How to make IVF treatment successful after failed attempts?

Luca Gianaroli, MD
Scientific Director of S.I.S.Me.R., S.I.S.Me.R.

From this video you will find out:

What is the frequency of the meiotic errors in oocytes?
How to manage your IVF failure? How to use it to have success the next time?
What are the possible causes of implantation failure?
How many times should I try?
What are the live birth rates with PGT-A?
When should I move on to egg donation treatment?

How to make IVF treatment successful after failed attempts?

How to achieve success after IVF failure?

In this webinar, Dr Luca Gianaroli, Scientific Director of S.I.S.Me.R. located in Bologna, Italy, has been talking about reasons for failed IVF attempts and how to turn them into a successful outcome. If we look at the factors causing infertility, they range from genetic factors, and congenital factors to acquired factors, like infections or diseases. BMI, diabetes and other disorders, as well as ageing, can also impair your fertility. Different causes require different solutions. Prevention is better than cure. The first step is not to wait too long before seeking medical advice if you are ready for a baby. A comprehensive diagnostic workout for a woman and her partner is required to be sure that the ART and related techniques are the options we need to use for the best treatment. On the other hand, if you are not ready for a baby yet, think about fertility preservation (social freezing), mainly for females, it’s probably the most effective way to avoid failed IVF treatment. Fertility preservation is oocyte cryopreservation for medical or nonmedical reasons, it is performed for future use within an IVF treatment with a higher success rate because your age is the age at the time of oocyte collection. For better outcomes, it’s recommended to do it before you turn 35, you can do it after 35 but then you have to realize that maybe more than 1 oocyte retrieval would be necessary to collect a suitable amount of oocytes. You also need to remember that the success rate of a subsequent IVF treatment may be lower than expected. If we look at the age of female patients below 34 up to 40 and so on, you’ll see the proportion of oocytes that are impaired, they are carriers of an incorrect number of chromosomes. When you have an oocyte that has an incorrect number of chromosomes, the chance to deliver a baby is dramatically lower. At the age of 41-43, 1 out of 8 oocytes is still suitable for delivering a healthy baby. If the age is more advanced, 96% of oocytes are going to be aneuploid at the age of 44 and over. The more oocytes you cryopreserve, the higher chance you have to deliver a baby. If cryopreservation is no longer an option for you, then some other ways can be managed to overcome IVF failure.

Implantation failure

If you had a failed cycle, you need to seek medical advice and try to realize that your choice of medical advice is the right one. You may consider doing another treatment, perhaps PGT might be a solution for you, or Endometrial Receptivity Test (BeReady) and finally, gametes donation. Having an unsuccessful IVF means to have a failure of implantation. You can have a failure of implantation because your embryos went into arrest, you had an early miscarriage, or your embryos did not implant even though your embryos were euploid. There are a lot of reasons why recurrent implantation failures happen. RIF (recurrent implantation failure) is characterized by the specific need of a group of patients. The major problem is that this group of patients is a heterogeneous population. Many factors are involved in repeated IVF failures, starting from immunological reactions to karyotypes that are altered in one of the partners, not necessarily the female. There could be endometrial anomalies, so the uterus looks normal, but the endometrium has anomalies, there is an important factor related to sperm contribution, so even the male factor plays a role, and it doesn’t matter if the parameters of the analysis of sperm look normal, there could be something more subtle. Genetic factors can affect the competence of the oocyte and the competence of the male gamete. The development of a full-time pregnancy has 2 phases. The endometrium must be receptive, which means there shouldn’t be any uterine anomalies, coagulation defects, no endometrial anomalies, or immunological reactions, even if they are rare, should not happen in that specific individual. On the other hand, there is an embryo, which has to be viable, which means that gametes have to be healthy because their contribution is very important to the formation of a normal embryo, the embryo must be able to develop normally. Then if IVF is performed, the conditions of the lab as in vitro culture are crucial to generate a healthy embryo. Furthermore, the procedure itself of embryo transfer can also play an important role. Data show how the repetition of treatment is crucial. Looking at the percentage of patients who deliver after the first transfer, we can see it is 36%, all the remaining non-pregnant patients came back, and another percentage of them became pregnant. Of the remaining patients, less than 50% came back again for their 3rd transfer, and again some were able to achieve pregnancy. What’s important is that almost 3 patients out of 4 achieved pregnancy, which is why it’s so important not to give up. If you have at least 3 failed IVF attempts, the concept of selecting embryos for aneuploid screening might be beneficial. Avoiding the transfer of abnormal embryos can reduce implantation failure and miscarriage but also the cost of treatment and what is more important reduce the time to a full-term pregnancy.

Endometrial Receptivity Test (BeReady test)

If you have a few failed attempts, you should look into your window of implantation. One of the tests called the BeReady test helps to find the best time for embryo transfer. They’ve selected 67 genes and the accuracy is quite good because it goes down to a single molecule, and it is cost-effective. The biopsy is done during a monthly cycle and then the full sequencing is done to select 67 genes that are involved in implantation you end up with information, and you can detect the receptivity of your uterus that is expressed as a score called a receptometer. There can be three scenarios, it can be pre-receptive, receptive and post-receptive. According to this data, the transfer can be done at a certain point in time or can be postponed.

Sperm donation & egg donation – indications

If the gametes of both oocytes and sperm are so limited that it is almost unadaptable to reach pregnancy with these gametes, then you should think about egg or sperm donation or both. Sperm donation is usually indicated in azoospermia, which is quite rare or when there is a congenital factor or medical causes like chemotherapy, or surgery. It is also indicated in the case of sperm chromosomal abnormalities or genetic disease in the male partner occur when we have an infectious disease that has destroyed the potentiality of the individual sperm. Egg (oocyte) donation is an option when the quality of the oocytes is very low because there is a primary ovarian insufficiency or there is no chance to get more oocytes, like in premature ovarian failure or menopause. It is also an option when the female partner has a chromosomal or genetic disease, they can still produce oocytes, but their quality is extremely low. It is advised for poor responders or with previous IVF failures using their own gametes, or in cases of recurrent miscarriages. If you have impaired ovarian function due to chemotherapy or surgery, endometriosis is another reason to look at egg donation.

How to achieve success after IVF failure? - Questions and Answers

I have just completed my 1st cycle of donor egg treatment, which failed. In failure, I have a follow-up meeting with the consultant in Spain this week. Are there any questions I should be asking regarding the changes to my next donor egg cycle? I am on a pregnancy guarantee program. I am 45.

No, you shouldn’t be too worried because you shouldn’t forget that a part of the program in which you have a pregnancy guarantee. One embryo transfer appears to be considered from the physiological point of view, like you being a fertile, normal young woman having intercourse with a fertile man. If pregnancy does not occur, you are not surprised too much, so here you are comparing the same thing, and before being worried, you should have at least another or two other attempts.

I am 33. I have had 3 failed rounds of egg donation, and I’m starting to lose hope. I have requested PGS testing on my 4 remaining embryos. Is there anything else I should be doing? My clinic says it is an implantation issue.

I also agree with your clinic, it’s possible that it’s an implantation issue, and for this reason, before you go for another embryo transfer, you should do an endometrial receptivity array (ERA) test first.

I’m 44 years old. I had an early miscarriage from my first IVF cycle. We went ahead with a donor egg (had PGD testing and Microchip). I also have an autoimmune disease (irritable bowel). I have been told, I will be on immune therapy next time. Is there anything else I should consider for my next cycle to help improve my chances?

What has been suggested and recommended to you is the right way to go.

I am 41, and I had 5 natural miscarriages in 18 months. We did IVF with PGT-A. 3 embryos made it to blastocysts, and all were tested normal. One embryo was put back but failed. Is there hope for the last two embryos? What other tests should we do? We’ve done all standard fertility tests, and all were normal with both of us.

Yes, I think that if hysteroscopy has not been done, it should be done just after the period, while a 3D ultrasound scan should be done in the luteal phase, so just before the menstrual period appears. It’s important to understand if your uterus is ready for implantation. I would not be worried about the endometrial receptivity. I would be happy to see your cavity as it has been already damaged by those five natural miscarriages.

How badly can TSH serum level impact the transfer success? I started with TSH at 5.1 approx 3 -4 months ago, but the latest test showed 0.17, and the healthy range is 0.5-2. I’m supposed to have a 3rd-day fresh transfer on Thursday ( assuming my embryos survive ) The doctor recommended skipping my Levothyroxine ( 75 mg daily )in the next couple of days and repeat the test on Wednesday.

There is not enough data showing that the TSH low level is crucial for implantation, but the range 0.5 to 2 is now an accepted range, and anything that can be done modulating or tuning the treatment the thyroid therapy or anything that could help to maintain these values is the most important thing. I think that skipping the medication as it has been suggested is correct. Actually, your TSH level looks like it’s being too compressive. That’s maybe stopping the treatment for a few days will make your TSH level increase and reaching the normal range. I am in favor of this decision.

I have had one round of IVF with failed implantation, looking to have another IVF round in January. Before IVF, I have had day-3 hormone blood tests and day-21 progesterone blood test, TSH blood test, and scan – all the results were normal. I’ve just turned 42. Would you suggest any other pre-tests before I have another round of IVF? I got pregnant 12 months ago naturally, twin ectopic pregnancy.

If no pregnancy has occurred before and if your uterus never had a reproductive accident, miscarriages, or termination of pregnancy, or so on, then no. Otherwise, hysteroscopy is recommended, and don’t forget that at the age of 42, your chance of delivery is around 12-15%. If you want to have a decent percentage of a full-term pregnancy, you should enter the concept that you need 5-6 embryo transfers if you want to use your gametes. The fact that you had a pregnancy 12 months ago is encouraging because it shows that your body is ready to get pregnant. As you had an ectopic pregnancy, this could also show inflammation of the tube and a small malformation of the uterus, so it would be good to double-check your uterus and your uterine cavity before you start another cycle. It has to be done with double test 3D ultrasound and hysteroscopy.

Should the 3D Ultrasound and hysteroscopy be carried out at a certain time in my cycle? Are you able to advise on the approximate cost of both these tests?

I cannot answer the second part of the question as the price is very much depending if you’re using a national health service or if you’re going to a private clinic. I can tell you that in Italy both tests would cost not more than 600 EUR in a private clinic and they are for free in a public hospital. Hysteroscopy should be done just after the period, while a 3D scan should be done just before the period.

When would you recommend growth hormone?

The only reason why growth hormone could be recommended is if you are a poor responder. Apparently, in some subgroup of poor responder patients, growth hormone seems to be of some benefit in growing more follicles, hat means more oocytes to be collected.

I have had 3 cycles and only 2 embryos. My last cycle was fertilization failure due to egg quality. I just turned 40. Should I just give up, or should I try something else? I didn’t get embryos to the PGS test. My AMH is low. Is donor or adoption my only two options?

To say that there are only two options is too drastic, but if you want to look in a pragmatic way at the chance you have to deliver your baby and using your own gametes, your chances are extremely limited. It’s a combination of your age, AMH, and most probably how your body has been designed in terms of conception. Perhaps, you started to have periods quite early, or maybe somebody in your family had early menopause, your aunt, your mother, etc. It looks like your age is different from your biological age or the biological age of your ovaries. Most probably if for you and your partner a baby is not defined as a complete overlapping of genetic material, but if for you, a baby is an individual that you are carrying on, that you are delivering, that you will educate, and you will accompany during his life, maybe the oocytes donation is a good program for you or is the best program.

I had one failed transfer back in July: it was potentially due to a polyp being discovered during a baseline scan but decided to carry on anyway. I’ve now removed it. Do you think I should check anything else? My lining thickness was perfect in July.

Don’t check anything else but recheck your uterus because sometimes polyps can come back, and there is a tendency for patients that have a polyp to repeat the production of this pathology. That is not only a mechanical pathology, but polyp is a sort of the tip of the iceberg of inflammation. Actually, when you have a polyp, the total endometrium can be inflamed and thus imply a reduced chance of pregnancy.

How do you know if your endometrium is inflamed? How do you find out, and what kind of tests you can do?

The elective way to understand if you have inflammation is to do a hysteroscopy. There are now tests that are in progress that can avoid even the office procedure just producing or aspirating a little bit of fluid that is inside the cavity of the uterus.

I am 46. I had an egg donation transfer, which failed. I had hysteroscopy last month, and I had 1 polyp removed. I’m going for 2nd attempt at IVF. My lining is 6.8, and my blood result is on the borderline. Do you think I should wait for next month?

Yes, you should, and you should also increase a little bit the amount of estradiol valerate because it would be nice if your lining were above 7.

When would you recommend getting immunological tests?

I would say when you are desperate because the chance of getting good results in terms of being positive results from immunological tests is quite rare. You have to be sure that all the other aspects that we have looked at are negative, so keep this as the last point of your diagnostic procedures.

I have Irritable bowel syndrome (IBS) and Hypothyroidism/Hashimoto. What can I do to improve implantation knowing I am 44 years old and we are looking into egg donation? Would you suggest immune therapy?

I would only suggest keeping the level of TSH in the normal range, as we have discussed before.

I had a termination at 19, miscarriage at 38, I am now 40 just finished one round of unsuccessful IVF treatment. I have Hashimoto. I will be going through a second round of IVF in January. I am considering a natural round of IVF. Would you recommend this?

No, definitely not because it’s not going to make your oocytes better. It will only delay it and make it a long time to achieve pregnancy. Again, check your uterus and try to get as many eggs as possible. If you can produce many embryos, maybe you should accumulate after one or two or three oocyte recovery and do PGT-A to check the euploidy in one shot to reduce the costs. Since two accidents have occurred to your uterus in this case, hysteroscopy is compulsory.

Is it possible to have ovulated during IVF and still collect the remaining eggs? I had 7 follicles of varying sizes on the scan, 3 collected, and there was no egg collected from the largest follicle, which was a surprise to me. Is this normal, or could it mean that there was ovulation before collection? Would it be possible for the clinic to tell if this had happened?

When you have very large follicles that are not with the others, they look like follicles, but they are empty follicles, or it’s a small cyst with a very limited quality of egg if the egg is collected. You can collect, or you can aspirate follicles even if you have already ovulated, but to have good quality eggs, ovulation should have occurred very recently because otherwise also the remaining follicles, containing the remaining oocytes impair the quality of the gametes so, in other words, you will collect not very good quality oocytes. It would be possible for the clinic to tell that this happened, but not with 100% accuracy. If you do a blood sample and you measure your progesterone, this could also be helpful to tell you the real story.

Next month I am having FET in the native cycle (with stop injection Ovitrelle). I have regular cycles and regular ovulation, but usually, I have a little bit of thin endometrium at the time of ovulation (cca. 7mm). What can I do? Would you recommend me using 3 or 4 days of estrogen right before ovulation?

You can do it, but I’m not sure that it will help. If you tend to have a thin endometrium, I think that you should go for a full artificial cycle, starting with Estradiol valerate since the first day of the cycle and carry on with 4-6 milligrams per day.

Do you recommend frequent monitoring during the IVF cycle for a higher success rate? Bloods, USG Scans, how often is enough, and what blood test monitoring do you think are mandatory? My clinic only did 2 scans and pre-op blood tests.

If you are a so-called easy patient, you don’t need much monitoring, but if you had already failed cycles or if you are a poor responder or if your cycles are not regular, you need a different and a few monitoring. You should think about a personalized treatment every time if more than one failure has happened to you. The general concept of all the clinics is quite simple, you can divide all the clinics around the world into 2 categories, and this doesn’t mean that one is better than another or that one is worse than another, the two categories are as follows: the first category is to make everything easy, reduce the stress, reduce the cost, reduce the visit to the clinic. The other group of clinics is in which everybody is obsessive to monitor more, to get more information from you, to personalize more your treatment. I think that the best clinic is the one that can combine the 2 previous categories. If you are an easy patient, if the indications are clear, if the diagnosis is properly done, if no failure has occurred before, maybe for you, a so-called easy IVF is sufficient. On the contrary, if you are in advanced maternal age, you had recurrent miscarriages, you have failed many cycles, and you feel like it’s your last chance, you are looking for something that can give you an answer, so the same clinic should perform a personalized treatment for you.

Who is a poor responder? This is my 1st cycle. I had 10 follicles growing, and there were 5 eggs retrieved.

You are not a poor responder. There is a definition for poor responders that is accepted all around the world, and it’s called Bologna criteria for poor responders. It has been published 9 years ago, and now it has more than 1500 citations all around the world. The criteria are very simple, 3 or fewer oocytes, the age over 40, failed oocyte recovery. If one of these criteria has already occurred, you can enter the category of the poor responder.

What is the cause of the thin endometrium? Low level of estrogen?

There are two major factors for this. One is a morphological situation of the uterus. If you have leiomyomas, fibromas, fibroids, or your uterine wall is not normal, vascularization is impaired, this could play a role in the thickness of the endometrium. On the other hand, you can have a perfectly normal uterus with perfectly normal endometrium, perfectly normal myometrium, no pathology in the uterus, but then the level of hormones is not the correct one, so the endometrium does not respond, or it responds pathologically because it doesn’t just receive the right amount of information from the endocrine system. There can be both or a combination of two.

I am 38. I retrieved 10 eggs this year in 3 retrievals and had 0 fertilization. Then I got pregnant naturally but had a miscarriage at 8 weeks. I live in Japan and no options for donors, but what do you suggest I do. I am considering going to Spain next year if traveling becomes easier, but until then I would like to know what you suggest?

There could be a male problem, so it would be very important for you to perform a FISH test, which is a chromosomal analysis on a certain number, generally a few thousand sperm. When you do chromosomal analysis from your blood, you know everything about the chromosomal composition of all the cells of your body, skin, eye, heart, Sidney, any organ but not of your eggs, and that’s the same for your partner. The reason for this is that when you or your partner wear 8 cell embryos inside the tubes of your mother, you already had 1 cell that has been designed to prepare gametes. Sperm for your partner, and oocytes from you. The only way to know if your oocytes, or in this case, the sperm of your partner is chromosomally normal, is to check directly that. The FISH test should be performed using the highest technology with the highest number of chromosomes to be analyzed.

What do you recommend I do next after one failed round of IVF? I am 40.

If in the first round you had decent embryos or good quality embryos, you should go for another attempt. If you have quite a large number of embryos, PGT for aneuploidy could be an option to shorten the time to pregnancy.

I have heard a few times about 3D ultrasounds, are all ultrasounds 3D?

Not all the machinery is designed for 3D, and even if they are designed, the clinician can perform a simple 2D. I think that in the era of IT and computer, it’s very easy to understand that what the 3D does is to construct because of a specific software the 3 dimensions of the womb and the uterus, so is a sophisticated way like magnetic resonance and this can help the clinician to check for small pathologies or small abnormalities. If you combine the direct visualization of the cavity of the uterus via hysteroscopy with 3D, you will have a full vision of this extremely important organ. Since it’s not invasive or just a bit invasive and is not painful, and it also requires only 20-30 minutes of exams, I think that in that sense, it should be done.

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Authors

Luca Gianaroli, MD

Dr Luca Gianaroli has been a specialist in Reproductive Medicine since the end of the 1970s. He is the Scientific Director of S.I.S.Me.R. (Italian Society for the Study of Reproductive Medicine) and he holds the position of Scientific Director of I.I.A.R.G., the International Institutes of Advanced Reproduction and Genetics and of IIRM SA. He is also an Honorary Professor at the School of Biosciences of the University of Kent. Dr Gianaroli is an active member of several international scientific societies in which he has covered and currently covers roles of primary importance, he has served as Chairman of the Italian Society of Reproduction and of the European Society of Human Reproduction and Embryology (ESHRE). He is a member of the ESHRE Certification Committee, and he is the coordinator of the Steering Committee of the ESHRE ART Centre Certification Program. Dr Gianaroli is author of more than 250 papers in international scientific journals and publisher or co-publisher of 9 books. Throughout his professional career, he collaborated with several Italian universities (Università degli Studi di Teramo, Università degli Studi di Modena e Reggio Emilia, Università degli Studi di Trieste, Università degli Studi di Roma Tor Vergata, Università di Bologna).

Event Moderator

Caroline Kulczycka

Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.

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