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Repeated implantation failure – patients’ stories

Ksenia Khazhylenko, MD
Obstetrician-gynecologist, Fertility specialist & Geneticist, IVMED

Embryo Implantation, Failed IVF Cycles, Success Stories

From this video you will find out:
  • What does Recurrent Implantation Failure (RIF) mean?
  • What are the possible causes of implantation failure other than embryo aneuploidy?
  • What investigations and treatment options should be performed in patients with repeated implantation failure?

How to overcome implantation failure?

In this session, Dr Ksenia Khazhylenko, Obstetrician-gynecologist, Fertility Specialist & Geneticist at IVMED – Fertility Center discussed 1 difficult case about a couple with previous IVF failure and diagnosed with recurrent implantation failure. Dr Khazhylenko explained the tests performed and treatment plan in details that allow the couple to finally achieve a pregnancy and a healthy baby.

How to overcome implantation failure? - Questions and Answers

Why did you think that PGT-A of frozen embryos was not a good idea for this patient?

I meant it is not a good idea to do PGT-A on frozen embryos because to do the biopsy, we need to thaw them, then do the biopsy and on the same day freeze them again. This is a very stressful procedure, 2 procedures in one day, it needs double precision with thawing, biopsy and freezing the embryo again. It is evidence-based that after this type of biopsy, the embryos are usually quite weak on the next transfer, and we know that the next transfer can be unsuccessful just because of this biopsy.

I had a similar situation concerning NK cells, and we did follow all the protocols until my fourth cycle, then I stopped all medical things, and after 6 months, I got pregnant completely naturally. Unfortunately, I miscarried in 2.5 months.

I don’t know where you are from, but it is a good example. In that case, it would be worth checking the chromosomal status of the embryo, I mean a product of conception. It’s very important because, in the case of NK cells or other immunological parameters, it is very important to analyze the chromosomal status of the embryo. Then we do something to support pregnancy. We have to know that this embryo is healthy because sometimes the reason for miscarriage is different. You can have a high level of NK cells but, still, have a normal pregnancy.

I have had more than 10 miscarriages, but back in India, they said it’s normal and suggested to just keep trying.

Unfortunately, every next miscarriage increases the risk for another one. I want to help all the patients with a miscarriage. The best thing is possible to try to get another consultation. Look for a second opinion first, and due to the COVID pandemic, online consultations became much easier than two years ago. Maybe you need some online consultation to hear a second opinion about what to do because ten mystery miscarriages are sad enough, and it carries a very high risk for the next. In case of repeated failure despite treatment, there is an additional risk. You should check the endometrium, for example.

Can you see the adenomyosis on conventional ultrasound?

Yes, there are a lot of signs of adenomyosis in conventional ultrasound. Conventional ultrasound is the best way to see adenomyosis, and there are different types of adenomyosis. There was one picture with ultrasound signs of adenomyosis. This is a typical sign of focal and dynamic diffuse of adenomyosis, and in this patient, miscarriage is a risk factor. Often these patients have diffuse adenomyosis with high uterine wall thickness, and one wall is thicker than another, but some of them have focal adenomyosis very similar to myoma or fibroids, but they’re different. There are some different ultrasound signs, but it’s well visible in conventional ultrasound.

I have a frozen pelvis with hydrosalpinx, so most surgeons in my country don’t want to operate on me. I have had two failed fresh embryo transfers. What is your advice?

I didn’t explain all the possible reasons for implantation failure, but hydrosalpinx is one of the most common reasons. There is a lot of evidence that there is an association between hydrosalpinx and implantation failure. The recommendation to do surgery after an IVF failure is logical to me. Sometimes I can do the transfer in patients with hydrosalpinx or even two transfers, firstly explaining the possible problems. Especially, if we have enough good embryos, not one or two. If we have good quality embryos, we can try a first or even second attempt and then go back to hydrosalpinx if these attempts are unsuccessful, but sometimes some patients have successful pregnancies even with this hydrosalpinx. I think two IVF failures is an indication of the surgery.

How do you use intralipids?

It is a recommendation of my German colleague who has most publications about intralipids use, and her recommendation is to use 100 or 200 milligrams firstly before transfer – 3-5 days before transfer, but then they recommend repeating this infusion if the pregnancy test is positive. Regarding the history of the patient, sometimes they repeat this infusion every 2 weeks till 10 or 12 weeks of pregnancy, especially in patients who have had a miscarriage before. Sometimes we use intralipid infusion just once – before the transfer, and sometimes we repeat this until the positive test, like in my case today. After getting a positive test, we can do blood tests on intralipid level, and if it becomes normal, we don’t provide the next infusion.

What to do when having an abortion due to antiphospholipid syndrome?

Anti-phospholipid syndrome is one of the main reasons for miscarriage, and the treatment of antiphospholipid syndrome is not just well-known, but also is very effective. It’s known that a patient with antiphospholipid syndrome can have a successful pregnancy and take home a baby without treatment, just in no more than 15-20 per cent of all these cases. But, if you treat them, we can have a successful pregnancy in almost 80 per cent, so it means like in a healthy woman. So, the treatment of antiphospholipid syndrome is using low molecular weight heparin plus aspirin.

We don’t use any hormones, such as Prednisone, we don’t use immunoglobulin infusion, just conventional and quite effective low molecular weight heparin and aspirin. I want to stress that antiphospholipid syndrome means quite strict criteria for this syndrome. It’s not enough if you have a high level of antiphospholipid antibodies one time to make this diagnosis. We need to have a high level of antiphospholipid antibodies twice over at least 12 weeks between the first and the second test, and also it can be positive lupus anticoagulant additionally. So if these criteria are met plus clinical evidence like a repeated miscarriage (two or more miscarriages) occurs, it means you have the syndrome, but if we don’t have the clinical criteria or just weak laboratory results, it may not be antiphospholipid syndrome. It’s very, very important.

I have high NK cells, should I avoid fresh transfer? I also react badly to estrogen, and my TSH rises, so I don’t like to use estrogen in frozen embryo transfer. Should I have a fully natural FET, or should I use stimulation?

In my opinion, a natural cycle for transfer is the best idea. With my patients, I use this type of preparation in 80% of all transfers. It’s a good idea for everything. I just don’t use a natural cycle in patients who never had ovulation. It can be quite difficult to induce, so if the patient has natural ovulation, it’s always a good idea not to use estradiol. Thyroid problems and NK cells level in a natural cycle and artificial cycles will be similar. I only suggested an additional progesterone prescription after the ovulation to decrease these levels but not estradiol.

I asked the first question because in the case study you said to avoid a transfer if stimulation protocols are present.

If you mean fresh cycle, you mean cycle of stimulation, because usually in a stimulated cycle, NK cells level will be generally higher. There is some publication comparing the level of NK cells in endometrium and the blood of a patient in fresh embryo transfer. By fresh, I mean a cycle of stimulation, because cycles with the transfer of frozen embryos in the natural cycle is a frozen transfer in a natural cycle. But fresh transfer means that it’s a stimulated cycle. In this type of cycle, you can transfer the embryo if you have high NK cells. In the stimulated cycle, the NK cells level will be higher.

RIF is difficult in younger women. What about 40 plus? We don’t have that much time and that many good blastocysts to transfer. Do you recommend screening routinely for some conditions before we face the problem?

It’s a difficult question because RIF is difficult not just for young women, but at any age. Usually, young patients have a mostly good prognosis, and when despite the good prognosis, they became RIF patients, it’s very sad. But when we are talking about age, it is mostly a problem for chromosomal pathology. With age, we must take into account a high number of chromosomal pathologies in the embryo. If these embryos are genetically tested, it doesn’t matter what the age of the patient is.

So when it comes to additional tests, you’re right. Sometimes when I get one or two embryos from a 40 plus patient, or even younger patients 30-38, before transferring this embryo, I sit with my patient and explain that we could transfer, and it can be normal and it will be following the protocol. We can transfer in a natural cycle. But if the result will be negative and we won’t have any embryos later, we can be very disappointed. We can think why didn’t we do some additional tests before this transfer. So sometimes if you have a few embryos, I can discuss with patients some additional examination. Sometimes it can be really important, for instance, testing for chronic endometritis if a woman has had a miscarriage or some complicated pregnancy before. Then we plan a transfer of just one embryo she has, so it will be better to do something just to get her some insurance.

Are there any signals/symptoms that the immune system gives apart from failed implantation? How can we confirm that? What tests are used?

It is a difficult question again. Most patients don’t have any immunological reaction to the implantation, they don’t have any signs. Sometimes I can suspect something when the patient, for instance, has some autoimmune condition, autoimmune thyroid or some other general conditions with immune antibodies.

Ksenia Khazhylenko, MD

Ksenia Khazhylenko, MD

Dr Ksenia Khazhylenko is an Obstetrician-gynecologist, Fertility Specialist & Geneticist at IVMED -Fertility Center. She is an author and co-author of more than 50 publications on international and national issues and has over 25 years of working experience in the field of human reproduction. Dr Khazhylenko is a member of ESHRE, UARM. She graduated from Bogomolets National Medical University in Ukraine. Her main professional interests are - recurrent pregnancy losses treatment; recurrent implantation failure; premature ovarian insufficiency; reproductive genetics; reproductive immunology; uterine anomalies.
Event Moderator
Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is managing 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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