- the definition of implantation failure and recurrent implantation failure
- more on biochemical pregnancy
- risk factors for implantation failure
- anatomical reasons for failure like fibroids or polyps
- endometrial-embryonic synchronization
- hydrosalpinx, thrombophilia, and other factors
What can be done differently if the embryo failed to implant?
Have you suffered a failed IVF or egg donation cycle because of embryos failing to implant? What to do if the embryo does not attach to the uterus? Could anything have been differently in that cycle? Should the doctors try a different approach during your next IVF cycle? These and more questions have been answered during a live webinar with Dr Harry Karpouzis, MD, Scientific Director and Founder of IVF Pelargos Fertility Group.
Dr Karpouzis talked about different approaches to implantation failure which could occur during an IVF treatment or in natural conception. According to statistics, only about 25% of all couples trying to conceive naturally, get pregnant every month. The rest experience what we may call an implantation failure.
Recurrent implantation failures – definition
According to Dr Karpouzis, there are several different definitions of recurrent implantation failures. It is referred to either as 3 failed IVF cycles with good quality embryos or 3 unsuccessful cycles with 2 embryos of at least good quality. Additionally, other sources describe a recurrent implantation failure as a failure of clinical pregnancy after 4 good quality embryos transferred (with at least 3 fresh or frozen cycles) in women under the age of 40. What is important, one needs to make sure not to confuse a recurrent implantation failure with a recurrent pregnancy loss.
Recurrent implantation failures – the risk factor
Dr Karpouzis admits that the major risk factor for recurrent implantation failure in IVF is maternal age.
It makes things worse in several ways:
- it increases the risk of aneuploidy,
- causes higher endometrial-embryo asynchrony,
- and reduces the oocyte retrieval as well as blastocyst formation,
- additionally, it affects endometrial thickness.
Other important factors that may negatively contribute to recurrent implantation failures are a high BMI, stress, and smoking.
Causes of recurrent implantation failures
All the causes of recurrent implantation failures may be divided into maternal, paternal and embryo factors. When we talk about maternal reasons, we think of anatomic abnormalities (e.g. endometrial septum, fibroids, polyps, adhesions), thrombophilia (disturbed blood flow), immunological issues or non-receptive endometrium. The embryo causes relate mainly to genetic or chromosomal abnormalities that affect the embryo implantation. However, an implantation failure may sometimes occur even if both a mother and the embryo are all right. Then it is generally the matter of the synchronisation between the embryo and the endometrium.
Dr Karpouzis stresses that all of these causes may be dealt with either surgically (like in case of fibroids or polyps) or pharmacologically (as with the use of hormones to increase the endometrium thickness). There are also innovative methods that help to increase the implantation rate, such as PRP (Platelet Rich Plasma) and GCSF (granulocyte colony stimulating factor) that are proved to have a therapeutic effect on the endometrium. Finally, when all the treatment types fail, surrogacy might be the solution. However, it is a complicated issue as it entails a lot of legal and financial aspects. Interestingly, a lot of clinics today use endometrial scratching as the cure for almost all endometrium-related implantation failures. In Dr. Karpouzis’ opinion, this method is definitely overused. It should be prescribed only when endometrial factor is obvious, and a hysteroscopy is needed as well.
Other factors responsible for implantation failures
Two other important factors responsible for implantation failures after IVF programmes are infections and endometriosis. The former can be treated with the right doses of antibiotics. When it comes to endometriosis, doctors must choose the right protocol for each individual patient. With severe disease, they need to operate before and reduce its impact before they go ahead. Sometimes, when AMH is very poor and there were previous surgeries in a patient’s medical history, they prefer not to operate but to down regulate the AMH level instead. However, Dr Karpouzis stresses that it is important not to down-regulate too much as otherwise the ovaries would not recover as well.
As mentioned before, some risk factors for a recurrent implantation failure might be of embryo origin. An embryo can be affected by both egg quality and sperm quality. In the case of a male factor, it is advisable to do both DNA fragmentation and oxidative stress analysis to investigate the problem properly. Then, if DNA fragmentation is diagnosed, there are fertilisation techniques in the laboratory that can be used, such as PICSI, MACS or IMSI.
Dr Karpouzis says that the quality of eggs depends on only one factor – a woman’s age. Of course, ovarian reserve, AMH and AFC are all contributing factors. However, as every case is different, doctors have to ensure the best protocol for each female patient in order to choose the proper duration of stimulation as well as the right trigger and its timing. Only in that way they know that the quality of the egg is not affected by the IVF protocol but by the genetic material.
Chromosomal abnormalities, on the other hand, are not only in women but also in couples who have implantation failures. So, it is highly important to conduct karyotype testing on both a woman and a man to determine a higher rate of mosaicism and chromosome rearrangements such as translocations or inversions. When the chromosomal abnormalities are observed, doctors may do an advanced PGT-SR test to help in identifying aneuploid embryos and – as a result – choose only “the healthy” ones. Definitely, the treatment needs to personalised here, too.
In conclusion, Dr Karpouzis admits that implantation failures are common, and it is usually possible to determine their causes. Of course, it requires a thorough analysis of a patient’s medical history and the use of tailor-made protocols and advanced diagnostic techniques. Only then doctors can choose available treatments and medications. The best thing to do is to offer the right treatment in the right case or use a combination of treatments. According to Dr Karpouzis, only personalised care and adjusted treatment can bring satisfying results.
Questions and Answers from the event
What is the ideal thickness of the endometrium to allow good implantation?
The ideal thickness is more than 8 mm. Everything more than 8 mm is good. But it is not only the thickness. It is also the way the endometrium looks like. It’s a trilaminar endometrium that is sometimes more important. More than 7 mm of trilaminar endometrium can have very big chances of success. More than 8 mm of trilaminar endometrium is ideal. If it is a little more than that, it could be equally ok. When we are talking about the endometrium that is less than 7 mm, then this is not ideal – even if it is trilaminar.
Would you recommend endometrial scratch?
I already said in my presentation that endometrial scratch is done a lot and it shouldn’t be done in every case. Actually, recent research shows that there is no clinical evidence behind it. We were doing it as well but according to the new research, I wouldn’t offer it to patients with recurrent implantation failures. I wouldn’t definitely offer it to people that didn’t have any problems before. If we need to do the hysteroscopy in the month before the IVF to identify the fibroid, to see how the inside of the womb looks like or we suspect the infection, then we can do endometrial scratch at the same time. In such case we do not have anything to lose. But to make a patient pay money for an invasive procedure without any clear evidence behind it, especially when we deal with people who don’t have recurrent implantation failures, then I’d say no. I would only do it if we had other reasons to do the hysteroscopy.
For MTHFR 667 (heterozygous), PAI 4G/5G (heterozygous) and factor V Leiden normal, is Clexane or Aspirin necessary?
It’s a hematologic question. It depends a bit on what the previous history was and if we have recurrent implantation failures or not. If we have recurrent implantation failures, then we could give Clexane. For heterozygous MTHFR Clexane is not needed. Aspirin should be fine. Clexane is needed for homozygous MTHFR. It has been shown that in such a case Clexane helps. But if it’s heterozygous and it’s not associated with any abnormalities, then usually it is not needed. The only exception is women who had a lot of recurrent implantation failures before.
Do you check for any infection before the implantation aside from the normal blood test in the process?
Actually the infection cannot be checked by a normal blood test. We are talking about the infection inside the lining of the womb and it is very difficult to identify, especially if this is a chronic one. What we do in a normal practice is that we usually check for chlamydia, mycoplasma, ureaplasma because it has been proved that they may be associated with an implantation failure. And when we see the infection, then we treat it. Sometimes if a woman is not checked for all those things, we may cover with antibiotics, without really knowing if there is an infection. We do it just in case if there is an infection. When we have the case of a recurrent implantation failure and we do the culture, chlamydia, mycoplasma, ureaplasma or other microbes may not be there. But when we do the hysteroscopy and we take the inside of the womb and do the endometrial culture, we may see that the infection is there and it is chronic. So in recurrent implantation failures, we prefer to do that as well, have a look at it and treat it with big doses of long-duration antibiotics. In a normal IVF case, the best thing to do would be to check for those things with vaginal cultures. If they’re positive, then treat them, and if they’re not checked, then give antibiotics just in case.
What can be the causes for an ectopic pregnancy when the procedure was through IVF?
IVF by definition increases the chances of an ectopic pregnancy. Unfortunately, we know that when do IVF, the chances are higher. The cavity communicates with the tubes so sometimes the embryo can just go through the womb to the tube and stay there. Definitely, the risk is higher when we have previous ectopics or if we have chlamydia infection. In these cases, if the tubes are present, the chances are higher. If we have hydrosalpinx or we know that we have problems in the tubes, then sometimes it is better to remove the tubes beforehand in order to reduce the risk of an ectopic pregnancy.
I had 4 failed transfers and only one implanted embryo, missed miscarriage at 11 and a half weeks. I have borderline AMH (at 35 years old). Autoimmune thyroid is under control. Endometrium would be thinner but it gets good with medications. Spermiogram is normal. Do you suggest DNA fragmentation? Planning to go for a donor egg. What else do you suggest?
It depends on how poor the ovarian reserve is, how many eggs were retrieved every time. The age of 35 is good. Even if we get a small number of eggs, in the end, it may result in a good quality embryo. Did you have a good quality embryo transferred or not? It could be related to the eggs, it could be related to the sperm. Because of the borderline AMH and the history of 4 failed IVFs, it looks as if it was related to the egg. If you go for a donor egg, then it would be a good idea to take a DNA fragmentation test as you have the history of a late miscarriage and failed IVF attempts without any obvious reasons. I understand that DNA fragmentation costs some money so you need to balance everything. But it is better to know in advance because sometimes we find DNA fragmentation even in normal sperm analysis. In this case, administering 3 months of some antioxidants and vitamins to your partner beforehand may help improve DNA fragmentation. If it is related to the sperm, it may make things better even with a donor egg. Most probably though, we would have to go through the whole history with all the details. I cannot answer this question basing just on that. But most probably donor eggs would help a lot and maybe this is the issue.
Would you suggest to test progesterone level before and after transfer?
We usually do it before transfer. It’s a matter of precaution. Of course most of the time we get the right progesterone levels with the right protocol of progesterone supplementation. But if we are talking about a fresh IVF and, for example, polycystic ovaries, the later usually creates a high level of progesterone. So when you have a lot of follicles and very increased levels of oestrogen, then progesterone may be high as well. If we take it at the time of egg collection, about 3-4 days before the fresh transfer, and it is high, then we always advise the frozen transfer. So in our practice, the answer to the question is: ‘yes’. We take blood tests throughout the procedure of the ovaries stimulation and sometimes when we think it is needed, we take it at the time of egg collection as well. When we talk about the frozen embryo transfer, sometimes we check it before the transfer to make sure that the dose of progesterone was enough.
We had 6 attempts with donor eggs. I got a positive pregnancy test but it has resulted in a chemical pregnancy, ectopic pregnancy and empty sac. I was using Clexane and Prednisolone, too. Could it be male factor affecting the embryo? I have 2 frozen embryos to test for PGT-A.
I don’t know if you have checked PGT-A before. Have you checked if the embryos were healthy or not? After all this history with donor eggs, we need to make sure if it’s a matter of endometrium, if there are general immunological issues or if it is a matter of the embryo. Sometimes Prednisolone in a small dose may not be enough. When we talk about 6 cycles with donor eggs, obviously you had more than one donor. If you had two or three donors, not all of them could have bad quality eggs. So there is a possibility of the whole issue being related to the sperm as well. You can check the embryo to see if it is healthy, you can do a PGT-A. If it is a healthy embryo, you can transfer it. But if the embryo is not healthy, then I would check the male factor as well. It is the only common factor in all your IVF attempts.
What are your thoughts on DHEA supplements for over 40s and their (monitored) taking because your levels are low?
There were a lot of studies on DHEA, the initial ones showed some evidence, the recent ones are against it. First of all, DHEA does not get people pregnant. It doesn’t make miracles. According to some of the studies, if it is given for a proper duration of time to women who have a very poor ovarian reserve, it may slightly increase the recruitment of follicles. What you may earn thanks to it, without any evidence, is one or two follicles more. You may earn one or two eggs more. But the quality of these eggs depends on other things. It depends on your age, for instance. If you are 43 or 44 and you get one egg more, I do not think that it plays an important role. But sometimes the answer is yes. It may help in getting one or two eggs more, without any clear evidence behind it.
Is removing tubes safe? Would that not be a risk factor for infections or other complications?
It’s a surgery, you remove your tubes by having a laparoscopy or hysteroscopy from down below. And like every surgery, it does have complications. An infection is one of them, however, it’s very rare. On the other hand, it depends on what you want to achieve. There is conclusive evidence that, if you have hydrosalpinx, then you need to remove the tubes. If you have fluid inside, then you need to remove the tubes because it increases the chances of IVF. So you compromise your chances of IVF if there is fluid inside your tubes and you keep them there. There is clear evidence behind it. Obviously it makes no sense to remove the tubes without any reason before IVF.
I had 2 failed transfers using donor eggs. My medications were steroids, Intralipid, Aspirin. I have one frozen embryo left. I’m 42 years old. What would you change in the next cycle?
It’s difficult to answer without some basic information. It’s too general. First of all, we need to rule out other issues. We need to make sure we have investigated all the other things. We need to ask why steroids and Intralipid were prescribed. Is there an immunological background? Has NKC cytotoxicity been checked? What was Aspirin prescribed for? Is the sperm ok? Was the quality of the transferred embryos good? If we have a bad quality of the transferred embryos, then steroids and Intralipid wouldn’t do anything. If the embryos were of good quality and the patient was investigated about other things, there could be a lot of other reasons. It could be a matter of the endometrium, the synchronisation, a matter of the previous infection, the lining of the womb and its thickness. We need to know it. Even if the patient has an immunological background that might play a role, steroids and Intralipid cover about 80% of the immunological cases.
I had 3 IVFs at the age of 36-38 years old with day 3 embryos, without any implantation. I’m 41 years old now and this year I had 1 IVF with donor eggs, a day 5 embryo, again without any implantation. The endometrium thickness is 8,9 mm, it’s trilaminar. Progesterone levels are high, without other pathologies. What should I do next? Can ERA test help? PGS is not possible because the law does not allow it.
Again, it is very difficult to answer this question without having a full background. I’m not sure what was the quality of the embryo transferred. The endometrium sounds good. If progesterone levels were checked at the time of the embryo transfer, then they’re ok, too. It’s one egg donation that has failed. We cannot be sure what exactly happened there. How many eggs were there, was the sperm ok? We need to investigate all those things. PGS in egg donation is a very conflicting issue. Sometimes it may help and sometimes not. ERA test can be done, it may play a role, especially because of the past history of IVF. I do not know if the patient was checked about thrombophilia, if she had Clexane or Aspirin or other medications after the embryo transfer. I don’t know if there is any immunological background and if she had steroids in the previous embryo transfer. All of those things could be done, there are also all some other investigations, like e.g. DNA fragmentation. We need to balance all those things and see into your history, check what exactly happened in the previous IVFs. Only then I would be able to give the answer to what the priority is.
Is ERA test accurate? Has it been proven to work? Or is it no guarantee of the successful implantation?
The answer is: there is no guarantee of successful implantation. But there is some evidence behind it saying it increases the chances of success. Unfortunately, all the recurrent implantation failures are multi-factorial. So maybe there are other factors as well. We do ERA test when we have checked everything else and we haven’t found any reasons. ERA test and immunological testing are the last things that we check. There is evidence that it may help if it is a matter of synchronisation. But there is no guarantee.
I had 4 fresh IVFs, I always get blastocysts and day 5 transfers. Hysteroscopy, laparoscopy and immune tests were all ok. DNA fragmentation is also ok. Everything looks good and the lining is perfect. I am 42 years old. During the last cycle this spring we got 8 blastocysts but no implantation. I didn’t take any steroids or Intralipid. What would you recommend?
At the age of 42, 8 blastocysts are a very good result. If you transferred all of them and there was no implantation, maybe PGS or PGT-A would help. It could show you if there is a chromosomal problem. When you have only two or three blastocysts, PGS is not worth it. Then it is enough to put blastocysts back and see if they get implanted. But if you have 8 blastocysts at the age of 42, maybe you should check if they are chromosomally normal or not. If they are not chromosomally normal, this may be a suggestion to look at other solutions, like e.g. donation. I cannot see any other reasons. One more thing you can do is to see if you do not have the suspicion of previous endometritis and the infection inside the womb. Then antibiotics would be a good idea as well. But the main issue would be if you could make chromosomally normal embryos or not. PGS could help you with that.
Can Aspirine (75-100 mg) affect the embryo/fetus if administered until the 7th month of pregnancy? Literature data indicate the contraindication of Aspirin during pregnancy.
We usually advise Aspirin till 12 weeks of pregnancy. At 12 weeks we check about with dopplers and we do some initial testing with pregnancy. If there is a reason, like for example an increased possibility of preeclampsia, hypertension, pre-term delivery or anything like that, then sometimes it is advised to carry on with Aspirin. There is a small risk of Aspirin but sometimes you need to balance the risks against the benefit. So if there is a specific reason with abnormal dopplers and a very high chance of preeclampsia or anything like that, then Aspirin is recommended.
What would you class as a good day 5 embryo? What is the minimum grade?
First of all, the grading system differs from country to country. We have 4AA and 5AA as top quality embryos. When we say 4 or 5, we mean the size. AA is the grading system of embryologists in the laboratory to see exactly how the blastocysts look like. A morphologically normal and perfect embryo does not mean a chromosomally normal one. This is something we have to keep in mind. Anything above 3BB would be a good embryo.
I had 3 very good day 5 hatching blastocysts transferred with good lining up to 12,8 mm at the age of 40 and 41. I’m not sure what to do next. Is it just my age? I had between 9 and 3 eggs during egg retrieval.
Yes, it can be the age. We know that the chances of success with IVF at the age of 40 are specific. You started IVF at this age knowing that the chances were about 40%. Apart from that, if it is your first IVF and you had 3 very good day 5 blastocysts, maybe I would try again. However, I do not know your story exactly. Most probably it’s age-related. At the age of 40, you cannot be sure about chromosomes of even good blastocysts. But the fact that you initially create good quality blastocysts, may say that you’ll find one blastocyst that can give you pregnancy. Of course, we need to think about other things. Were there any other issues? Fibroids, polyps? Is hysteroscopy clear? Was there any infection history or any endometriosis? We need to see all those things.
Some clinics do not offer more than 8 mature oocytes even if the donor produces more. How many embryos will I have towards the end?
I understand we are talking about egg donation. We cannot guarantee how many eggs a stimulated woman will get. We do not bombard donors with hormones. We do have a guarantee of minimum of 8 eggs as well. If there are more than 8 eggs, you may get them. If you start egg donation with 8 mature oocytes coming from a donor and the sperm is ok, there are very good chances of having at least 2 blastocysts. In the end, it always depends on the donor egg and the sperm, it’s a combination. If the sperm is not ok, out of 8 mature eggs you may not conclude in having more than 2 blastocysts. You never know. But the number of eggs you get from a donor depends both on a clinic and a donor.
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