Good embryos and poor outcomes. What to do?

In this session, Dr Raul Olivares, Medical Director & Owner of Barcelona IVF talked about various reasons for failed IVF attempts, he also explained what can be done if we receive good embryos, but there are still poor IVF results. Dr Olivares started by first comparing all these cases, and the implantation failure is probably 30% of the cases that we have, then there are biochemical pregnancies, and clinical miscarriages and only 25% of the embryos that we can create are going to become babies. This shows us how inefficient reproduction is. These implantation failures can be due to problems with the embryo, mostly genetic issues, or they can be due to endometrium or environmental problems in the woman. On the graph with the live birth as women get over 40, the live birth is very low, and this is exactly the opposite that happens regarding the genetic issues in the embryos and the miscarriages. The live birth is very similar to the other graphic in which they were checking the successful implantation and the miscarriages. These are very similar to this other one where they were preventing the aneuploidy. It’s going to be very different to study an implantation failure when the patient is 29 when we know that most of the embryos will be genetically normal than when the patient is 42. In this case, more than 90% of the implantation failures are going to be due to abnormalities inside the embryos. How we can define implantation failure? When we talk about young people at IVF Barcelona clinic, once there are 2 blastocysts transferred, and the patient is younger than 35, or when we are doing egg donation, and we don’t achieve a pregnancy, we may start studying or requesting some tests to see if we can find the problem. When the patients are over 40, then transferring more good embryos in terms of morphology is not enough, we need to be sure that we are transferring genetically normal embryos. As an example, the results of a 41-year-old woman showed that from 19 genetically tested embryos, only 2 were suitable for transfer. All the others were abnormal, so you should expect to have a lot of genetic issues in the embryos and before starting considering endometrium biopsies, blood tests, immunology, and things like that, first, we must be sure that the embryos are of good quality. Therefore, once we transfer good embryos and the patients don’t get pregnant, the first thing is to confirm that there are no anatomic issues that may interfere with the implantation, such as having septums in the cavity, hydrosalpinx that may reduce the implantation rates. Fibroids, polyps, or chronic symptomatic endometritis, all these kinds of things are treatable, it’s possible to reshape the cavity, it’s possible to remove the hydrosalpinx, or fibroids, or give antibiotics and get rid of this chronic inflammation and create a better environment for the patients.

What can be done with recurrent implantation failures?

Another thing that Dr Olivares explained was that obesity reduces uterine receptivity, and patients with high BMIs have poorer implantation rates. The problem is related to the hyperestrogenic state that an overweight patient has. The results from studies done on egg donations where the quality of the eggs is somehow guaranteed are quite low. There are around 10 000 studies that confirm if your BMI is high, the implantation is going to be lower. In cases of egg donation, the first thing to do is try to reduce the weight of a patient with BMIs over 30, and for sure, over 35, because the implantation rates are going to be much higher. The same happens with smoking, the big studies carried out in egg donation cycles show that when you smoke, the receptivity of the endometrium is going to be lower. The issue with smoking is that it’s not something that if you give up the next day, you’re going to completely solve the problems. There is kind of a stacking effect with smoking, and you may need more time to eliminate these side effects, but the sooner you stop, the better the outcome. If you stop smoking at the beginning of the pregnancy, the risk of complications in the last 3 months is going to be much lower. The same happens in reproduction, it is probably better if you give up smoking 2-3t years before considering getting pregnant, but even if you are in treatment, and you stop smoking in a few months, you’re going to get the benefit. Hysteroscopy has been the first-step treatment for many years, unfortunately, one of the studies, which was published in 2016, shows that hysteroscopy, when there’s nothing wrong with the scan, does not help at all to increase the live birth. This study involved 700 patients with several IVF cycles that hadn’t had a hysteroscopy in the previous 2 months and there was a kind of algorithm to balance the different characteristics of the 2 groups, so they were very similar, the results show that the risk ratio between the hysteroscopy group and the control group were the same. When the scans were normal, hysteroscopy was inefficient in terms of increasing live birth. Therefore, there is no reason to recommend a hysteroscopy for an implantation failure if the scan is completely normal. The scratching has been one of the most controversial issues. There was a study published in 2003 where it was suggested that doing the scratching could increase the implantation rate, but it was very well known from you know 40 years ago that when the endometrium biopsy was a very uh frequent uh test that people there was a group of people that after the endometrium biopsy got pregnant naturally you know while they were waiting to start the treatments. The idea that doing something in the endometrium could improve receptivity has always been there. The thing is that this initial study unfortunately has not been able to confirm that, though there was 1 study where they showed a slight benefit that favours the injury. This meta-analysis was very criticized because the studies were very different, and it depended on when they were doing the scratching, how often, and things like that, so it was tough to compare the studies. More recent studies suggested a randomized control trial showed that there are no differences at all, and even in some cases, there is a trend toward having an adverse effect. Endometrial injury in women undergoing assisted reproductive techniques looks for the trigger of an inflammatory response, though the exact mechanism is yet unknown. It seems to be useless, or even worsens the outcome, in patients without a clear recurrent implantation failure. If it’s done, it must be done during the inflammatory phase of the previous cycle. Using low-molecular-weight heparin in patients with two or more unsuccessful IVF/ICVSI cycles does not help. Using heparin compared to placebo or using aspirin does not help at all, it does not increase the live birth. There are certain conditions like thrombophilia and antiphospholipid syndrome, which may help. These kinds of problems increase the miscarriage rate, and these miscarriages take place because there are local thrombotic problems when the embryo is trying to implant. If the issue was at the implantation, there could be other cases in which this thrombosis may also prevent the implantation from taking place, and that give an apparent and given thrombophilia or given aspirin may help a subgroup of implantation failure may help. The ERA (The endometrial receptivity analysis) sounded very promising, it is a test in which a lot of research has been done. It is a test that is done to see if the window of implantation is opened. The window of implantation is opened by the progesterone, not by the dose, but when you start the progesterone, this window of implantation is 2-3 days, during which the embryo is allowed to implant in the endometrium. Based on some studies that check several genes that are activated, this test was developed to know whether the endometrium is receptive or not when we are transferring the embryos. ERA test is only useful in cases, in which you are using hormone replacement therapy because the conditions should be very strict to make it useful. It is useless for IVFs, it is useless for natural cycles because, in these cases, every cycle is going to be different. It’s only useful in cases in which you use hormones. The idea is to do a biopsy when the embryo transfer is going to take place, and then depending on which genes are activated and which genes are suppressed, they tell you if the window is pre-receptive, receptive and post-receptive.

My experience is not very good with this, and unfortunately, one of the groups already published this big study of 5 years of experience, and they are now recommending that in all cycles of IVF, the embryos should be frozen. Then the patient must undergo this test to work out the window of implantation. Then transfer frozen embryos with this personalized treatment. I think that they are completely wrong because the only data that increases is cumulative live birth after 12 months. You must invest 1 year of transfers to detect any significant benefit, so it’s something that they would just recommend in cases of patients who are doing cryo transfers or egg donation. I wouldn’t recommend going to this kind of freeze-all IVF at all because the benefits are so tiny that the cost involved in doing these things and the cost of the test as well, which is close to 700 EUR or something. I think it’s not worth the effort, and I’m afraid the ERA is still far from being as useful as they claim.

Another thing is if there is any kind of dysbiosis or chronic endometritis, it has been designed by the same group that the ERA test released, and they all can be, done in a single biopsy, but according to Dr Olivares, this test is much better. You do an endometrium biopsy on the day of the theoretical embryo transfer, and then you check if the bacteria that the microbiota should be in the endometrium is the correct one and if there are any bacteria present at that level. There should be more than 90% of lactobacilli. The result shown on the slide was completely abnormal with a 0% and an active infection caused by streptococcus, and after solving this problem, the patient got pregnant. It’s quite a new test that has been around for probably not more than 2 years. Information is still gathered on this, but it seems to be very useful in some cases of patients who should have gotten pregnant, and they didn’t, and after fixing this issue, the patient has got an ongoing pregnancy. The idea is to do the biopsy and then, if there is an infection, to give antibiotics to get rid of that infection, and if there is a dysbiosis, so the percentage of normal cells is abnormal, then you use vaginal probiotic suppositories. With this combination of antibiotics and vaginal probiotics, it’s possible to overcome this issue, sometimes in the first attempt or after 2 or 3 attempts, because it’s not so easy to eliminate this problem. The main problem is that this chronic endometritis is causing these hyperinflammatory statuses that damage one side, the bacteria may damage the embryo, but also the embryo may find it very hard to implant because of these high pro-inflammatory or hyperinflammatory statuses. EMMA and ALICE tests sound like really good tests, very promising to explain some cases of implantation failures. Vitamin D is another controversial thing, the first study in 2010 suggested that it could affect endometrial receptivity, but it was not a very big study, since then, there have been a lot of people trying to confirm if the vitamin D was important for the oocytes and the receptivity. What is clear is that vitamin D is important for pregnancy. We know that patients that got pregnant with low levels of vitamin D are going to have more complications in the last 3 months of pregnancy, in terms of preeclampsia, intrauterine growth retardation, etc. Vitamin D should be tested and treated. Vitamin D may not improve the implantation rates, but it is going to reduce the obstetric risk. Another study carried out by a Spanish group, testing the vitamin D levels in 162 donors, found no differences at all between the groups of low levels and high levels. It seems pretty clear that vitamin D deficiency does not affect the quality of the eggs. Two big studies published in 2014, where they checked the vitamin D levels on IVF outcomes showed different results. One of the studies suggests that vitamin D is relevant, and the other says it does not affect it at all. Therefore, it is controversial, they concluded that vitamin D level does not affect the implantation. In regards to Vitamin D, many factors may interfere with the results (when it is done, which type of vitamin D you are checking, seasonality, ethnics, and the technique used to assess the levels). It is still unknown at what level causes the problem (oocytes, endometrium). It looks like transferring good embryos (donated oocytes, euploid blastocysts) mitigates the impact of the deficiency. There is no current strong evidence of its usefulness, at least if the embryos are of very good quality. However, patients should still have normal levels because of their relationship with obstetric issues (preeclampsia). The most common test is to check the NK (Natural Killer) cell levels. Natural killers in blood have nothing to do with the NK cells of the uterus, so all the tests that are based on assessing levels of natural killers in the blood are useless, they have the same name, but they are completely different cells. Natural killers in the blood are cytotoxics, and they help us to get rid of various viruses, and control cancer cells, they are cytotoxic. Natural killers in the uterus have very low cytotoxicity, and this cytotoxicity is triggered in very specific circumstances, they need to be activated by the KIR receptors in the mother. There is an interaction between mother and embryo, they help the placentation because they induce vessel generation. They are very important because they control the deepness and pattern of placentation. People must have a natural killer in the uterus, and the levels around the implantation are very high. All the tests that say that you have high natural killers are completely useless, and completely out of date, especially if they check blood natural killers. What happens when there are immunological problems? Most of the time, people are given immunotherapy, which according to Dr Olivares, is a big mistake. The American Society for Reproductive Medicine guidelines shows there is good evidence to recommend against the routine use of corticoids during stimulation. However, a lot of clinics still use prednisone from the very beginning, but we now know that the embryo needs some degree of inflammation before that. If we give immunosuppressive drugs in all cycles, we may be reducing the inflammation at the level of the endometrium, making it more difficult for the embryo to implant. Therefore, it’s not recommended to use corticosteroids in general IVF as it’s not going to help, and it’s going to make things more difficult for you. With regards to the intralipids, and immunoglobulins, there is insufficient evidence to recommend this kind of treatment, it is only advised in very specific conditions of immunological disease but not based on natural killers, not based on TH1 TH2 ratios. It’s better not to use them because the evidence is against the rotating use of these drugs. It’s because they just focus on treating natural killers, and there are other cells involved in the implantation, such as T cells, endothelial cells, macrophages, dendritic cells, and natural killers. When you use immunosuppressive drugs, you are not just affecting the natural killers, you are affecting all these cells. The implantation works as an orchestra, it’s a very coordinated process, and if you start balancing natural killers, you may end up with a bunch of kids making a very hateful noise, so first, do no harm and the use these steroids in these cases is probably harming a lot of people. According to one of the studies published 2 years ago, the role of immunotherapy in IVF and recurrent pregnancy loss, immunotherapy should be used in the context of research, and should not be used in routine clinical practice to improve reproductive outcomes. This study was carried out in London, and the conclusion is based on the systematic reviews of many studies. When we speak about thyroid function, the first study in 2010 suggested that the TSH between 2.5 and 5 could increase miscarriage, especially in the first trimester. In the second study published in 2015, where they were transferring good embryos, the TSH didn’t seem to be as important. Recent studies suggest that TSH is only relevant when there is clinical hypothyroidism, which means TSH levels are over 4.2 -4.5 depending on the laboratory results, but it is just 1 study recently published, so it’s still quite controversial. The main problem with thyroxine is that it is very important in the early stages of pregnancy, thyroxine is an anabolic hormone, so it’s very important when there is a lot of cell activity and you can imagine how many cell divisions take place in an embryo in the early stages. Therefore, when the patient has these levels between 2.5 – 5, it may be enough to lead a normal life if you are not trying to conceive, but if you conceive and the TSH is close to the cutoff point, it may happen that these normal levels may not be enough to support the pregnancy. When the TSH levels are above 2.5, it may make sense to send the patient to the endocrinologist and assess the overall state of this patient. Then individually decide if it’s worth giving thyroxine or not. If the endocrinologist says it is not necessary, then it’s going to be very easy, you just wait until you’re pregnant. As soon as you’re pregnant, you need to check your TSH level again, and if it raises to the levels, you can have a kind of subclinical hypothyroidism, and then it’s better to start the treatment, both approaches work pretty well.

Summary

What is not recommended is hysteroscopy, which is going to be useless in terms of increasing your life birth. It’s an invasive procedure that, in some cases, could be expensive, and it’s not going to help you in a recurrent implantation failure. It’s better to have a good 3D scan, and if it comes out normal, there is no need for hysteroscopy. Immunology is very controversial, the treatments are not free from side effects, they are expensive, the evidence is very low, and some of them should be avoided unless there is a very specific condition or immunological disease. Test for natural killers TH1 TH2 ratios, CD138 don’t have enough evidence to support that idea. The scratching could be useful in some cases, in cases of recurring implantation failure, it seems that it does not make it worse, but you should avoid it when there is no systematic procedure in all cycles or a normal IVF. It’s better to avoid using heparin and aspirin as a routine treatment in all IVFs. The evidence shows that they don’t increase the live birth, but in specific cases of thrombophilias or antiphospholipid syndrome, it may make sense because it’s going to reduce the risk of miscarriage. They could help to make things easier for the embryo to implant. Vitamin D is controversial probably it could be useful to correct and fix it and focus on it when you are not going to transfer good embryos but if you are working with egg donation or you are transferring euploid embryos, it is not going to have any critical impact in the outcome. However, it should be fixed when you are trying to get pregnant because it has been demonstrated that it may increase the obstetric risk. When it comes to the thyroid, just let the endocrinologist decide. Taking a bit of thyroxine is never going to be an issue but if you wait until you’re pregnant and then check the levels again and they are high, then treat it. Smoking and obesity are factors that have proved to reduce implantation. Try to have the best BMI, smoking could also affect the ovarian reserve, but it’s always better to quit smoking before you try to get pregnant and the sooner you do it, the better the results are going to be. The last thing is the EndomeTRIO, which is the name of the test that includes the ERA, EMMA, and ALICE according to Dr Olivares the ERA test is still very controversial, however, EMMA and ALICE tests that check the microbiota has proved to be very relevant in many other specialities like in the gastroenterology and pneumology and also in gynaecology because we know that the microbiota of the vagina is very important.