Practical tactics for patients with recurrent implantation failure

Diana Obidniak, MD
Fertility Specialist, Head of ART of Birth Clinic, ART of Birth Clinic

Category:
Embryo Implantation, Embryo Transfer, Failed IVF Cycles, Miscarriages and RPL, Success Rates

From this video you will find out:

Practical tactics for patients with recurrent implantation failure

IVF and Recurrent Implantation Failure

Have you experienced recurrent implantation failure with donor eggs or your own eggs? If yes, you might be wondering if there is a treatment for it. Watch this recording of the webinar organised with the Ava-Peter Clinic from St Petersburg, Russia to find our more about recurrent implantation failure.

Implantation failure and IVF

When IVF repeatedly fails it often leaves patients feeling shocked, heartbroken and frustrated, wondering what next and starting to doubt whether their treatment will ever end with a positive outcome. In this webinar, Dr Diana Obidnyak, Head of the International Cooperation department at “AVA-Peter” clinics, in Russia, discusses the diagnostic approaches and treatment recommendations she believes can aid implantation, offering hope to those suffering from recurrent implantation failure.

Implantation is the process of a delicate interaction between an embryo and the endometrium. It is something which needs to happen in order for a pregnancy to develop. Whilst having a high-quality embryo is absolutely key to a successful implantation, it is important that patients understand it’s not the only factor.

During a natural menstrual cycle, a woman’s endometrium changes daily in preparation for receiving a fertilised egg. The body naturally knows how to do this and creates a synchronisation between the newly formed embryo and the uterine lining. This is known as the window of implantation and during this time the endometrium is at its maximum receptivity. In IVF, any fertilised eggs are cultivated in a laboratory and developed in vitro (outside of the body), without connection to the endometrium into which it will, hopefully, implant. Helping an embryo to implant is an imperative part of the IVF procedure and a very important topic to discuss. Despite the advances in technology and reproductive knowledge, it is a process that fertility specialists still find challenging. The quality of the embryo is crucial to a successful outcome. With the use of PGS (pre-implantation genetic screening) and time lapse incubators, embryologists now have greater information which helps them to select only healthy, euploid (chromosomally equal) embryos for transfer. In situations where aneuploid (abnormal) embryos are transferred, the endometrium observes any functional and morphological alterations and, in most cases, doesn’t allow the embryo to implant; it acts as a natural defence and a biosensor of embryonic quality.

When patients are using donated oocytes (eggs), it is typically expected that only good calibre embryos will be transferred. If an IVF cycle does unfortunately fail following donor egg IVF, it is likely to be another determinant which is to blame.

Role of growth factors in embryo implantation

Various growth factors can play a critical role in contributing to, or hindering, a successful nidation (implantation) and Dr Obidniak advises that chronic endometritis has been found to account for 66% of recurrent pregnancy loss and 45% of repeated implantation failure. Chronic endometritis is a type of inflammation in the endometrium which occurs when harmony between the uterine immune system and the body’s microorganisms (bacteria or viruses or fungus) breaks down. Patients are unlikely to know they have this condition as it only manifests itself with infertility and / or a change to menstrual bleeding. If endometritis is diagnosed, it is possible to cure with antibiotics or minor surgery. Dr Obidnyak stresses it is essential that clinics test for this in women who are suffering with recurrent implantation failure.

Immunological and pathological factors in embryo implantation

Immunological and pathological factors such as NK (Natural Killer) cells, thyroid concerns and / or thrombophilia (blood clotting), are all believed to have an adverse effect on implantation. If a diagnosis of any of these issues is confirmed then treatment options are available.

Dr Obidniak also recognises that regenerative medicines, such as PRP (platelet-rich plasma) treatments are currently being used to create natural defences within the body.

Human blood contains platelets which, in turn, contain hundreds of proteins that are important for healing; PRP therapy can potentially improve the function of the body’s immunity against any fertility related immunological conditions. However as yet, not all additional treatments are fully medically approved, although studies and research are continuously being conducted to help medical scientists improve their knowledge and further understand how to help heathy embryos implant. Dr Obidniak advises that a full medical history is necessary before doctors can even begin to treat women suffering from repeated IVF failure. Medical teams must remember that each patient is unique, their situations are all different and clinics should always create fully individualised treatment protocols for every woman. Recurrent implantation failure is distressing however, treatment options are available to increase the likelihood of implantation and improve the possibility of an embryo developing into a healthy pregnancy and live birth.

IVF and Recurrent Implantation Failure - Questions and Answers

What diagnostic tests, in which priority order would you recommend for patients with recurrent implantation failure?

Usually, the priority order is to be identified according to your individual case. In any case, you should assess the endometrium—through a hysteroscopy, so this is a surgical diagnostic test, but it is very delicate—it lasts around three or four minutes but it is the so-called golden standard for the assessment of the endometrium. In this case, we can assess it not only with our eyes and by the video equipment but also with the following histological examination, which can give us information about severe problems with the endometrium, if there are any. Also, we should assess if there are any defects with the blood, for example, hereditary thrombophilia. If we are talking about a patient over 35 years of age, we should also take into account the possible problems with the embryos, so sometimes we recommend implantation genetic testing of the embryos, and after that we perform selective embryo transfers, so usually we only transfer one embryo, which is approved by the implantation genetic testing.

I wasn’t advised to do PGS with a donor egg—do many women do these tests?

Well, in ordinary egg donation programmes, we do not recommend preimplantation genetic testing, except in cases when there are severe problems with the sperm—because then there is a high risk of abnormal formation of the embryos. We perform preimplantation genetic testing in egg donation programmes when the patient insists on additional testing or there will be the need to transfer a specific embryo, for example through gender selection, boy or girl. So, we see that in most cases, because we pay close attention when selecting egg donors. We check not only the karyotype but also if the donor is a carrier of any genetic diseases. There are not many clinics that perform such intensive elimination of donors. But even in such cases, after such examinations, we receive some embryos which are abnormal, but all these cases were associated with severe sperm defects. So if unfortunately, your couple has some severe problems with sperm, so you see a low number of normal spermatozoa, or the volume of the ejaculate is very low, it is better to perform preimplantation genetic testing, even in egg donation programmes.

I have a fibroid which is impacting on the lining. How long would I need to wait if I had it removed before starting treatment?

Well, it depends on the size and location of the fibroid, because if the fibroid is located mostly in the uterine cavity, we would recommend that you perform a hysteroscopy and surgically remove the fibroid. In this case, you would need to wait around six months before starting treatment. However, if it would be required to do a greater surgery called a laparoscopy, then usually you would need to wait one year to be sure that the uterus is ready for [inaudible]. So, if you are going to use your egg or egg donation, it is better to perform IVF before [inaudible]. But, the prognosis is always beneficial after [inaudible] so if the size of the fibroid is more than 4 centimeters, according to European guidelines, we have to recommend surgery for this patient.

I have autoimmune conditions like arthritis, high NK cells. I had 6 cycles with no implantation. I had the ERA done. What do you recommend as part of IVF treatment for someone with underlying autoimmune conditions?

Unfortunately, when we talk about patients with arthritis and high NK cells, we usually observe very poor quality embryos. So, if we talk about embryos that were obtained from your eggs, you should perform the preimplantation genetic testing, as unfortunately in most cases, the treatment of arthritis and some autoimmune conditions will do a lot of harm to the quality of the egg. So, usually in this situation, the reason for the implantation failure is the quality of the embryo. When it comes to egg donation programmes, we have to assess the quality of the endometrium, but this time not for chlamydia or polyps, but because there are also autoimmune diseases of the endometrium. In this case, we should provide regenerative medicine, and this is the only situation when I recommend the application of intravenous human immunoglobulin treatment, which provide the proper function of the immune system because this is not only the key point for recurrent implantation failure but also it plays a crucial role in miscarriage. Unfortunately, in this situation there is a high risk of miscarriage, so we should be ready and provide prophylaxis for this severe situation.

I am 44—what are my chances of getting pregnant with donor eggs?

Well, with donor eggs, the chances of getting pregnant are very high—just in an ordinary programme without preimplantation genetic testing and the use of a donor egg, we have around 70% chance. So, if there are no problems with the sperm, or the problem with the sperm is not very severe, then we don’t recommend preimplantation genetic testing and the success rate is 70%. At this age, we usually recommend proper hormonal support because usually in women around this age, we observe some problems and hormonal issues, so we should provide the proper prevention of miscarriage, so we prolong hormonal treatment to ensure that the pregnancy will progress.

I’ve had six embryos transferred from three different donors. Would aspirin and prednisolone be a good low-cost option for my next cycle?

Maybe yes, but I recommend you to perform extensive diagnostics before the performing next transfer of embryos, because six embryos transferred from three different donors suggests that the problem is not in the quality of the embryos. We should pay attention to your endometrium and exclude any concomitant diseases, so I would strongly recommend that you do not perform another embryo transfer before undergoing additional examinations because I’m afraid that just prednisolone and aspirin will not give you a good result. In some cases it’s very effective, but only when there is a reason for administering it—usually when there are problems with the blood, for example, antiphospholipid syndrome. However, you need to perform more extensive diagnostics. If you don’t mind, just send me your embryo protocols—I’d like to look to be sure that the quality of the donors and the embryos were good enough because maybe there is also an additional problem with the sperm.

I am 48 — what is the success rate for donor egg implantation?

The rate of success is the same, so about 70% — but before performing the egg donation programme, we usually examine you, to make sure we are doing the embryo transfer into an endometrium which is perfectly prepared for an embryo transfer and pregnancy—this is a crucial point.

Does adenomyosis also hinder implantation? I have an underactive thyroid so am unsure if I should try again after three failed IVF attempts.

Adenomyosis always affects implantation but there are also some stages of adenomyosis—not many women have severe stages of adenomyosis. Endometriosis and adenomyosis are some of the most difficult diseases in gynaecology and reproductive medicine. Today, we have some very effective algorithms of preparation—we can make two or three injections where we stop your menstrual bleeding—in this situation, your uterus becomes more compacted so this is a great way of making the implantation successful. Usually, there is endometriosis-associated chronic endometritis, so we should be sure that there is no point in compromising endometrium. I’d like you to pay attention to your menstrual bleeding, because from this, we can see some brown-ish bleeding at the end of the menstrual bleeding—this is a characteristic sign that there is a problem with the endometrium. I would recommend a hysteroscopy to exclude other problems with the endometrium—a hysteroscopy is not just a diagnostic tool, but also the first stage of treatment, because we can fix some problems just with manipulation. After this, we would recommend an individualised treatment plan using data obtained from the hysteroscopy, and after that, perform an embryo transfer which should result in pregnancy. As for the underactive thyroid, well, it depends—the most important thing is the cause of the underactive thyroid, not just the level of its functioning. If there is a problem with the morphology of the thyroid or the cause is an autoimmune disease, then the tactic will be different, but in any case, the prognosis is good, so please don’t give up—you just need the right preparation.

I have done IVF egg donation four times and it didn’t work, even though I took aspirin, injections for blood thinning and also progesterone injection.

I understand that you are very disappointed after these dramatic experiences, but unfortunately, I need more information about you—for example what diagnostic tools were already applied to be sure there are no problems with your lab tests or endometrium. Progesterone injections or just progesterone administration is just a routine practice in egg donation programmes, so according to the information I have, I have a feeling that the support and preparation of your endometrium were routine.

Is there any 100% guarantee with IVF egg donation?

Well, in any case, there’s no 100% in one cycle, but in our clinic, we provide so-called IVF with a guarantee programme. It means that we guarantee to help you with the pregnancy with free embryo transfer and if there is no pregnancy after these embryo transfers, then we guarantee to refund you 50% of the price of this programme. So, only clinics which are very reliable and have proven results can afford it. When we talk about egg donation programmes, we might mention a very high percentage of success rates, but as you see, if the egg recipient’s condition is underestimated, we see an unsuccessful result. So, we have an algorithm for examining and preparing the woman—sometimes it lasts two weeks, while in other cases it can take three months; it depends on the person. Our goal is to provide you with a healthy child in just one embryo transfer, so we pay great attention to the preparation of the endometrium, uterus and the organism in general—we also care greatly for the emotional status of the woman, especially after recurrent implantation failure. That is why we are proud to announce our very high success rates. To summarise, unfortunately, nobody can guarantee a 100% success rate in one embryo transfer, but in three embryo transfers, the statistics state that the cumulative pregnancy rate is around 98%, and that is very close.

Can I do donor eggs without using Crinone gel? My nurse told us today we need to use it with injections.

Well, we have to recommend that you are given hormonal support with some form of progesterone—Crinone gel is considered to be one of the most convenient forms of progesterone, as it is the vaginal form, but if you have some uncomfortable feeling after this, then we can give progesterone in the form of tablets or in the form of injections. We usually don’t recommend injections as they aren’t very “friendly” for patients, are uncomfortable for patients and we usually observe a greater risk of patient mistakes. So, we prefer forms of vaginal progesterone application, for example, Crinone gel or tablets. In cases of severe progesterone insufficiency, we recommend injectable progesterone. There are different forms of progesterone, but you will have to select one which is the most convenient for you and most appropriate for your medical need.

I have had one chemical pregnancy with a donor embryo. I am thinking of trying donor egg again. I have just had an ERA test done. Are there any other tests I should do?

It was a very wise decision to do an ERA test. Usually, when we mention a biochemical pregnancy, we understand that the window of implantation is uncompromised because if the window of implantation is delayed, unfortunately, we will not observe any interaction between the embryo and the endometrium, so in this case, we wouldn’t observe any biochemical results, like enhancement of hCG. A biochemical pregnancy means that the window of implantation is good, so we can repeat the embryo transfer, just in the same condition but you should pay close attention to greater progesterone support, for example, a combination of vaginal and tablet progesterone—also pay attention to concomitant diseases: maybe you’ll need to take aspirin or injections of Clexane. In any case, a chemical pregnancy is not our final goal, but it is the first step to a successful result, as when we have a biochemical pregnancy, we know many things were done properly, for example, the window of implantation, etc. Please pay attention to the status of the endometrium—be sure there are no micro polyps as sometimes general physicians just don’t see them by ultrasound but try again and I’m sure you will manage to get pregnant.

Does embryo glue, scratch, intralipids help with implantation?

In patients with recurrent implantation failure, we try and do our best and sometimes we apply scratching, embryo glue, intralipids or human immunoglobulins, even though they have not been proven effective according to evidence-based medicine. Unfortunately, there is a lack of experience in applying these methods worldwide. We have some couples who have succeeded when we applied scratching or intralipids, but it should always be administered individually. We should also pay attention to the method of application—for example, scratching was suggested when we perform it in the middle of the luteal phase, that is day 19 to day 22 of your menstrual cycle, and this should be the previous cycle, just before the cycle during which you will do the embryo transfer. So, if you do the scratching on other days of your embryo cycle or two or three cycles before your embryo transfer, it will simply not work. Concerning intralipids, it’s not a simple medication, so you should be very accurate with it. Usually, we perform it when there is an autoimmune disease or antiphospholipid syndrome, so it’s not recommended for just any patient. So, if you provide me with some more details of your medical history, I can recommend something for you.

I had two embryo transfers with donor eggs. In both cycles, I had fluid in the womb which cleared up before the embryo transfers. I don’t have polyps or cysts. Why would this happen?

Well, fluid in the womb is considered to be a type of chronic endometritis. According to European and Russian guidelines, we always have to examine the endometrium more closely. We usually need to administer antibiotics to fix the problem, even when we don’t have any signs of polyps. Usually, we just cancel the embryo transfer until we have optimal conditions in the endometrium. If the quantity of the fluid is significant, we would be worried about flushing out the embryo. If the quantity of the fluid is smaller, we would also be worried about an inflammatory process that could prevent the pregnancy to be initiated. Overall, it’s a very bad prognosis, so we never perform embryo transfer under these conditions.

We have a case of premature ovarian failure and into our second cycle of IVF where in round one there were no symptoms to indicate otherwise. Now I have been recommended Menopur. Would you recommend this?

I’d need to know your AMH, FSH and LH levels. Even though we have a lot of patients with AMH levels of 0.1 or 0.2 and we have clinical pregnancies, when we talk about the selection of medication, we should assess not only AMH but also FSH and LH. Nowadays, all over the world, the combination of two medications [inaudible] is considered to be very effective for patients. But also, I need to know your age. We have around 20 types of ovarian stimulation, so we can match a particular method to an individual very well, but I’d need some more information.

AMH less than 0.01, FSH is 17, age 32.

32 years old is a great prognosis. Usually, we would recommend for you a combination of [inaudible] about 300, and letrozole around 4 tablets a day, but we should also assess your BMI and your physician should perform folliculogenesis monitoring by ultrasound. Please don’t take any medication before consulting with your physician. In general, this is a rather tough situation, but the prognosis can be very good because of your age.

Two questions. It’s winter here in the UK. I like to sit right next to the heater — can this have a negative effect on donor transfer? Also, I find it hard to drink a lot of water — how much do you recommend to drink to aid implantation?

Well, concerning the heater, please don’t be worried about this. Even if you sit right next to the heater, it is better to be sure that you don’t get ill or get the flu, so stay comfortable. Concerning the recommended volume of water, it should be around 1,5 litres per day. [inaudible] But not more than 2 litres. But please don’t pay too much attention to this, as in natural life, women get pregnant without monitoring the volume of water they drink. It plays a more significant role with IVF cycle and controlled ovarian stimulation, but not for donor transfer. So don’t make any changes in your life that will make you distressed, as this will have a more negative effect on implantation.

Could too much estradiol (doctor advised a gel and pills of the hormone at the same time) be the reason for a failed implantation with a good embryo?

Usually, we recommend estradiol when we have to prepare the endometrium, and some doctors prescribe big doses of it in the event of a thin endometrium—to tell you the truth, this is the only reason when they can prescribe too much estradiol. So, I can bet that the dosage of estradiol was not the reason for the failed implantation but rather the endometrium was underestimated. Bad growth is a sign of a compromised endometrium. I would recommend performing a hysteroscopy to investigate your endometrium, and after that, you should perform PRP (platelet-rich plasma) therapy because this is a good way to fix the problem with the endometrium without using high doses of estradiol or other hormones, as it is regenerative medicine. Please pay close attention to your endometrium and don’t plan another embryo transfer without a detailed examination of your endometrium.

Also been prescribed Levothyroxine even though my thyroid levels are fine, is this normal? Apparently, I am told it needs to be below 2.5?

When we talk about a non-pregnant woman, the normal level of TSH is 2.5. But, when we talk about pregnancy and implantation, we can see TSH at around 1.5 so in some cases we prescribe very low doses of Levothyroxine—around [inaudible] mg per day, but we usually do not prescribe it without a reason. After implantation occurs, there is a very high release of TSH. Before embryo transfer, though your level of TSH could have been 2.5 or 3.1, a few days after implantation it can be found to be 5 or 6. If you have never had issues with your TSH, then I would not recommend Levothyroxine, though I would recommend you monitor your TSH levels and we would usually prescribe a blood test a 2-3 days after embryo transfer, so that if a surge in TSH occurs, you can be given medication.

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Authors

Diana Obidniak, MD

Dr Diana Obidniak, MD is the Head of ART of Birth Clinic in St. Petersburg, Russia. Dr Obidniak is a Fertility Specialist, Affiliated Professor at St. Petersburg State University. She is also a member of the American Society for Reproductive Medicine and the European Society of Human Reproduction and Embryology (ESHRE). She is also a National Representative of Russia at the ESHRE Committee.

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