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Recurrent Implantation Failure – solutions & success stories

Vladimiro Silva, PharmD
Embryologist, CEO, Founder & IVF Lab Director at Ferticentro, Ferticentro

Embryo Implantation, Success Stories

From this video you will find out:
  • What does recurrent implantation failure mean? What causes it?
  • What can be done to prevent it? Is PGT-A always recommended in such situations?
  • What should be evaluated when it comes to endometrium receptiveness?
  • How is the ERA test performed?
  • Why does the microbiome matter? What are the tests available to check the microbiome?
  • In which cases, can hysteroscopy help?
  • What about immune and haematological tests?

What are the diagnostic and therapeutic options in recurrent implantation failure?

In this session, Vladimiro Silva, PharmD, Embryologist, Founder & IVF Lab Director at Ferticentro, Coimbra, Portugal, has talked about repeated implantation failures. Dr Silva explained the main causes, treatment solutions and outcomes, all based on real-life patients’ cases.

What are the diagnostic and therapeutic options in recurrent implantation failure? - Questions and Answers

I’m going to do IVF this month. I’m 43, and I don’t ovulate anymore. I have two daughters, but we want to have one more. I’m afraid of failure. Anything you can advise?

I don’t know if you’re doing IVF with your own eggs or with donor eggs, but the first thing we have to do is assess your ovarian reserve to see if your ovaries are still working. If they are still working, we should use an aggressive ovarian stimulation cycle as soon as possible. If you are willing to do that, we can even do more than one stimulation to accumulate eggs. With donor eggs, the odds immediately climb up to 60% or maybe 70%,  depending on the context of the patients. You have two positive factors in your favour. First, you already have two daughters, so you have proven that you’re capable of receiving an embryo and implanting an embryo and taking a pregnancy to term, and you have done that twice. I don’t know if the father is the same or not, but if so, your partner has already proven that he’s a fertile person. In principle, I wouldn’t advise you to do any further tests because you have everything to become a good prognosis patient. My advice would be to just move on with egg donation, create the embryos, do a standard protocol because, in principle, this seems to be a good prognosis case.

I was wondering if you recommend mini-IVF for patients over 40? My first IVF failed. I’m 40, my AMH is 0.83, and my FSH is 4.7. I ended up with 7 eggs and 2 day-3 embryos that didn’t implant. I’m wondering if a lower stimulation might produce a better egg quality.

You had 2 day-3 embryos, we don’t know whether they would make it to the blastocysts stage or not. Assuming they wouldn’t because the pregnancy result was negative, I think the only way is to try. On the other hand, with 0.83 of AMH and 4.7 of FSH despite being 40, I think it still makes sense to try conventional IVF with a more aggressive ovarian stimulation. We can also perform pre-implantation genetic testing for aneuploidies (PGT-A), but if you can’t do this or don’t want to do it or if it’s too expensive, we can also try the mini IVF. Mini IVF was a technique that everybody was talking about 10 years ago or so. Theoretically speaking, we could obtain just 1 or 2 eggs of better quality instead of 7, for example, as you mention here with the lower quality. Nowadays, the tendency worldwide is the more eggs we can get, the better. I think it’s a respectable strategy, at our clinic (Ferticentro), we usually don’t do it, we prefer to try a more aggressive stimulation in these circumstances because, in our experience, it works better.

In Colombia, the medication used for endometrial preparations is changed every month. Can combined estrogen preparation with transdermal patches, gel and spray affect the window of implantation and pregnancy rates instead of the oral estrogens?

The window of implantation is more about the progesterone, it’s not so much about the estrogen. The principle behind the ERA test and other tests are that under the same type of protocol, the women’s endometrium will behave the same way. Before they started doing this test, they were tested in thousands of patients,  they have confirmed that the cycles were reproductive. The women’s uterus will respond the same way to the same type of strategies. Our advice is to try to do things the same, so if you start with transdermal patches, you should stay with them. If you start with tablets, you should stay with tablets and so on. It is never good to change the way of administration of the estrogen from one cycle to the other, but still, the estrogen is not the critical factor. What I would change is the way of implantation of the progesterone. If you’re using injectable progesterone, you should always keep injectable progesterone. If you’re using it in gel, you should keep it in the gel. If you are using it on tablets, as we do in Portugal, you should stay with tablets. If you can, keep the same strategy. If you cannot because medicines are not available, don’t worry too much, as long as you can keep the progesterone way of administration in steady dosage and the way of administration.

What are the good bacterias of the uterine microbiome?

The lactobacillus.

If we don’t have a period, we don’t ovulate. When is a good time to do IVF?

There is no problem with that. We can do artificial cycles, and so we do what we call hormonal replacement cycles. Everything is artificial, you don’t need to ovulate since you’re doing treatment with donor eggs. Since we are using donor eggs, the eggs are already there. We will create the embryos in the lab, so we just need to prepare your endometrium to receive and implant an embryo. IVF with egg donation can even be used in menopausal women. By doing ultrasound scans and programming the cycle with the right hormones, we can control timings. Your doctors will be able to identify the best moment we need the endometrium to be at least 8 millimetres thick, sometimes some patients can never get to that, but there are different strategies to improve the endometrial conditions.

I was prescribed 2-milligram progesterone, 2-milligram estrogen for 4 days before my day-3 embryo transfer (beginning on egg retrieval day). Since the implantation failed, would you say the fault could be with the embryos and the endometrium or both?

We will never know. I mean, if we’re transferring a day-3 embryo, we would recommend for the embryo transfer to be done after 3 days of progesterone unless a window of implantation test said otherwise. Assuming that your window of implantation is not displaced, I would say that you shouldn’t think about this, you should think about hours as day-3  embryos should be transferred after 72 hours of progesterone that’s the most important. If it was transferred after 96 hours, for instance, then maybe it was too late, I would have to know the results of your window of implantation, but if that was the case and the embryo transfer was not done at the right moment, this could be a reason.

Can I take prednisolone in the treatment with frozen embryos even though I am lactose intolerant? Are there risks for the implantation? I am starting the treatment tomorrow.

In principle, prednisolone is a steroid and a powerful anti-inflammatory drug. We sometimes use it in cases where there is a risk of immune rejection of the embryo. Sometimes we use it just as a prophylactic approach, and yes, we use it a lot in frozen embryo transfer cycles, and as far as I know, there is no relationship with lactose intolerance. However, I’m not a specialist in this field, I can only say that I’ve never heard about it.

What about scratching, PRP procedure?

Scratching was something that we were doing a lot until more or less 4 or 5 years ago, and we did it a lot for maybe 10 years or 8 years. Initially, scratching had very promising results. These days and especially in recent years, there was some research published that in most patients, it didn’t improve results, for certain patients, it could be worse. The group of patients for whom this could be beneficial was very short and very specific, so at our clinic, we’re not doing it anymore, we stopped doing scratching like 5 years ago or so.

PRP procedure is a little the opposite, it’s a new treatment, and it stands for platelet enriched plasma, it can be used either inside the uterus for women with very thin endometrium, they are injected directly in the ovaries. When it comes to low ovarian reserve, I don’t have any experience with this personally or in our clinic. We’ve had patients who have done this in other clinics in collaboration with us, and the results were not so great. There are a lot of recent publications mentioning very good results using it, so I would say that PRP could be the future. Published studies are all very recent and include low numbers of patients, but the results seem promising. I don’t think scratching will be done for much longer, it tends to be abandoned.

Which probiotics do you give, how long in which mode of application? Which antibiotic treatment do you apply in the case of chronic endometritis? What is your thrombophilia protocol?

Normally, when we work with Igenomix, they give a list of probiotics available in many places around the world. Probiotics don’t have the same name everywhere, it depends on the country, there are the ones used either for 7 days or 14 days. They are used interventionally at night, and we don’t make a distinction between different types of probiotics, so all of them can be suitable. We cannot say that a certain probiotic is better than the other. Regarding antibiotics, it will depend on the bacteria that are causing endometritis. Normally, when we get the results from the biopsies that I’ve identified the presence of pathogenic bacteria, we also get the list of antibiotics that work against them. It’s not always the same, sometimes we use Amoxicillin, sometimes Metronidazole or Azithromycin, so there are plenty of antibiotics that can be used. 

Regarding Thrombophilia protocol is a little the same because we work with haematologists, we don’t have a standard protocol for all patients, but typically these protocols use heparin aspirin, and they use steroids. The dosages and the regimes are variable according to many factors, including the type of Thrombophilia that is identified. Not all thrombophilia is the same. The dosage of this medication is not always the same from the beginning to the end of the cycle. There are plenty of things that can be used.

If I’m not mistaken PGT-A, is not recommended for donor eggs. Most of the time it’s not done, and yet you found that a large percentage of embryos were aneuploid. Do you think it’s important to do PGT-A for egg donors every time?

We don’t recommend PGT-A for donor eggs. The example I gave was a very particular situation because it was a patient who had 2 miscarriages, and she was the same age as the egg donor. She miscarried twice, and then we did a treatment with her own eggs, and none of the embryos were viable. We did PGT-A, and they were all abnormal, and so it was because of this very particular situation and context that we did PGT-A in the egg donation case. In the first cycle that she has done,  out of 3 blastocysts, none was viable. In the second cycle, out of six, five embryos were viable. We have seen that PGT-A below the age of 35 doesn’t make much of a difference, and all egg donors are less than 35 years old, so I don’t recommend PGT-A for egg donation.

I don’t think it makes a difference, maybe it is useful when we have a lot of embryos, and we need to prioritize them, then there are regulatory issues. For example, in Portugal, to do PGT-A with egg donation, we need a special permit. In the case of the first patient, we had to file for that permit, and the Portuguese IVF authority authorized this, but we had to explain why we were requesting that. Without the proper explanation they wouldn’t have allowed us,  so it was a very specific situation. It’s not something that we can generalize for all patients. Globally speaking, I would say PGT-A is not recommended for donor eggs.

How long and which dose of amoxicillin do you apply?

It will depend on the bacteria and the recommendations that we have. Typically, it’s about a week, and honestly, I don’t remember, but I believe it was 500 milligrams every 8 hours, I would have to take a look because this is these protocols are tailor-made, they are different according to the patient. There are situations where we have to do longer therapies, it’s variable. 

How important is the ERA test, especially if there was failed implantation in the past? Not all clinics are suggesting this.

here are other tests, there is ERmap,  the WinTest, I’m talking about the ERA test because that’s the one we work with. We’ve been working with this for five years now, but they are all very similar. They test a lot of genes, they include 248 genes. We know how to interpret their results, so this is why we’ve been working with this test for quite a while now. It is important because this kind of problem affects 3 in every 10 cases of recurrent implantation failure. We find a lot of women with displacements in the window of implantation. There is a certain consensus in the scientific community about the importance of these tests, whether it’s the ERA test, ERmap or the WinTest.

I will certainly recommend them, and I think among all of these tests for recurrent implantation failures. This is probably the number one test to be made because it’s the one we are more likely to find. Sometimes, we don’t know why treatments are not working. We have to start with the issues that we are more likely to find and then go to the ones that we are less likely to find. The ERA test is the one that’s more likely to be there.

Is it always done a month before transfer (ERA test)?

There is a logistics problem because when we are doing an ERA test, it takes more or less 21 days to prepare the endometrium, we do the biopsy, we get the result in about 2 to 3 weeks. When we stop the medication, the patient has her menstruation more or less a week to 10 days later. When she bleeds, we still don’t have the result, so we lose this cycle, we have to wait for the next cycle. If the patient is on menopause, we don’t lose that cycle, we can manipulate things with the pill, we can even start the cycle and wait for the result to arrive in the middle of it and start immediately. There are ways to solve this problem, but typically we would lose a cycle between the cycle where we did the ERA test and the cycle where we do the embryo transfer, but we can lose more time. These results are typically valid for 9 months. After 9 months, we should repeat it because these profiles can sometimes change for multiple different reasons.

Vladimiro Silva, PharmD

Vladimiro Silva, PharmD

Vladimiro Silva, PharmD, embryologist, CEO, founder and IVF Lab Director at Ferticentro and Procriar, two of the leading IVF centres in Portugal. Doctor of Pharmacy, Faculty of Pharmacy, University of Coimbra. MSc in Health Economics, Faculty of Economy, University of Coimbra. Post-graduated in Health Services Management, Faculty of Economy, University of Porto. Post-graduated in Clinical Analysis, Faculty of Pharmacy, University of Porto. Author of hundreds of lectures, oral communications, posters and scientific articles in Portugal and abroad. Vladimiro Silva speaks: English, French, Spanish, Italian and Portuguese.
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