- IVF definition and proccess
- types of treatment
- most frequent causes of unsuccessful treatment
- potential solutions after failed IVF
Options and solutions to consider after failed IVF cycle
Along the IVF road there are many twists & turns. As much as you might want to, you can not always predict what might happen next including future IVF failure.
As with all tough and challenging experiences, failed IVF entails a lot of tough questions that need to be answered – mainly in order to spare ourselves similar challenges in the future. In this webinar, Dr Laura García de Miguel [Medical Director at Clinica Tambre] tells us more about what to do if our IVF cycle fails.
Dr Laura García de Miguel starts with reminding us what we mean by in vitro fertilisation (IVF). By definition, it is a reproductive treatment that creates embryos in a laboratory to maximise the chances of implantation. It is generally differentiated into a few types, such as own eggs and partner’s sperm, own eggs and donor’s sperm and egg donation (with partner’s or donor’s sperm). Additionally, there is also the ROPA method for lesbian couples – called ‘shared motherhood’- in which one partner is the egg donor and the other carries the pregnancy. Each of this treatment types can be conducted with so-called ‘normal IVF’ (when the egg and the sperm are left in the laboratory dish to fertilise on their own) and the ICSI (intracytoplasmic sperm injection) procedure when one sperm is injected directly into the egg. Dr García de Miguel also talks about the various stages that the IVF cycle takes including ovarian stimulation, egg retrieval, sperm retrieval, fertilisation, embryo culture and embryo transfer.
If IVF is done with egg donation, it requires the selection of an egg donor. Generally, such a person is younger than 30 years old and she has to undergo complex psychological, medical and genetical tests. In Spain, egg donation is anonymous – however, the selection is always done on the basis of recipient’s physical characteristics. The donor and the recipient have their cycles synchronised with hormonal treatment – the donor undergoes ovarian stimulation and egg retrieval whilst the recipient has the embryo transferred to her uterus and – as a result – gets pregnant and gives birth to a baby.
At least, this is the desired scenario. But as we all know, life isn’t always this way and IVF treatments can be unsuccessful. Dr García de Miguel reminds us that the 50% of unsuccessful IVF is due to embryo abnormality. It is caused by different factors, such as poor ovarian reserve, male factor, poor embryo morphology or chromosomal disorders. Apart from that, the outcome of IVF may be negatively affected by endometrial receptivity and uterine abnormalities as well as coagulation and immunological disorders.
IVF failure solutions
Fortunately, there are some potential solutions for IVF failure that include cutting-edge technology and treatment techniques. If IVF failure is caused by a male factor, sperm diagnostics may be an answer. There are some diagnostic tests to be performed, such as Comet (to detect simple and double sperm fragmentation), Chromosperm (to confirm if sperm chromosomes are balanced or not) and FISH (to assess if all chromosomes in sperm are absolutely normal). Depending on the detected abnormality, there are different fertilisation techniques which can be used – e.g. Fertile Chip, MACS or SpermSlow.
IVF failure caused by eggs
Dr Laura García de Miguel goes on to explain IVF failures caused by eggs. In such cases, there are two options possible: doctors may decide to go for another round of IVF with own eggs or turn to egg donation. In case of the former, it is possible to use melatonin, change a stimulation protocol, do a dual trigger shot or go for dual stimulation. If egg donation is a second choice, then the recommendation is to go for a fertility proven donor, do donors’ immunological selection if necessary and always do a day 5 embryo (blastocyst) transfer.
Dr García de Miguel reminds us that the blastocyst culture is of great importance for the success of IVF as well. As 50% of human embryos cease to develop on day 3, transferring the ones that outgrew the rest on day 5 significantly maximises the pregnancy rates and assures a better embryo-endometrium ‘dialogue’. When conducting embryo culture, it is recommended to use time lapse incubators that enable uninterrupted embryo development along with real-time monitoring and recording.
In the case of previous implantation failures, it is very important to confirm that karyotypes of both partners are normal. Dr García de Miguel advises to always use PGS (preimplantation genetic screening) in order to select chromosomally normal embryos. PGS is said to increase the chances of a healthy baby by reducing the risk of miscarriage and increasing the chance of pregnancy per transfer.
IVF failure and endometrial receptivity
Another very important issue to confirm is endometrial receptivity. Dr García de Miguel says that 30% of patients have changes in the window of implantation. Doctors may evaluate the receptivity of the endometrium by conducting the ERA test. Apart from that, there is also the ALICE test, that makes it possible to exclude endometrial infection, and the EMMA test that studies microbiome in a patient’s uterus. All three tests (ERA, ALICE and EMMA) are included in the EndomeTRIO test. According to Dr García de Miguel, undergoing this test before another round of IVF will help to exclude all endometrial problems. Additionally, it is necessary to confirm progesterone levels before the embryo transfer.
Another reason for IVF failure may be uterine abnormalities. This is why it is important to use a scan to exclude uterine malformations (septum, double uterus) and pathological conditions, such as polyps or fibroids. Hysteroscopy allows to view uterine cavity while 3D scan helps to confirm if adenomyosis is present and if particular pre-treatment is necessary before the embryo transfer.
Finally, Dr Laura García de Miguel talks about coagulation and immunological disorders. There are women who have potential blood-clotting problems, such as thrombophilia or antiphospholipid syndrome. They could be decreased by using the treatment with heparin which modulates coagulation and improves implantation. When it comes to immunological disorders, it is necessary to conduct thyroid test (TSH + antibodies) to check if pre-treatment with thyroid hormones is needed. It is also common to check vitamins (D, B and folic acid) and study natural killer (NK) cells. Doctors may also want to confirm if the patient has a type of celiac disease she may not even be aware of as well as KIR (killer cell immunoglobulin-like receptors) + HLA (human leukocyte antigens) system to know if there is a negative prognosis that requires a specific pre-treatment or immunological selection of the donor.
Questions and Answers from the event
Could you please explain how the fertile chip is working?
The man who is having a very high fragmentation in the double break of the sperm needs to take some pretreatment with curcumin in order to decrease that fragmentation. Usually, the normality is not achieved – it would be less than 60%. So on the day of eggs fertilisation, we need a fresh sample. With this specific technique, the biologists will exclude the sperm that are very highly fragmented and we will only confirm and work with the normal ones.
are there to increase the number of eggs in stimulation?
Of course it depends on your ovarian reserve. If you’ve had your last IVF route with a maximum dose of gonadotropins, then we are not sure if we could increase the number of eggs. Usually, we recommend to use contraceptive pills to synchronise all the follicles and then, depending on the case, we do recommend to go with 300 units of gonadotropins in order to maximise the response of the follicles. And on the day of the trigger shot, we recommend to use not only one but two injections, Decapeptyl and Ovidrel beta HCG, to maximise the response of mature eggs.
I was also suggested KIR + HLA test with my egg donation treatment. Could you please explain this?
KIR is a part of receptor in our cells that needs to be done before another round of embryo transfer. If you have had an implantation failure, we have to confirm if you have a negative prognosis, such as KIR AA. Then we really need to select a donor that would have HLA system C1/C1 to maximise the possibilities of ongoing pregnancy. So it really depends on the results of the KIR if we need to select the donor immunologically or do pretreatment in case of own eggs.
If doing donor egg + donor sperm and failed one time, does it also apply KIR+HLA?
Yes, if you’re having many rounds of embryo transfers with double donation, it’s necessary to do KIR to learn if the immunological selection of donors is necessary or not. Not only with one previous failure – if you’re having two or three rounds of embryo transfers and you need to go for another round with another donor, then it’s necessary as well.
Does using a double ‘trigger’ injection (the HCG) have any positive effect on egg collection?
Usually, the main focus of double trigger is the maturity of the eggs. If you’re having less than 50% of metaphase-II of mature eggs, it’s really indicated. Usually, if we’re having low recuperation, we also use it to try to maximise the number of eggs in egg retrieval.
Is it true that 5 days after the fertilisation it can’t be said what the quality of the blastocyst is?
No, it’s not true. With the blastocyst stage, we can really confirm if the blastocyst is good or not. First, we have the number of blastocyst. The higher the number is, the better for the blastocyst. Secondly, we will have two letters. The best is letter A – this is the best quality for blastocysts; however, the letter B is also good. So for instance, the blastocyst 4AA is a very good blastocyst whereas the blastocyst 1CC or 2CC is very bad quality.
What is endometrial biopsy and is it recommended for failed embryo transfers?
Endometrial biopsy is a process such as a smear test, but instead of focusing on the cervix, we’re taking the sample from the internal part of the uterus. It is not necessary to go for sedation, it’s not a surgical procedure. It’s a routine in our consultation and it is highly recommended for failed transfers.
What do you recommend for someone with MTHFR?
Depending on the abnormality of MTHFR and other parameters, we would recommend high dosage of folic acid and also heparin treatment.
What do you think of Tacrolimus 4mg/day + 20mg Prednisone/day + Lenograstim?
It’s really high dosage of immunological treatment so it’s really important to review with an immunological doctor if all this is necessary or not. We know that some women have a lot of immunological pretreatment and it is negatively affecting the implantation. In my opinion, it is really a lot and it needs a deep study to confirm if all this is really necessary.
Is it really necessary to proceed with a fresh sample with the fertile chip? Can’t we leave the sample and freeze it at the clinic? Is that a recommendation procedure?
Yes, it is really necessary that we are using the fertile chip with a fresh sample – because it’s not working with the frozen one.
Will the fibroids removal improve the chances of pregnancy?
It’s a very good question. We know that fibroids are not positive for implantation so all women having fibroids, have simply lower chances of implantation. But in order to have the indications for surgery, it is very important to know what kind of fibroids there are – in terms of location and measurements. It helps to confirm if the surgery is necessary and beneficial or not.
Is there a way to increase egg quantity if you have low ovarian reserve?
Unfortunately, we cannot change your ovarian reserve. The only thing we can do is to change your ovarian response. So we cannot do any treatment to increase the quantity of your eggs but we may try to focus on the better response.
I’ll be using an egg donor and a surrogate. Along with everything you spoke about, is there anything that I really should be on the lookout for to have a success this 11th time that we do an IVF cycle ?
I’m sorry for all your previous failures. Probably, if you’re going for a donation, I would recommend to use a fertility proven donor. If you’re going for a surrogate, you obviously do not need all of this. However, I would recommend the blastocyst and to confirm the sperm – it’s absolutely normal before going for the next round.
Both me and my partner have done a karyotype test. Both came back normal. I’m having a frozen embryo transfer (FET) done next week. Will I need to have any further testing done during a pregnancy?
If you’re both having a normal karyotype, it means you do not have additional risks for abnormality in the embryos. But then, during the pregnancy, it’s of course really necessary to confirm if the embryo is normal. So you’ll need not only to do the scans but also to study the risk of Down syndrome or even do a genetical test to confirm that everything is normal.
What is the optimal level of progesterone on the day of the transfer to help implantation? What if it’s too low or too high on this day?
Progesterone is to be confirmed before the embryo transfer – mainly by doing progesterone vaginally. But if you’re doing subcutaneous injections twice a day, this is not necessary. The recommended level is more than 10-11 nanograms per milliliter (ng/mL). It’s not a problem when it’s higher than this – the only problem is if it is lower. So the recommendation is to test the progesterone the day before the embryo transfer and – if it is lower than the mentioned level – to add the injections of subcutaneous progesterone.
What tests would you recommend before a frozen transfer of a day 5 embryo and after failed fresh cycles?
If you had only one fresh cycle and then you went directly for the frozen one, the recommendation is to check the window of implantation – so the ERA test or the EndomeTRIO. But if you were having more failures, then all coagulation, immunological and uterine tests are necessary to exclude any reasons that could minimise the chances of implantation.
I am 44 yrs old, had 9 rounds of own egg IVF (with additional embryo transfers with the frozen embryos) with 3 different clinics. I always had very good results and excellent/good quality embryos. The 3rd cycle worked, however, I had a missed miscarriage at 10 weeks. I have now moved to donor egg /own sperm – we froze all embryos (all 6 of excellent /good quality). I’ve had two embryo transfers from the donor egg /own sperm cycle, with one embryo each time – however, there was no sign of implantation. I’ve had hysteroscopy 2 years ago and a 3D aquascan two months before the donor egg /own sperm cycle which showed nothing… I’ve had basic immune tests and my partner sperm (including DNA fragmentation) analysis and all was good. My clinic in Greece is suggesting another hysteroscopy before a further frozen embryo transfer (FET). I don’t know – is this is necessary? Or are there any other tests I should have?
If hysteroscopy was normal 2 years ago and there are no abnormalities in the scan, I think another hysteroscopy is not really necessary. I would focus more on endometrial receptivity as well as on coagulation and immunological tests to see if we need pretreatment to maximise the possibilities of implantation.
At 37 -38 years old, I had 3 IVF with own eggs – 2 embryos each time, transferred but all failed. Now, I’m 41 years old and had 2 frozen embryo transfers (FET) with donor eggs – each with 1 blastocyst of good quality transferred. Both transfers failed. I had no PGS and ERA test. There are no other issues than the age. Endometrium is trilaminar (0.10-0.11 mm), progesterone on the transfer day was 23 ng /l and on beta day – 8 ng/l. I had treatment with vitamins: E, D, Folate, Zinc, Selenium, baby Aspirin (MTHFR and PAI mutations), Omega 3. We still have 2 day 5 embryos and 1 day 6 embryo left. I know that PGS is not a solution now but what should I do next? I don’t want to do another transfer without changing anything.
I would definitely recommend going for the EndomeTRIO test. So not only the ERA test, but also the two others, EMMA and ALICE, just to confirm if receptivity and everything internal is ok. And I’d also study immunological conditions. With 2 embryo transfers from egg donation, we really need to know where your problems are and what we can do to improve your chances. It’s true that PGS is not recommended when embryos are already created. However, if you should do another round of egg donation at another moment in the future, then yes, it would be indicated, too.
What happens to embryo if it doesn’t implant?
The embryos are going out with menstruation. It’s exactly the same as with the natural cycle. When we are having the bleeding in the menstruation, the endometrium and all the cells are removed.
The egg donor was selected with the same HLA, there was a decrease in the number of natural killer (NK) cells. Is the prescribed dosage of Tacrolimus 4mg/day+ Prednisone 20mg/day+ Lenograstim neccessary?
It really depends on NK. If the selection of the donor was done and NK was in the normal range, I think it’s not that necessary to do all this pretreatment – especially with all these 3 medications.
Have you heard about the Matris test? Is it necessary or important before the embryo transfer (donor egg+ donor sperm)?
The Matris test is another kind of endometrium receptivity test. It is recommended just like the ERA test or the EndomeTRIO test in case you have a story of implantation failures. It is done to confirm if there is any problem in your endometrium.
What is the average number of IVF attempts before success?
It depends if we’re going for own eggs or egg donation. In case of own eggs, it depends mostly on the patient’s age. It’s different in each individual case. In my clinic, with egg donation we have 70% of success rates with first attempt. Normally, in the first, second or – maximum – third embryo transfer, we should achieve an ongoing pregnancy.
Can you do all these tests at one time if required when traveling from the UK? I have had 9 failed transfers: 6 with own eggs and 3 with donor eggs. All followed the same protocol so I’m anxious about further treatment. With all these options, it appears that the success would be more possible. What are the success rates for pregnancy in 44+ age group at your clinic?
Yes, we have lots of patients with implantation failures coming from the UK. During the first consultation, we do all the necessary tests in one day. When you’re going for egg donation, your age is not important. Again, it would be around 65-70% of success rates per embryo transfer. So depending on the number of cumulative embryo transfers, it could achieve 95%.
My doctor recommends Clexane injection and Adiro tablets before the frozen embryo transfer. Is this necessary because I don’t have a history of blood clotting?
It really depends on what kind of history you’re having but my recommendation is not to use Heparin and Adiro if you’re not having abnormalities in your test. I know that some of my colleagues, only on the basis of a patient’s history, are introducing Adiro and Clexane to maximise the chances. But our recommendation is to do all the tests and introduce a specific treatment only if necessary.
What is the name of your clinic? What is the average price for own egg IVF with sperm donation?
The name of our clinic is Clínica Tambre and it’s based in Madrid. The price depends on the package you want to take with egg donation, but we start with 5900 Euros.
I have heard from 3 different doctors here in Switzerland that fibroids have nothing to do with IVF success. Can you add some light on this?
As I said before, it really depends on the location of fibroids. If you’re having an implantation failure and you’re having fibroids, it’s very important to study if these fibroids need to be removed to maximise your chances. If fibroids are affecting the endometrium and they’re submucosal fibroids, it’s 100% necessary to have them removed. If they’re completely external, then it is not necessary. If we have intramural fibroids, it depends on their measurements to decide if the surgery is necessary or not.
I’ve missed what you said about adenomyosis? Do you treat this?
Yes, we treat adenomyosis. It’s very difficult to know if the patient is having adenomyosis or not. If you’re having adenomyosis and a story of implantation failures, it is recommended to do specific medical pretreatment. Such pretreatment with three months of agonist is to minimise the activity of adenomyosis, try to reduce the risk of miscarriage and – as a result – maximise the implantation rates.
What number of eggs is satisfactory to obtain after a stimulation? I have a daughter after IVF 7 years ago. After that, I had 10 IVFs with more than 15 eggs obtained and good quality embryos but it was not good enough. So there was no implantation. I had to take a 2-year break due to breast cancer. Today I am 44 and my doctor says it is okay to make one or two last attempts. I suppose that trying with own eggs will give basically no chances. What would be your suggestion?
Thank you for your question. I’m sorry to hear you had breast cancer but I’m happy you’re ready for another round. We cannot say there are zero chances for pregnancy with own eggs at 44 years old, but it’s less than 3%. So with your story, I would definitely go for egg donation to maximise your chances. Generally speaking, when patients are more than 43 years old, we are always recommending 100% egg donation.
I’m new to IVF. What tests can I & my partner do? We are doing a tandem cycle soon.
Before going for a round of IVF, it is necessary to do the general tests, such as ovarian reserve, AMH, scan and all other tests that IVF treatment requires. If everything is normal, then IVF can start. If there is any abnormality, we would recommend you to do some specific pretreatment.
In my case, the doctors say a surgery cannot help with taking out the fibroids, due to the fact there are too many of them. Under the fibroids, there are already next ones growing. They all grow in the uterus. I had the surgery already 4 times in a specialised clinic. Is there any other possibility different than a usual surgery? I was also that said my uterus is 8 times bigger than a usual one. Does that help?
It is important to have a doctor with expertise in fibroids to really understand what is necessary in your case. The doctor is to decide if you need medical treatment or surgical treatment. It really depends on the individual case. We will be very happy to help you and confirm if there are no other reasons apart from the fibroids and if the embryo is of good quality. The fact that you’re having such a large uterus is not helping. In fact, it’s decreasing your chances. It is very important to confirm if something is necessary before the next embryo transfer.
After a failed donor embryo transfer, I am now scheduled for an open myomectomy to remove a fibroid that had started to grow into the womb cavity. How long would you recommend I wait after surgery before doing IVF? My fibroid is 4 cm and I’m having open abdominal surgery. Will I have to wait longer after this?
Normally, after removing a fibroid, it’s around 2-month wait (3 months maximum). If it’s not very big, we can sometimes do it even next month. However, if it is an abdominal surgery and if endometrium is opened, then we need to wait at least 6 months.
What questions should one ask on the day of FET about the embryos? Mine is scheduled for next week in Spain and it’s my first time!
In my clinic, a patient does not have to ask about anything. Before the embryo transfer, doctors and biologists will explain how the thawing process went and what the quality of the blastocyst is.
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