Implantation failure can be just bad luck – but not always

Explained by: Pavel Otevřel, Dr., Reprofit International
Category:
From this video you will find out:
  • What are the most common implantation failure causes?
  • Can PGT-A can help if we face the embryo factor?
  • Do cavity shape and the condition of the tubes matter?
  • How does the window of implantation (WOI) work?
  • What are the steps after failure no. 2 and failure no. 4?
 

Was my last implantation failure bad luck?

In this session, Dr. Pavel Otevřel, Head Doctor at Reprofit, Brno, the Czech Republic has been talking about all factors that cause implantation failure and what can be done to get that successful IVF attempt.

Was my last implantation failure bad luck? - Questions and Answers

I am 42, and I feel the questions around PGT-A are still very valid over 40, if not more, as I don’t have embryos to waste. If embryo results are poor, could they potentially correct themselves? So I am interested to know why PGT-A is recommended more for women over 40.

I can answer based on a particular case. If the patient, and it doesn’t matter if she is 40 plus or under 40, has one embryo only of good shape, I would recommend transferring it without genetic testing. As I showed you in my slides, the test is not improving the embryo quality of a particular embryo. It’s recommended for 40 and 40 plus women based on the statistics. If you see a study that compares different age groups you can find a huge improvement, especially if you compare patients 40 plus with and without PGT-A, you can find a huge improvement. But it is statistics, it is not a picture of one particular embryo. In such an approach, we will do the PGT-A. We simply exclude bad embryos. Then, these embryo transfers are not performed, and it looks like the embryo transfer of genetically tested embryos provides better results. So it is why you can find the recommendation that 40 plus patients have a profit from PGT-A, but if you are a patient in my office, and you have only one embryo, and you are asking me whether to do genetic testing or not, my recommendation would be not to do it. Do the embryo transfer.

Would you recommend the same rational approach for all ages or only stay calm and believe if you are under 40? Is there a different rational approach over 40 to begin investigation sooner? I have one failed implantation and considering what I should do next?

There is one point of view that must be taken into the consideration. That point of view is that a patient around 40 or over 40 will probably have one embryo only of good quality. I can simplify this situation. In my example, if there is a patient over 40, we have to be happy that this patient has one perfect embryo and for this embryo, we should do the maximum. I would agree that it could be taken into the account and considered if the patient is older or younger. It is important to be patient and stay calm. It’s more recommendable in the younger age group than in the aged ladies.

Is taking 50 milligrams of ubiquinol helpful?

Yes, it is.

For a patient who had several implantation failures (six transfers). Would you test the implantation window in your clinic?

Yes, we do. Generally, we are trying to arrange more tests in one day because if the patient is coming over here for the implantation window test and if there is a rational reason to do more tests, we are trying to do them all on one day. We do it because the laboratory, which does the tests is in Spain. We appreciate the Spanish laboratory service because it’s very easy to send the tissue sample to the lab and the communication and paperwork are very useful and user-friendly. It is information regarding the ERA test, and it’s valid worldwide. A patient could undergo this sampling in her facility, and the sample will be sent to Spain.

What is the ideal dose of Ubiquinol? How much better is it than coenzyme Q10?

It’s a reduced form. In the body, there are three forms of coenzyme Q10. Ubiquinol is the most effective form when it comes to the utilization of energy. You can imagine the egg, like a battery that is lying 40 years in the garage. There is some energy inside, but not too much, and you have to recharge it. Ubiquinol is most effective in adding energy to the egg. If you compare all three different chemical structures of coenzyme Q10, ubiquinol seems to be the most effective.

Is CoQ10 recommended for males?

Yes, it is similar to sperm.

Can I continue taking Ubiquinol while doing the stimulation?

There is no negative impact on stimulation, so yes.

Is taking vitamin D3 4000 milligrams, vitamin b12 10ug, and Pregnacare max prenatal vitamins all good for donated embryo was frozen embryo transfers?

The question is about the coenzyme Q10, vitaminD3 for sure at least 2 000 per day, so approximately 4000 looks better. Coenzyme Q10 is questionable in donated embryos because, to my knowledge, the most important effect is on the reproductive cells quality – sperm and eggs. In this described question, we are talking about an embryo, so vitamin D is good for sure, B12 as well. Coenzyme Q10 is not necessary.

 

Do you have any advice on how to prepare for frozen embryo transfer?

My experience is that if the patient is ovulating, I would rather recommend doing a frozen embryo transfer in a modified natural cycle. There is evidence that the natural yellow body, corpus luteum is present in the ovary and the outcome are better. There is a lower risk of miscarriage. So if there is a possibility to do it after a natural or triggered ovulation, I would prefer it. I would recommend testing progesterone levels before and after. I think this is the most popular and supported by the evidence approach. On the other hand, this approach is not comfortable for a patient undergoing long-distance treatment because it needs more ultrasound control, more blood samples, and it could be time-consuming, and it could be not comfortable with communication. It’s perfect for local patients undergoing frozen embryo transfer. From a medical point of view, the natural cycle is better, but from my practice, I see that it could be more complicated to set up a natural cycle adequately long distance.

Can vitamin D3 be taken continuously, or is it necessary to take a break?

In wintertime, it could be taken continuously. 2000 mg if there is a lot of sunshine where you live. About 1000 a day could be taken continuously, with no detrimental impact.

What could we do to prevent immunity issues regarding our lifestyle?

When we’re talking about reproductive immunity, there is no possibility to affect it positively or negatively. Reproductive immunity is such a specialized part of immunity that I don’t think that your lifestyle or something like this could improve it. There is no easy way, and if there is a necessity to correct immunity, it must be done by steroids or immunoglobulins. I don’t know about any easy way how to do it yourself.

What’s your opinion on Prednisone in general, specifically for women with a high TSH level (mine is 3). I’ve read that Prednisone interacts with medicines for an underactive thyroid. Besides, the number of Prednisone’s side effects and lack of firm evidence raise my concerns.

It’s good to take if the TSH level is high. On the other hand, if you take five milligrams per day only, there are almost no side effects. I think that it makes sense to take it, talking about the thyroid issues, if there are antibodies against the thyroid, in such a case it could be considered, but I don’t think it’s a standard treatment. If I should answer in one word, I think TSH elevation is not a reason to take Prednisone.

I’ve done two egg collections, and the long protocol produced almost double as many eggs as the short protocol (34 versus 18). Now I’m looking for a new clinic, but some only do the short protocol. Should I turn them down right away or be open to trying a short protocol again?

With 34 eggs in the long protocol, there is a very high risk of hyperstimulation. You will probably need some prevention from hyperstimulation syndrome. I can answer that for you in different ways. I would be afraid of the long protocol because of the hyperstimulation. It would not be possible to do the fresh transfer. In the long protocol, all embryos must be frozen, and generally, I would be happy with 18 eggs. It depends on what your goal is. If your goal is to be pregnant and to have more embryos of good quality, I would be happy with a short protocol and 18 eggs. I admit that there could be a reason for this if you would like to have as many eggs as possible, I would go with the long protocol and freeze-all strategy. If you were in my office talking about what to do, and we are open to doing both long and short protocols in our clinic. My first question would be what was the maturation and the quality of eggs. I would like to decide according to the egg quality. If you had very good eggs in the short protocol, I would be happy with 18 eggs with the short protocol. If the quality would be better in a long protocol, I would agree with a long protocol with the possible prevention of hyperstimulation. My first choice of protocol is the short one.

I am on Prednisone due to TH1 /TH2 imbalance. The dosage of 20 milligrams daily looks rather scary.

If the TH1 activity prevails, it is the reason to take Prednisone, and for these reasons, two milligrams per day is too small. 20, must be recommended, at least 10, but in my experience, 20 is the correct dose, and you should take some pills to protect your stomach ache and inflammation of the stomach. I would agree with this dosage in this specific diagnosis.

I’m a patient at your clinic. I had one unsuccessful egg transfer with a fresh embryo. Now I’m waiting to do the second egg transfer. My endometrium thickness is quite thin on the ovulation day (6-7mmm), but I have regular cycles and ovulation. What do you recommend? Is a natural cycle with few days of estrogen support right before ovulation a good idea?

The question is about the combination of a natural cycle and the addition of estrogen in the natural cycle. I think we should continue with the natural cycle. You will probably receive Ovitrelle two days before your ovulation, and because in the endometrium there are receptors for LH, we know that Ovitrelle could add one millimetre of thickness to the endometrium. So if your endometrium is on the edge between 6 and 7, I would agree to use Ovitrelle for sure. If you take two milligrams of estradiol before ovulation and also after ovulation, it could help. I would be happy with endometrium six or seven in a natural cycle. It could be modified by additional medication. Please remind us about it while you will be discussing this issue with us before your ovulation.

When would you recommend the use of intralipids?

There are two approaches. One approach is to use intralipid only in case of a clear reason, like immunity disbalance, talking about an NK cell issue. In this group of patients, it seems to be clear. Elevated NK cells, repeated implantation failure. What we can do is experience-based treatment immunoglobulin’s scratching and Prednisone. The second possible approach is to use intralipids without a clear diagnosis, just in case, in patients with repeated implantation failure. Here in the clinic, we recommend intralipids only in case we know the diagnosis that there is an immunity issue.

After a chemical miscarriage at five weeks from adopted embryo frozen embryo transfer, would you add anything to the protocol other than the Estrofem, Utrogestan, and folic acid?

If it was the first miscarriage in your life, I wouldn’t change anything. Simply continue with the same protocol.

Should progesterone be tested seven days before transfer, on the day of transfer, and seven days after transfer?

Yes, because the premature elevation is important in both kinds of treatments. You can find a lot of clinics that implemented this progesterone control in their standard protocols. Let’s discuss ovarian stimulation and fresh embryo transfer. In this particular treatment, it’s recommended to check progesterone level on the day of the trigger shot, and some clinics cancel fresh embryo transfer if progesterone level on the day of trigger shot is higher than the number they want. We need it to be as low as possible. If the patient is undergoing ovarian stimulation, and it is also the patient with repeated implantation failure, you should also check the protocol after. On the day of embryo transfer and after embryo transfer. That’s my recommendation for fresh embryo transfer. Talking about frozen embryo transfer, if we are talking about the previous failures, we have to check the progesterone approximately one day before the patient starts to take progesterone, and it should be as low as possible, and on the day of embryo transfer, and again the transfer. You understood correctly, it doesn’t matter if the protocol is the fresh transfer or frozen transfer.

If the level of progesterone is too high when checked on the day of the trigger shot. Can triggering egg collection go ahead but not the transfer?

A collection will continue. It’s only about the endometrium. The collection will be performed, but embryos must be frozen.
I had two miscarriages after five weeks. The first was a natural pregnancy, the second was an embryo. In the first cycle, HCG only got to 54 on the frozen donated embryo. I think it is time to start an investigation. My concern is despite the implantation happened, there is still a reason to do the receptivity test because the miscarriage in the biochemical stage could be also caused by asynchrony between endometrium and embryo. I do not recommend the ERA test, an endometrial receptivity test only in case the patient has a history of clinical pregnancy. It means the patient underwent frozen embryo transfer, it doesn’t matter when and if there will be a visible embryo on the screen in the ultrasound, and the embryo was successfully implanted and was visible on the ultrasound. We call it clinical pregnancy, and in such a case, it is not necessary to do an additional endometrial receptivity test in Spain. If we are talking about biochemical pregnancy, it is the reason to do an ERA test. My first suggestion should be to transfer a genetically tested embryo next time. Even though the adopted embryo is created from cells of a male donor and a female donor, there is approximately a 20 per cent risk that the embryo is not genetically correct. So I would recommend you to go again with a genetically tested embryo, and on your side, I would consider the ERA test and the immunity test.

Do you recommend any specific supplements to a female undergoing donation?

Coenzyme Q10, vitamin D, and folic acid. That’s it if you have a normal lifestyle, normal food if you are not a vegetarian, and so on. I would recommend this supplementation. Vitamin D because it was a big step in IVF. Three or four years ago, there was an investigation on vitamin D in connection with pregnancy, and surprisingly vitamin D plays more role in the body than we had thought before.

Would you recommend the same steps for failed donation FETs? After the first time to stay calm, after the second time to stay calm after the third to consider additional testing?

All right, that’s the way to do it.

Regarding the repeated failure of implantation, what is your opinion on embryo glue and assisted hatching?

We have a here at the clinic, a department of science, and a doctor who is a very experienced researcher, published in Nature journal, and we were talking about this topic of embryo glue and assisted hatching. EmbryoGlue is a very promising treatment. It could help, but we don’t know for whom. There are more findings, more investigations on hyaluronic acid, and we know more and more that the embryo needs this acid for implantation. We have no test available to distinguish which patient really needs it and which patient doesn’t. It is taken into consideration, and if we are thinking about what to recommend in the next cycle, it is one of the possible recommendations. I didn’t mention it in my lecture because we don’t know for whom it is necessary. And assisted hatching is probably the natural selection criterion for implantation, and very probably, the embryo which is not able to hatch naturally is not able not to implant. So assisted hatching probably, doesn’t improve implantation rate, but for your knowledge, I would have to add the information that all embryos that are frozen are artificially hatched because the assisted hatching is a part of the technical performance of freezing embryos So you can count that all your frozen embryo transfers are done with artificially hatched embryos. In case of fresh embryo transfer, there is a habit or a recommendation, that we will do assisted hatching in case that the zona, the shell on the embryo, is too thick. We can do, and we proactively recommend assisted hatching, but generally, assisted hatching is not important and, although there is evidence that it might be, assisted hatching routinely doesn’t improve outcomes.

I was diagnosed with a heart-shaped uterus (3- 4 millimeters fundus dent). Could this pose a problem for successful implantation?

In my experience and knowledge, it is not an important aspect. This kind of t-shaped or heart-shaped uterus. T-shape uterus may have some negative impact but the heart-shaped, no.

Do you believe you can improve your egg quality? Some doctors believe in supplements, and lifestyle changes can do this. What is your opinion?

Coenzyme Q10 seems to be the most promising supplementation. Making eggs younger, finding the way to improve egg quality is the Holy Grail of IVF specialists. We were asked by some journal what we as IVF specialists would wish the most, and we mostly answered that we would like to find the knowledge on how to make eggs younger. Apart from Q10, I don’t know about anything else.

I have had an adopted PGT-A tested frozen embryo transfer at your clinic, and it was a failure. How many failures are normal with tested embryos? When should I start to panic? I’ve already had an ERA test.

It is a maximum we can do on the embryo side. Adopted embryo comes from young people, young donors. It will be selected, and it will survive freezing, thawing, and will be genetically tested. It is all we could do in connection with the embryo itself. If there was an implantation failure, despite this effort on the embryo’s side, I think it could be the time to start to think about the ERA test. If you have had an ERA test, don’t panic. Not yet, at least. It’s all good, you can still check some other things.

What do you think about using Aspirin before and after the frozen embryo transfer?

Aspirin is used very widely. It is my favourite drug, to be honest, in a patient with implantation failure. You will find a lot of statistics, there is no evidence that aspirin is improving the outcome, but because a very low dose is normally used, 50 to 100 maximum per milligrams per day, it’s very safe. We have to exclude the allergy patients, as they are allergic to Aspirin, they are not allowed to use it. If the patient is allowed to use it. It’s an easy approach that I would recommend before and after the transfer.

Could taking propanolol for a long time affect egg quality?

I think it is a medication against high blood pressure. I’m not sure if the propranolol is for blood pressure treatment, this kind of beta-blockers is safe for egg quality.

How soon before starting IVF treatment should thyroid be checked? I had it checked twice this year, and TSH was 2.59, then reduced to 2.43. However, antibodies were not checked. Are these levels ok for treatment, and should I have antibodies tested before the next treatment?

It should be checked approximately six weeks before. In case of finding some pathology or imbalance, it takes approximately 4 to 6 weeks to correct it. It is better to combine it with 3- thyroxine and antibodies that the anti-TPO and FT4 tests are not easily reachable in some countries. The GP or gynaecologists are not open to test them, so we have to be happy to accept TSH only. But if there is a possibility to test all the triple TSH and TPO, and FT4, I would appreciate it. The recommendation about the possible treatment or supplementation is done based on the result of all three hormones.

Does your clinic help with correcting if needed, or do I need to see my GP? They were reluctant to even when the result was above the optimum level.

We are happy to recommend a specialist. Sometimes we randomly discover a patient with a really serious disease of the thyroid gland who didn’t know about it until she arrived for treatment. The patient has no problem, and we recommend doing tests because of the IVF, and surprisingly we realize that there is a serious problem. In such a case, we recommend contacting GP and solve it with GP. If it’s the only correction of the normal range, we will recommend the doses of supplementation ourselves.

Is there any difference between intralipid and smoflipid?

I don’t think so. I think it’s the same drug, the same solution. Maybe the difference will be in concentration. You have to check the label. The drug inside must be an intralipid 20:20 per cent solution.

Is the effect of Ovitrelle and Decapeptyl the same after the trigger? What happens to the eggs from trigger to retrieval? What could be done to get more mature eggs?

It is a very important and interesting difference. The effect on maturation is the same, the difference is that the Ovitrelle can cause LH elevation in the blood directly because Ovitrelle is LH. So you will have an LH level peak immediately in the blood directly from Ovitrelle. And Decapeptyl function is to wire the hypothalamus. Decapeptyl first triggers the production of LH in the hypothalamus, and the hypothalamus will produce a peak in the blood. The problem could be if the hypothalamus is not working optimally, in such a case, the peak of LH is not high enough, and Decapeptyl is not working. If it’s working sufficiently, the effect on egg maturation is the same. If we are talking about the mechanism of maturation, a very popular thing is to combine Ovitrelle and Decapeptyl. This way, you will utilize natural hypothalamus mechanisms, but just in case, you will also have Ovitrelle. And there are some investigations on this, and it could be very useful, especially in poor responders or empty follicle syndromes. If you would like to have more mature eggs combine both drugs.

I’m also a patient at your clinic. I have now had four failed fresh and frozen transfers. My age is 39 now, and I always have 11 plus lining and good progesterone on the day of transfer. Are there any tests I should do for the next round of my own eggs?

I’m not sure about the genetic testing on embryos, so it could be one possibility to do the genetic testing on embryos. I don’t know if you have done any immunity tests. It could be done in case of failure next time.

If you do a progesterone test seven days before transfer and it was too high, and you decide to cancel the transfer. What would you recommend to do or change for the next cycle to make sure that that progesterone doesn’t get too high too quickly? Is there any medication to keep the progesterone low until the transfer date?

Mostly it is only bad luck because progesterone is produced by small follicles in this particular cycle. In the next cycle probably the number of follicles will be different, and most probably, next time, it will be a completely different situation. Progesterone could be lowered. In case we have a patient who has repeatedly high progesterone, it’s possible to conduct the protocol under down-regulation. It means the injections down-regulate your own hormones, including progesterone, and a premature elevation of progesterone is excluded.

Authors
Pavel Otevřel, Dr.

Pavel Otevřel, Dr.

Dr. Otevřel is a graduate of the medical faculty of Masaryk University; he was devoted to oncological gynaecology and surgery. His experience has been broadened into the field of assisted reproduction since 2006. After his attestation in 2009, Dr. Otevřel has become a head doctor in REPROFIT clinic. He has dedicated his work, especially into women's reproductive ageing.
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Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is an International Patient Coordinator who has been supporting IVF patients for over 2 years. Always eager to help and provide comprehensive information based on her thorough knowledge and experience whether you are just starting or are in the middle of your IVF journey. She’s a customer care specialist with +10 years of experience, worked also in the tourism industry, and dealt with international customers on a daily basis, including working abroad. When she’s not taking care of her customers and patients, you’ll find her traveling, biking, learning new things, or spending time outdoors.

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