Raul Olivares, MD
Medical Director & Owner of Barcelona IVF , Barcelona IVF
Category:
Failed IVF Cycles
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.
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