During this session, Dr Laura Garcia de Miguel, Medical Director at Clinica Tambre discussed all available tests that can help identify the causes of embryo implantation failure, and possibly increase the chance of getting pregnant.
Dr Laura Garcia started her presentation by explaining the definition of embryo implantation, it is when the blastocyst (5-day embryo) joins the maternal endometrium to carry on its intrauterine development. It includes different steps, it starts with the hatching, apposition, adhesion, and invasion. The implantation success depends mainly on gametes quality, eggs, and sperm that will produce the embryo, the technique and the correct moment of the embryo transfer is also important, there must be a proper dialogue between the embryo and the endometrium. If it does not occur, that may cause possible problems in coagulation or the immunological system, which can lead to failure. If the embryo is not transferred in the correct phase of the luteal phase of the endometrium, it’s not going to implant.
There are different definitions for implantation failure, one of those from the Spanish Fertility Society defines implantation failure as a failure to achieve a pregnancy in women younger than 40 years old after having transferred at least 4 good quality embryos (in cell stage) in both fresh and frozen embryo transfer.
What is not an implantation failure? Women older than 40 years old go through IVF because one of the main reasons these women are not getting pregnant is chromosomal abnormalities. Low ovarian response or low ovarian reserve leads to a poor number of eggs retrieved, and there will be a low probability of selecting good embryos. Other factors that are not the reason for implantation failure are some medical conditions such as endometriosis or hydrosalpinx, low-quality embryo transfer, and uterine cavity alterations such as polyps, and fibroids. Also, an inappropriate endometrium development, such as refractory endometrium, where the endometrium is very thin.
One of the causes of implantation failure could be clotting alterations in our haematological system. There could be some hereditary thrombophilia such as Factor V Leiden and factor II Prothrombin mutation, MTHFR mutation, which is evolving in the folic acid metabolism, Factor XII mutation and many others. There could also be protein C and S deficiency or Antithrombin III deficiency, which makes you more likely to get abnormal blood clots. In this kind of situation, the use of aspirin and, or heparin will be necessary. Other problems include antiphospholipid syndrome, where women are creating antibodies in their blood, such as Anti-cardiolipin, and anti-beta2 glycoprotein I antibodies, which could also affect embryo implantation.
For instance, there are many patients undergoing reproductive treatments that have anti-thyroid antibodies, which is necessary to treat with Prednisone. However, if there are high levels of anti-thyroid antibodies, levothyroxine is also used to try to have a good TSH level, and yet the embryo is still not implanting, Prednisone is strongly recommended.
Another issue is an antiphospholipid syndrome, which involves Anti-nuclear antibodies (ANA), Anti-cardiolipin antibodies (ACA), and Lupus anticoagulant, it could also be associated with previous failures or miscarriages as well as thrombosis. The treatment with aspirin and heparin is offered.
A lot of controversies are still related to the natural killer cells, but if 3 blastocysts with good morphology have been transferred to a good endometrium and it still fails, it’s better to check the NK cells, which can be done in the blood or the endometrium, that depends on each clinic. If there is an expansion of the natural killer cells, which normally prevent the organism from viruses and other infections, but in the context of the reproductive outcome, it could lead to failures. In such situations, an immunological consultation is required, the immunologist will either recommend corticoids such as Prednisone, intralipid infusions or immunoglobulin infusions to try to reduce the NK cells expansion.
Apart from higher NK cells level, some women have an expression in the receptor of their lymphocytes called KIR AA. This is linked to miscarriages, complications during pregnancy and also implantation failures. Therefore, in the event of not being able to find any other reason for the failure, in the case of egg donation, it’s best to select a donor having C1C1, which is the best combination for KIR AA. However, in the case of IVF with own eggs and one partner’s sperm, where it’s impossible to change the combination, immune medication is offered to make that response between KIR and HLA less aggressive and increase the probability of the pregnancy continue developing.
Some patients need to remove gluten from their diet because the reason for their previous failure is unknown. Such patients can have some genetic issues, and a higher risk of celiac disease, or they can be diagnosed with celiac disease. In such cases, a gluten-free diet is recommended at least 1 month before transfer and throughout pregnancy.
It’s very important to classify the embryo as good, intermediate or bad quality, depending on the cell number, the percentage of fragmentation in their cells, the nucleation, alterations in pronucleus or vacuoles and also the cell-division moment.
Not only the external quality of the embryo is important, but its genetics, at a more advanced age, the risk of aneuploidies is much higher. That’s why in women at 38-40 with previous failures, it’s recommended to perform PGT-A testing to check the embryos and whether they are abnormal or not.
It is always recommended to do a basic semen analysis and check concentration, volume, motility, but also DNA fragmentation, it should be thoroughly checked if it is a single or double fragmentation which is high and what can be done for the such patient in terms of pre-treatment and technique in the lab to maximize the outcome. In very specific cases, FISH or Chromosperm is recommended to see if there is a genetic problem. Even in normal sperm parameters, single-strand or double-strand DNA breaks inside sperm cells can be identified, therefore, the CometFertility test is recommended.
If there is a high rate of single-stranded DNA fragmentation, there will be a lower fertilization rate. If the issue is in the double-stranded DNA fragmentation, there is a higher chromosomal alterations risk in the embryo. Both will lead to lower implantation.
Genetic testing such as Chromosperm or FISH (Fluorescence In Situ Hybridization) is used to check if the possible issue of the failure is a genetic abnormality in the embryos and if the reason for that is the sperm. In such a situation, sperm donation might be the best solution.
For patients with multiple rounds of IVF, and multiple failed implantations, it’s always recommended to check the uterine cavity. It’s best to check with the 3D scan if there are any problems the 2D scan failed to show, such as very tiny polyps or fibroids in the cavity (submucosal fibroids). There could also be some other issues that could only be seen with hysteroscopy, such as Asherman’s syndrome.
Other things that need to be excluded are hydrosalpinx. In the case of hydrosalpinx, salpingectomy is required before any transfers.
Another situation is uterine malformations, which can be checked with a 3D scan or MRI. There could be a T-shaped uterus or a septum which needs to be evaluated by a surgeon on how to proceed to improve the cavity.
If the lining doesn’t have a good thickness, which is at least 6.5 millimetres (the ideal is to have more than 7 millimetres) before the transfer, it’s best to postpone the transfer for the next month. The endometrium can be prepared with the use of Aspirin, Viagra, or vitamin E or any other medication that could increase the size of the lining.
In the event of implantation failures, it’s always necessary to study endometrial receptivity. Tests, such as ERA, and TIME can help with that.
The window of implantation is known as the period when the endometrium has the best conditions for embryo implantation. The endometrium receptivity during this period is short and depends on the effect of estrogens and progesterone in the uterine lining. It varies between women. It is reported that 30% of women have an abnormal window of implantation, so it should be investigated before further transfers. 30% of patients will have abnormalities in this test and will have different gene expressions, so the embryo transfer needs to be personalized.
For microbiome infections, EMMA, ALICE, or META are used where the endometrium is biopsied. It will show if there are any infections or microbiome abnormalities. A pre-treatment with antibiotics, etc., is performed a month before another transfer to restore a beneficial microbiota.
Preimplantation Genetic Testing (PGT) allows the selection of chromosomally healthy embryos, and it increases the chance of having a healthy baby by reducing the risk of miscarriage, there is an increased probability of pregnancy per transfer because a single transfer is recommended in such cases. It also reduces the duration of treatment and the number of cycles needed. The indications for genetic testing are advanced maternal age, karyotype alterations and patients affected by monogenic genetic diseases.
There is no evidence linking these treatments to cancer. However, all medications can have potential risks. As the lady mentioned, these medications may reduce the immune system’s function, which is why we always recommend taking precautions. For example, during the COVID pandemic, it was essential to be extra careful and attentive.
By contrast, if the issue is related to the immune system, I would strongly recommend taking these medications. I’ve had multiple patients who experienced repeated failures, but after adopting a thorough immunological approach, we achieved success.
I’m sorry for these failures. I’m confident that with the right approach, you will be successful. First of all, it’s not uncommon to have a history of previous pregnancies and then face challenges like this. In your case, mild adenomyosis could still be an issue. Many clinics don’t consider an adenomyosis-specific protocol, but we always recommend addressing it in cases of failure. I suggest a three-month hormonal blockade (inducing menopause) to reduce adenomyosis activity.
I also strongly recommend the receptivity test (ERA) to confirm if your implantation window is accurate. If you’re currently using an artificial cycle instead of a natural cycle, the window might not align properly.
Regarding immune testing, it can sometimes reveal changes in your immune system that may have developed over the years. For instance, antibodies could now be present that weren’t before. Treatments such as prednisone or others may help, alongside blood-thinning injections. I hope this advice helps guide your next steps.
Sometimes, young women with PCOS may face challenges with egg quality or overall ovarian quality, which can affect success rates. In your case, I would recommend proceeding with IVF alongside PGT-A testing to ensure the embryos are chromosomally normal before transfer. This is particularly important given the prior termination at 13 weeks.
If all the other necessary tests have been completed, and you’re already on aspirin and prednisone, it seems the primary focus should be on ensuring embryo quality.
Unfortunately, thyroid issues can pose significant challenges in reproductive treatment. Sometimes, levels fluctuate rapidly, as in your case, with antibodies contributing to the problem. Before transferring another embryo, I recommend doing receptivity testing, especially since you have not had an ongoing pregnancy. A biochemical pregnancy could indicate an underlying issue, so it’s important to exclude problems with receptivity and infections.
Additionally, I advise consulting an immune expert to explore ways to reduce natural killer (NK) cells. Treatments like prednisone or intralipids may help optimize the environment for implantation.
You still have possibilities for success. If fibroids were present during your previous transfers, they could have been the reason for the failures. Many patients have experienced losses due to fibroids or polyps. I’m glad to hear that you’ve had the fibroids removed.
I wouldn’t recommend ignoring the ERA test entirely. It remains one of the possible explanations for implantation issues, even if you’re trying a new embryo transfer strategy. Before transferring again, I would strongly suggest reassessing receptivity.
Since you have Hashimoto’s, it’s also crucial to continue using prednisone and other treatments in parallel to optimize implantation. However, the removal of the fibroids might address the primary issue behind your previous failures.
It depends on whether you are homozygous or heterozygous for MTHFR and your homocysteine levels. Typically, 5 mg of methyl folate is sufficient, but in some cases, we also add heparin to optimize implantation further and reduce homocysteine levels.
It is always important to eat healthy, no matter which system in our body we support. However, not eating lots of vegetables and fruits is not the main reason for implantation failure.
That said, I always tell my patients that we must try to maximize all strategies for implantation. This includes avoiding tobacco and cigarettes, reducing alcohol as much as possible, exercising, and controlling body mass index. It’s also important to maximize antioxidants by eating fruits and vegetables. While these are helpful, they are not the main reasons an embryo might not implant.
For refractory endometrium, it is a significant problem, and we never know exactly what works best because there is no statistical evidence to clearly say what we need to do.
However, using plasma is a strategy to improve the function and thickness of the endometrium. This is something we sometimes do in our clinic.
Normally, our experts focus on working with our own patients because we have a very important immunology unit that deals with many complex cases.
However, it is possible to help in cases where patients from other clinics still have embryos and are interested in transporting those embryos to our clinic. In such situations, we could assist you.
If not only ALICE but also ERA was normal, and we excluded issues in the endometrium, then absolutely yes, I would recommend a 3D scan or hysteroscopy. Additionally, I would suggest coagulation and immunological testing to exclude any blood-related problems.
I am very sorry for your frustration, and I understand how difficult this must be. In this context, I strongly recommend doing a 3D ultrasound with an expert to exclude adenomyosis or any cavity issues. It is also important to check receptivity and microbiome testing again.
Additionally, I would suggest a second opinion with another immunological expert. Some patients have been prescribed very high doses of prednisone, which can suppress the immune system excessively and potentially hinder implantation.
We do not recommend antibiotics for everyone. In our clinic, antibiotics are used before egg collection to reduce the risk of infections in the ovaries. However, not before the transfer.
An alternative approach is to give probiotics before the transfer, as many patients have low lactobacillus levels. But in general, I would not recommend antibiotics for everyone.
No, Marianne. We recommend doing the ERA test regardless of whether it is a natural or medicated cycle. This is especially important if there have been implantation failures. The test should be done replicating the exact conditions of the real transfer cycle.
Not all euploid embryos are capable of implanting. When a euploid embryo does not implant, we start testing because we believe the embryo is competent for implantation.
However, not all euploid embryos are 100% able to implant. There may be issues with metabolism or other systems beyond genetics. Adjusting progesterone timing after ERA has improved success rates for many patients.
For submucosal fibroids (type 0 or 1), we always recommend removing them, regardless of size, because they are in the implantation line and can interfere with the process.
For intramural or subserosal fibroids, they would need to be extremely large to cause failure, as they typically do not interfere unless they are very close to the endometrium.
This is indeed a difficult case, but I truly believe you’ll achieve success. Antiphospholipid syndrome can be a significant challenge. While you’re being treated with Tinzaparin and Aspirin, if the antiphospholipid syndrome is contributing to failed implantation or miscarriages, we might consider additional medications to manage the condition.
Given that you’re 42, it’s crucial to maximize implantation success and reduce the risk of miscarriage. If the elevated uterine lining levels are confirmed with the repeat biopsy, addressing those findings would also be important. Additionally, your history of painful periods might suggest underlying issues like adenomyosis or endometriosis, which should be investigated further.
This is a research-based treatment. We use ion plasma from the patient and adjust the approach depending on the case.
For some patients, we do a single treatment before transfer on day 3. For others, we use multiple injections from day 0 to day 5 to maximize results. The strategy depends on the patient’s specific situation and needs.
We generally recommend starting prednisolone at least 10 days before the transfer, and it’s the same for Clexane. Some immunologists suggest starting even earlier, sometimes a month prior. However, the minimum effective time is typically 10 days before transfer.
The most likely cause of failure in this case is the embryos. If they are your eggs, I recommend performing PGT-A (Preimplantation Genetic Testing for Aneuploidy) to ensure we only transfer euploid embryos. Additionally, tests for endometrial receptivity, coagulation, and immunological disorders may be valuable in the context of repeated implantation failure.
In cases of painful periods, it’s crucial to rule out adenomyosis. Additionally, testing for embryo quality (euploidy), endometrial receptivity, microbiome balance, coagulation, and immunological disorders is important. If 2 embryos were transferred without success, a thorough evaluation is recommended before further transfers to avoid unnecessary embryo loss.
For patients undergoing their first IVF or egg donation cycle, we typically don’t recommend extensive testing right away. However, if a patient has experienced repeated implantation failures with euploid embryos, we suggest a full range of tests, including the immune system and coagulation assessments, 3D scans, and others. If a patient prefers to have all tests done before the first treatment, we can accommodate that as well.
Ferritin levels should ideally fall within the normal laboratory range, though specific targets depend on individual labs. For vegans, low ferritin is common, so supplements like ferrous sulfate are appropriate. Additionally, consider checking for other factors that could affect implantation. While ferritin at 30 is low, it’s unlikely to be the sole cause of implantation failure.
A 3D scan provides a reconstruction of the uterus’s shape, allowing us to identify issues like septa, malformations, or adenomyosis. It’s less invasive and more affordable than hysteroscopy or MRI but still highly effective when performed by a skilled sonographer.
While anaesthesia can help reduce pain and anxiety, it doesn’t improve implantation rates. If pain is unbearable, anaesthesia may be considered. Otherwise, I recommend a relaxed, minimally stressful transfer environment.
No, once embryos are confirmed as euploid, their quality and implantation potential are not dependent on the age of the patient. Both 35- and 42-year-old patients have the same success potential with euploid embryos.
