Immune factor in assisted reproduction

Fernando Sánchez, MD
Clinic Director
Assisted Reproduction and immune factors
From this video you will find out:
  • How can immune factors affect embryo implantation?
  • What is the relationship between the embryo and the mother in terms of immunity?
  • What are the types of immunity?
  • How to prepare for implantation?
  • Is endometrium an immune organ?
  • How the immune system aids implantation?



How does your immunity affect embryo implantation?

Watch the webinar recording with Dr Fernando Sánchez, Clinic Director at Ginemed, Spain, who has explained the immune factor and its impact on embryo implantation in IVF (in vitro fertilization) treatment.

Nowadays, everybody is talking about the immune factors in reproduction. However, the implantation depends on a lot of different factors. One of them is related to embryo quality, some are related to the transfer and materials we use, and some are related to endometrial receptivity. Probably, the embryo quality is the most important because sometimes we have implantation in the tubes. Endometrial receptivity is not depending only on immunological aspects, it depends on a lot of factors like the window of implantation, thrombophilic, metabolic, infections, etc. The immunologic aspect of implantation is only one part of the implantation. According to Dr Sánchez, the immunologic factor is one of the most significant parts of the implantation because the relationship between the embryo and the mother is made through the mother’s immunologic system. Therefore, we need to have a very good immunologic system to help the embryo implant.

Types of immunity

There are two types of immunity. The first one is the natural immunity system, which is related to the implantation and the infection like virus or bacteria, and then there is an adaptative immunity, which works with antibodies, cells that can prevent disease in the future by remembering what those substances look like. These cells and antibodies also produce some substances called cytokines, and these cytokines are chemical mediators in the body to help the body to do different things like, for example, opening the vessels at the time of implantation.

Types of immune response

Depending on the immune response, there is an immune response with antibodies or an immune response mediated by cells. All of these are very important because depending on that we are going to have one kind of immune response or the other. This immune response is also mediated by the ID the cells have. The embryo has an ID, and this ID is mediated by what we call HLA antigens. This HLA antigen is the identification of the embryo and this identification of the embryo is recognized by the immune system of the mother, especially by the natural killer cells (NK).

Therefore, you need to remember about HLA C or HLA G or HLA F, that is some information that the embryo gives to the mother’s immune system to answer to this embryo.

Preparation for implantation begins with the action of semen, which reaches the uterus, and when these spermatozoa, which are different to the mother, reaches the uterus, a number of immunological changes happen in the uterus to help the embryo to implant.

When IUI (Intrauterine insemination) is performed on a woman with a man, the chances of implantation are a bit higher. It’s due to the seminal fluid that reaches the endometrium. Once these changes begin, all the cells in the endometrium begin to change, and these changes are very important. The main cell in the endometrium, especially at the time of implantation, is the uterine natural killer cells.

The endometrium is an immune organ and is as significant as can be another immune organ in the body. It is a door for an embryo to implant, and it’s related mainly to these natural uterine natural killer cells. These cells change during pregnancy and the cycle. It’s important to know that because when we study this kind of cells, we start to study them in the blood, and there is no correlation between the values of these cells in the blood compared with values of these cells in the uterine cavity. We need to only consider the values in the uterine cavity, not in the blood.

Natural Killers

When we are talking about the uterine NK cells, these are the cells that are mainly producing cytokines to help the embryo implant. When we are talking about the peripheral NK cells, these are mainly high cytotoxic, but they are mainly in the blood, not in the uterus.

These uNK cells produce cytokines, and growth factors and these growth factors help the implantation (G-CSF, GSF-1, IFN-α), etc. There are only two: Interleukin-2 (IL-2) and Tumour necrosis factor alpha (TNF-α) that are inhibiting the implantation, but most of them are helping the implantation.

The embryo is genetically different from the mother, and the immune system helps the implantation. The communication between the maternal immune system and the embryo is done through the innate immune system, mainly through NKs that account for up to 70% of all immune cells at the time of implantation. The embryo communicates with the natural killers through HLA antigens, mainly HLA C, HLA E, HLA F and G. The natural killers identify this HLA through the KIR receptor
(Killer cell immunoglobulin-like receptors), this receptor identifies the embryo, and they are classified into 2 groups, KIR A and KIR B. Depending on the combination between the identification of the embryo HLA C-1 or HLA C -2, the natural killer response helps the implantation or makes it more difficult. Therefore, depending on this combination between KIR and HLA, the embryo implants or not.

These changes that the cytokines do are mainly in the endometrium and are mainly related to the blood vessels because we need to open these blood vessels to give enough blood for the embryo to implant. After all, if we don’t have these cytokines reaching the blood vessels, we can have implantation failures, abortions, prematurity, preeclampsia or intrauterine growth retardation. All of these are related to bad communication between the embryo and the natural killers in the endometrium. Depending on the time of the pregnancy, the cells are changing.

When the communication between the embryo and the antibodies is good, and we have a normal pregnancy, it is called TH2, and if the answer is TH1, it is not good, there will be problems with implantation, abortion, preeclampsia or premature deliveries.

Immunologic studies

It’s possible to study the immune system, but there is no clinical evidence, it has to be assessed individually because there is no study for everybody with one clear answer. We have to have biological plausibility when we are talking about the treatments we need to do. The KIR of the mother needs to be checked, as well as ANA (Antinuclear Antibodies), NK cells at the uterine level and parental HLA-C compatibility. The main diagnostic we have is clinical. We have to look at the clinical symptoms, not the analysis because if we only look at the analysis, it’s not going to work.

There are a lot of treatments for immunological symptoms, but you have to remember the concept, of homeostasis concept, we can have exacerbated immunity, and we have to reduce this immunity to help the implantation. We can have an inhibited immunity, and we have to increase this immunity to help the implantation, or we can have some imbalance in the immunity, and we have to modulate this immunity to help the implantation. The treatment options for exacerbated immunity (IVIG, anti-TFN-α, corticoids, etc.) are very good for this kind of situation, but they’re very bad if we have inhibited immunity. It’s very important to classify what we’re dealing with and what we need to do.

Related reading:

- Questions and Answers

I suffer from Crohn’s disease. What shall I consider?

Crohn’s disease is one of the things that affect the immunity system. One of the main immunity organs in the body is the gut, and if you have Crohn’s disease, you have a  problem with this immunity system in your gut. Many antigens reach the body through the intestine, so it’s very important to do a  treatment to reduce this exacerbated immunity before getting pregnant. Anybody who is suffering from Crohn’s disease has to do corticoids.

I’m about to start an egg donation. I’m 43, and I have never got pregnant, nor had I ever had a miscarriage. I want to make sure I have the best chances. Do you think the immunological exams will be useful? If so, which ones?

My recommendation in your case is not to do any study regarding immunological exams. Unless you have a previous illness or there is a problem in your family like a thrombophilic situation or infection situation. If there is no previous problem, you are going to start the egg donation program, and you never got pregnant or had a  miscarriage, you have a  higher chance to become pregnant. My recommendation is not to do anything. You can just do a normal study to be sure that your endometrium is okay, and with this, begin the treatment.

What would you suggest to do to progress with understanding if I have immune issues?

We can talk about having a problem with immunological situations if we have implantation failure.  We are talking about at least  3 transfers, and those 3 transfers were with blastocysts and no risk, a woman was less than 40 or is having an egg donor program, or you had previous miscarriages or an immune problem.  My recommendation is not, to begin with checking the immunological system because the problem is when you are doing this is that sometimes you begin to find results in the studies that are not so clear, and we begin to do treatments. I work in an implantation failure unit most of the time when a woman comes to us, and she had a couple of failed cycles. We have to take out the treatments because they are doing treatments that sometimes are bad for the women, it is not an immunological problem. So we can proceed with looking for immune issues only if there is any indication.

Do you recommend to take different immunomodulation like corticosteroids, intralipids, and IVIG together?

The idea is not to take this together because it is not going to work. If you are using corticosteroids, intralipids, or intravenous immunoglobulin, they are using the same target. If you combine this medication, you are going to reduce the response of your immune system, and you are not going to get pregnant.  For the immune system to work well, you need all the treatments we are using in medicine. These treatments are for reducing the response of the immune system,  mainly the corticosteroids. Most of the time, you need the immune system to work well to achieve pregnancy because if your natural killers don’t work, they don’t produce cytokines, and it doesn’t move the blood vessels to open the blood vessels. The treatment with corticoids or intravenous immunoglobulins you need to have only if you have exacerbated immunity because you have a previous problem, but you don’t use it all together for sure.

What are your thoughts about the role of gut microflora in infertility?

For sure, it is very important. The problem is that at this moment, I can’t tell you exactly what you have to do to improve your microflora, but the microflora is important for sure. This is the first barrier of the body, so microflora controls all the viruses, bacteria that are good and are first in contact with the microflora. Microflora is good bacteria, so it’s very important.

When comparing an embryo transfer to an organ transplant. Can we assume that an embryo from a woman’s own egg will automatically have better chances of implanting than an embryo from a donor egg?

It’s absolutely the opposite.  The immune system in a transplant works the opposite way that the immune system works in pregnancy. In pregnancy, if you are different, you have a higher chance to implant. In transplantation, f you are different, you have a higher chance to reject a transplant,  so it’s completely the opposite way.

I have Crohn’s disease, and I have been advised to do a test for NK cells, but I have also been told that steroids cannot be used for treatment. What can we do? I had two miscarriages this year, one naturally and one via IVF.

The biggest problem we have in reproduction is when you have to study the immune system, so there is not only a  question of natural killers.  In your case, as you have a problem of chronic inflammation in your body, it’s very important to reduce this chronic inflammation, and we can do it, for example, with corticosteroids, but we can also do it with some type of diet, or we can do with intralipids or other things. It is not the only way to reduce this chronic inflammation, and after that, we have to know exactly how your natural killers are going to respond. For example, we have to know how your KIR receptors are, how yours and your husband’s HLA-C are. Depending on that, we are going to find out how your natural killers respond.  If the response of your natural killers, for example, is low, we need to put more stress in your endometrium to have more activity of these natural killers, apart from Crohn’s disease. If, for example, you are having a low natural killer response, and let’s say you are KIR AA with C1C1, we need to reduce this.  Using donor sperm for me is the same,  so there is not a problem.

What is the best exam to check for the natural killers in the uterus?

This is an endometrial biopsy, and we have to do this endometrial biopsy in a time around implantation around 5 days of progesterone or 7 days after the peak of the LH. At this time, you have to do the endometrial biopsy, and in this endometrial biopsy, you have to look for some combination of the receptor of the lymphocytes to know if you are looking for a  lymphocyte T  or lymphocyte B or a natural killer,  it is another kind of lymphocyte. For example, if you take out CD3  negative, just with this, you avoid all the lymphocyte T, and you have to look for a combination of CD 56 and CD16.  So, CD3 negative, with some combination of  CD56  or CD16,  you can decide what kind of natural killer you have in your endometrium. The biologists also give you the number of these cells in the endometrium.

My wife has high NK cells. Is there anything she can do in terms of lifestyle to help or to improve her immune system?

The immune system with high natural killer cells is good. Having high natural killers is not a problem by itself, so the question is what kind of natural killers we are talking about. That depends on if we are talking about uterine natural killers to help the implantation or cytotoxic natural killers. Regarding lifestyle, the recommendation we use is to do the things that are good for your quality of life, they are good for your immune system.  The best recommendation is to do some exercise,  not to do heavy exercise but some exercise,  about half an hour of walking, for example, is good. Taking care of your diet,  not to eat too much fat. Also, to have a  relaxed life, to sleep well and a good number of hours, it is very important. All the things that help you to feel good, help your immune system.

I had a pregnancy with the donated embryos, which went perfectly fine until the 7th month. I was, and I am in perfect health otherwise. Then suddenly, I have preeclampsia. What would you suggest for my next try?

Preeclampsia is a problem of implantation, and it is very difficult to treat. You have to know that if you have preeclampsia in the first pregnancy, you have a higher risk of having preeclampsia in the next pregnancy. Usually, there is some way of controlling it with a low-dose of aspirin, 100 milligrams per day from the beginning of the pregnancy. It is also possible to control it with uterine artery Doppler ultrasound around the 20 weeks of pregnancy. There is no way to prevent preeclampsia in 100%. If you decide to go ahead with another pregnancy, you have to know that the risk exists, and there is no way to avoid it for sure. It happens much more frequently when you are older than 45, and it’s much more frequent when you are talking about the donated embryo, and it’s also much more frequent when you are talking about twin pregnancies, so the recommendation is to transfer only one embryo to avoid the chance of twins.

What do you think about KIR AA by the mother and HLA C1C2 by the father? Can IVIG help for a healthy pregnancy? HLA of the mother is C2C2.

It depends on the HLA-C of the mother because the KIR AA is not a  good combination, but it’s not a good combination only in the case when the mother has less C2 than the embryo, for example,  in this case, imagine that the mother is HLA C1C2 nothing happens and there is no need for any treatments.  If the mother is  C2C2, there is not a problem, you don’t need to do any treatments. The only reason for doing the treatment, in this case, is when the mother is C1C1 because you have  50%  chances of having a baby C1C2, and in this case, my recommendation is to use intralipids rather than IVIG. The results are almost the same, and the price is around  10 times less. With C2C2, there is no problem at all. You don’t need to do any kinds of treatment.

Is the KIR analysis recommended?

If you are studying the immunological system,  you need to do KIR analysis. If you study the immunological system, you need to also check the KIR,  the HLA-C, the natural killers, the macrophages, the microbiota, the antinuclear antibodies. There is a  couple of studies that are related to immunological studies, and KIR is mandatory.

You said that preeclampsia is more frequent in the donated embryo. What is the reason? Is it the immunological KIR?

The reason for that is not the immunological KIR, the reason is the way of implantation is when the embryo is donated and when it’s not donated. The way of implantation is a little difficult, and the risk of preeclampsia is a little higher, for example, if you are talking about the same age and same problems in women using her own eggs, the risk of preeclampsia is around 2 – 3 % at the age of 38-39. If you are talking about the same age and donated embryos the risk of preeclampsia is around 6%.  We have to live with this because there is no way to change this risk of preeclampsia.

Are you currently prescribing steroids for immune treatment? Is there any increased risk of getting coronavirus if on steroids?

Usually, I’m not prescribing steroids, it’s a medication that has a very limited indication, and usually, it is indicated when you have a previous condition, previous illness, and it is very difficult to need steroids to reduce the immune system because usually, we need to increase this system,  not to reduce it.  When you use steroids, you don’t have more risk of getting coronavirus. Even for coronavirus, one of the treatments you do is steroids. The main problem with coronavirus is that the response of the immune system is very different between people. In some people, it is normal, and there are no symptoms or very few symptoms. Some others have a very high response in terms of immunity. For these people, steroids are very good because they are reducing the immune coronavirus response. It is one of the coronavirus treatment options that is the best nowadays.

I am HIV positive, I have had multiple IVF failures. I did an egg donation with PGD. Do you have any other recommendations for me?

If you are HIV positive, you are under some treatments to control the immune system. Probably, in these cases, you need to modulate the response of your endometrium to the embryo.  We probably need a lot of studies on that just to be sure that this could be a possibility, but you’re doing egg donation, you have done PGD on this embryo, so everything from the point of view of genetics is okay.  Probably you can increase the chance of pregnancy with some Filgrastim growth factor in the uterus or subcutaneous growth factors.  You need a couple of studies to do. In this situation, it could be an approach for you.

What is the difference between uterine NK versus blood test?

The main difference is that the action is completely different. The uterine natural killers are natural killers that are mainly producers of cytokines, and these cytokines are chemical products that stimulate the blood vessels and stimulate the surrounding of the natural killer.  The blood natural killers are natural killers, which attach to the virus or the cells,  strange cells, or the bacteria and destroy these bacteria.  They produce a few cytokines, and these, for example,  are CD16 positive, when you are looking at the uterine natural killers are CD16 negative. It depends on if the natural killers are mainly producers of cytokines or cytotoxic. So blood cytotoxic,  uterus cytokines, the same name but completely different functions.

I have had 3 unexplained recurrent miscarriages. A couple of doctors have suggested I take prednisolone to see if it helps. I have high thyroid antibodies. He does not think I need all the tests at this stage. I am 44. I am considering donor eggs. Are there any things we need to consider to reduce the risk of my body rejecting the embryo due to immunological reasons? I was 38 and 42 when I had miscarriages.

If you are 44,  the reason for these miscarriages in 99% is due to a genetic problem. My recommendation in a situation like this where you have a 99% chance of having a problem is to avoid it. Probably to change to an egg donor program. It could also be an immunological problem,  it could be, but the chance of that is only 1%. At 42, the chance of having an aneuploid embryo is around 87%, at 38, it is not so bad. So my recommendation again is to go to an egg donation program and try to forget about the immunological problems, do a normal cycle of the egg donor, and your chance of becoming pregnant will be around 70%  with no miscarriage.

I have gone through several treatments with donated egg cells. Should I ask for an immunity test before the blastocyst will be transferred?

If you have done more than 2  transfers with the egg donation cycle,  of course, because it is not logical, so if you do a transfer with an egg donation cycle, the chance of becoming pregnant is around 70%. If you do a second transfer, you have 60% of this 40%,  so you reach 84%.  If you have 3 transfers, you have more than a 90% chance of becoming pregnant. If you are not pregnant for sure, there is a problem.  There is not a question of statistics, you have to look for immunity, thrombophilia, anatomical reason in the endometrium. You also have to look for infections in the endometrium,  you have to look for the blood flow of your uterus. There are a lot of things you have to look for if you had 2 or 3 egg donation failed attempts. It is not only immunity, but immunity is one part of this, and it’s important, but that is not the only problem.

I have Hashimoto’s, thyroiditis, I don’t eat gluten, soy, lactose. I’m 42, I got pregnant last year. During my first IVF cycle, I miscarried at 9 weeks. I got normal results of my NK cells. I just had 5th failed cycles. What examination would you suggest? My NK cells were checked by a blood sample, not via endometrium biopsy. Was that wrong and maybe invalid?

If you are looking at natural killers in blood vessels,  you can have an answer that could be important from a rheumatologic point of view, but I have no information at all regarding the pregnancy or something related to pregnancy like miscarriages or implantation failure or anything so this forgets about the results if they’re good or bad it’s not important because they are not related with the pregnancy. The second thing is that at this moment, the situation is different than it was before because you are talking about your  5 cycles and probably doing them had to take a couple of years, and I don’t know what happened before. Now,  you are 42, and with your history of 5 cycles, my recommendation is not to look for immunological problems or anatomic problems. I would recommend changing to an egg donor cycle because there is probably some immunological situation with you.  You could do both things, but if you are going to go with your own eggs, you have to do it with the PGT-A,  just to be sure that the embryo is normal and the chance to have a normal embryo at 42 is lower.  You have to think about it.

Can intralipids help with high uNK? Or, only for high NK in the blood?

Intralipid can help for high natural killers, but that depends on the indication.  That is the thing I tried to explain at the very beginning, so there is not just 1 test, and with this test, you have to do this, or you have to do the other. It’s a thorough evaluation of the women that can help you decide what kind of treatment is needed. Intralipids can help you, for sure. It depends on if this uterine NK is cytotoxic or not and when you do this biopsy, if it was the window of implantation, or if it was before.

Is it possible to use steroid treatment after 4 implantation failures?

Yes, if there is any indication, of course,  you can use this treatment, but this treatment has to have a high indication. It’s not okay if you didn’t do this, you’re going to try something else because if you began with this, and next you can do Heparin, or you can do a Neupogen, and you are doing another cycle and another. If you have  4 cycles with no pregnancy, you have to know what’s happening before doing any kind of treatments, and if the steroids are indicated, it is very good, but only if they are indicated. If not, it can be a really bad idea.
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Picture of Fernando Sánchez, MD

Fernando Sánchez, MD

Dr Fernando Sánchez completed his degree in Medicine at the University of Salamanca in 1989, then specialised in Obstetrics and Gynaecology from 1991 to 1995 at the Women's Hospital of Seville, Spain, in addition to carrying out an External Fellowship in Assisted Reproduction in Norfolk, Virginia (USA) at Eastern Virginia Medical University in 1995. In 1997 he received his Doctorate from the University of Seville with the honour of summa cum laude. He also holds a Master's Degree in Breast Pathology. Since 1997 Dr. Fernando Sánchez has worked at GINEMED. He opened Ginemed's Assisted Reproduction Unit in 1998 and has also managed it from the very start. He has authored several publications in national and international journals and is also an internationally renowned speaker. He also coordinated several international research studies. In 2017 Dr. Fernando Sánchez opened Ginemed's Specialised Unit for Complex Cases, Implantation Failure and Recurrent Miscarriage. In 2018 he started the Advanced Maternal Age Unit. In addition to seeing patients in the Specialised Unit for Complex Cases, Dr. Fernando Sánchez currently manages the GINEMED group which performs over 7,000 cycles each year and is comprised of 8 clinics, each with their own assisted reproduction laboratory.
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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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