through all the factors and maximize the chances of success in the next attempt. It’s important to do a thorough diagnosis and find the proper treatment for the patient. It’s also important to use the latest techniques and technologies in assisted reproduction. Each patient should follow a personalized treatment plan depending on their case, aiming for the best possible results. It’s also important to have good support and an individualized treatment plan to guide the patient through the process with the idea of succeeding in the end.
Yes, adenomyosis can be a significant factor. It also depends on the type of adenomyosis we are dealing with. Some forms, such as cystic adenomyosis, can impact implantation failure, especially if they interfere with the uterine lining. The treatment strategy depends on the type of adenomyosis and any previous treatments the patient has undergone.
Generally, we try to downregulate hormone levels by putting the patient into a temporary menopause-like state for two to three months. This helps lower hormone production and reduces the potential negative effects of adenomyosis.
There are many different supplements, including CoQ10 (ubiquinol) and inositol, that are believed to improve egg quality. However, it’s difficult to determine whether their effect is significant enough to impact the outcome of an IVF cycle. That being said, they might be beneficial, so why not consider them.
An ERA test can be a good option. In addition to the ERA test, I would also suggest considering the Emma and Alice tests, which examine chronic endometritis and the endometrial microbiome. This approach provides a more comprehensive understanding of the uterine environment.
The ERA test is generally considered valid for around two years. However, this depends on what happens in the meantime. If the patient becomes pregnant or undergoes uterine surgery, the results may no longer be reliable, and repeating the test may be necessary.
As for hysteroscopy, its validity is not time-based. If the results show no abnormalities, there may be no need to repeat it. However, if new symptoms arise or there is a suspicion of new issues such as polyps, repeating the hysteroscopy may be necessary.
Unfortunately, there isn’t a direct alternative to Heparin. Aspirin works differently and does not have the same anticoagulant effects. Other anticoagulants are generally not allowed during pregnancy. This is something that should be discussed with a haematologist to explore any possible solutions specific to your case.
There is no real difference. The name of the test depends on the laboratory performing it. The ERA test and ES Time are the same, while ES Meta is the same as the Emma and Alice tests I mentioned earlier. These are just different names used by different laboratories, but they essentially refer to the same type of test.
It depends on the patient’s age and personal limits. There is no fixed number of IVF cycles after which egg donation should be considered. Some patients want to keep trying with their own eggs, while others accept that their prognosis makes further attempts difficult and opt for donor eggs sooner.
Each case should be personalized. Some patients have undergone 10 or even 15 cycles before considering egg donation, which is quite extreme, but ultimately, it depends on individual circumstances and decisions.
Estrogen priming and other strategies might help slightly improve ovarian response. However, at 45 years old, the most likely issue is embryo quality. Most embryos transferred in her case were likely chromosomally abnormal, which is why implantation failed or led to miscarriage.
While ovarian response seems relatively good for her age, the primary concern is embryo quality. The use of estrogen priming is fine, but the main limiting factor remains the high probability of chromosomal abnormalities in the embryos.
It depends on the type of hormonal imbalance. If it involves the thyroid, treatment should aim to restore balance, as thyroid function is important for fertility. If it is related to polycystic ovarian syndrome (PCOS), there is no direct way to “balance” hormones, but we can focus on optimizing ovarian stimulation for IVF.
In many cases, there is no universal treatment for hormonal fluctuations, but we can find the best approach to manage each patient’s condition.
Regarding the DQ gene, it is related to the immune system. Depending on the specific genes identified, specialists determine whether it could have any impact. Some variations can be associated with conditions like celiac disease, in which case a gluten-free diet may be recommended. However, the interpretation of these results is more within the expertise of an immunologist rather than a general gynaecologist.
Since you are now 41 and have a low AMH, I would suggest considering PGT-A for your embryos and possibly using a dual stimulation approach. Given the suboptimal response in your last cycle, one option is to undergo a new stimulation, fertilize the retrieved eggs, and perform a biopsy on the embryos. Then, a few days after the first round, you could start another stimulation cycle. This approach allows us to see how the ovaries respond at different phases and potentially increase the number of embryos available for testing within a short timeframe.
Regarding the first question, we guarantee a minimum number of blastocysts at the end of the process. There are different packages, and depending on the patient’s choice, they can receive a guarantee of 1, 3, or even 5 blastocysts.
For the second question, it depends on the patient. Some prefer to transfer a fresh embryo, which is fine, but about 80% of patients choose to freeze their embryos first. This allows them to complete the treatment in a more relaxed manner, knowing in advance how many embryos they have and scheduling the transfer at the most convenient time.
Normally, we biopsy the embryo and freeze it while waiting for the test results. Although results can be obtained in just 24 hours, we generally do not recommend this approach because transferring embryos later than usual can affect the implantation window.
Currently, PGT-A is an invasive test, but it is designed to increase implantation rates by selecting embryos with the highest likelihood of success. While this technique may evolve in the future, the current standard is to biopsy and freeze embryos before planning the transfer based on the results.
It depends. If this is the first round, the sperm quality is good, and there are no additional concerns (such as high DNA fragmentation), PGT-A is usually optional. However, if a patient has had repeated implantation failures, previous unsuccessful cycles, or male factor infertility, then PGT-A could be beneficial. As always, the decision should be personalized based on the individual case.
It depends on the patient’s age. If the patient is young, some clinics may suggest continuing with more transfers since the embryos are expected to implant eventually. However, if the patient is older, PGT-A could be a reasonable option to ensure only genetically normal embryos are transferred.
Even if a sperm sample appears to be of good quality and free of major issues, advanced paternal age is associated with increased risks for the baby. Studies suggest that children born to fathers over 50 may have a higher risk of congenital heart conditions and psychological or psychiatric disorders.
Some patients, aware of these risks, choose to proceed without changes, while others opt to minimize potential risks by using a sperm donor. The decision ultimately depends on your personal comfort level with these considerations.
It’s true that, as I was saying before, the ERA test could be controversial. One of the reasons is that if the endometrial tissue renews every cycle, it might impact the implantation window. However, research shows that the implantation window is generally stable if there are no external changes. Of course, surgery or certain treatments can affect it. If we use a specific treatment to prepare for the ERA test and later change that treatment, it could impact the implantation window. Initially, there was an idea that it could change every month, but research indicates that the implantation window remains relatively stable in the following months after the test.
It might be a good idea to recheck your immune system, since immune status can change over time. Given that you also experienced a miscarriage, I would also recommend checking the uterus and endometrium for any abnormalities or chronic infections. Apart from the immune system approach, investigating potential uterine issues could be beneficial.
This is a common question. During embryo transfer, the procedure should be as gentle as possible to minimize uterine contractions. Progesterone is commonly used to relax the uterus. Some clinics have tried additional medications to reduce contractions, but studies have not confirmed their effectiveness. The key is to use an appropriate transfer technique—if the transfer is performed smoothly, the chances of uterine contractions are reduced.
Many patients indeed report changes in their cycles after hormonal treatments, including spotting. This is not necessarily related to implantation failure but rather to the body’s adjustment to hormonal changes. If the spotting persists, it would be a good idea to have an ultrasound to rule out any underlying issues that may have developed recently.
Yes, we have had patients with similar conditions. The main concern in such cases is how well the endometrium responds after cancer treatment. There may be an increased risk of a thinner endometrium, but if we can achieve a good endometrial response to medication, the chances of a successful ongoing pregnancy are quite high.
Not for that goal, to be honest. We always just use Metformin for patients who may have some kind of insulin resistance, but not to achieve a higher rate of mature eggs. Not for that.
Well, that happens many times because when we decide to prescribe some tests, we sometimes don’t yet know about an immune system problem. So, we do the ERA test first and later discover immune issues. What the laboratory suggests is trying to perform the treatment in a way that is as similar as possible to the embryo transfer procedure. For instance, if the patient normally uses Heparin, we also try to use Heparin for the ERA test because studies show it can change the receptivity of the endometrium. Other medications, such as Prednisone, are supposed not to affect the implantation window as much. In the end, we try to prepare for the ERA test in a way that is as similar as possible to the actual embryo transfer. However, we do not use certain immune system modulators in the ERA test preparation.
Well, it depends on the baseline condition of the patient apart from age. The patient is 36 years old, so the decision depends on the risks they are facing. If there are no additional problems—such as obesity, high blood pressure, or other health concerns—the patient is young and overall in good condition. In that case, transferring two embryos could be considered, even though twin pregnancies increase the risk of complications. If the embryos are of good quality, we usually transfer one at a time. Transferring two embryos can slightly increase implantation chances, but it also increases the risk of a twin pregnancy. In the end, we must find a good balance and communicate with the patient to decide on the best strategy.
