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Intralipid infusions – indications and prospects

Uliana Dorofeyeva, MD
Director of International Cooperations, Medical Director, IVMED
the-role-of-intralipid-infusions
From this video you will find out:
  • Why do autoimmune diseases occur?
  • What is the role of natural killer cells in implantation and pregnancy?
  • What causes high uterine NK cells?
  • What kind of immunological testing and treatment can be performed?
  • What is IVIG, what are the risks and side effects?

What is the role of intralipid immunotherapy and when can it be used?

In this webinar, Dr Uliana Dorofeyeva, Director of International Cooperations at IVMED, Ukraine, and a Medical Director at OVOGENE Egg Donor Bank discussed intralipids, how they work, when are they recommended, and in which particular cases should they be considered.

Unexplained infertility is infertility that is idiopathic in the sense that its cause remains unknown even after an infertility workup.
However, for many years, the list of tests to perform increased before the successful IVF treatment. Some of those tests include:

  • Semen analysis
  • Assessment of ovulation
  • Assessment of fallopian tubes in the woman

Nevertheless, another wide range of tests are also considered nowadays, yet some still need to be for clinical use and interventions.

Unexplained infertility – definition

When talking about the definition of unexplained infertility, it should be mentioned that is unsustainable and highly subjective because it depends on:

  • which tests have been performed
  • which tests have been allowed in the country
  • what is the quality of those tests
  • who performed the evaluation

Speaking of diagnosis workup, it is mentioned that it might be incomplete.

Basis of successful treatment

Regarding the basis of successful treatment, it is common knowledge that checking and taking care of the uterus carefully does not only include evaluations such as ultrasound and hysteroscopy but also some other tests that measure endometrial receptivity as well as evaluate other conditions and prepare the endometrial lining. Among other factors, immunological factors are said to have an important role.

Other factors include:

  • Genetic factors (needs to be assessed before the successful treatment)
  • Factors related to the oocyte/embryo

It is also mentioned that there are factors that can be worked on in advance for the most successful treatment possible.

Multifactorial causes of infertility

Regarding causes of infertility, if a couple probably had several unsuccessful trials that resulted with a miscarriage, it is possible that doctors found several factors.

Autoimmune conditions

They are those related to the individual’s immune system, which is responsible for defending the body from being attacked by infectious agents, such as viruses and bacteria. It is later mentioned that patients who suffer from autoimmune diseases have a malfunctioning immune system and, as a consequence, the immune system reacts inappropriately by attacking and destroying healthy body cells and tissues.

This situation can also occur during pregnancy, so women with an immune disorder are at increased risk for repeated miscarriages and other fertility disorders.

Mechanism of functioning of the immune system

  • Recognition of the body’s structures thanks to the major histocompatibility complex (MHC).
  • Production of antibodies by white blood cells or lymphocytes.
  • Destruction of foreign bodies by natural killer cells.
  • Establishing a mechanism of tolerance during pregnancy so that the mother’s immune system does not identify the baby as a foreign body and reject it

In autoimmune diseases, the immune system is unable to differentiate what is proper from what is foreign, so it creates antibodies to attack the body’s tissues.

In pregnancy, it attacks the embryo and destroys it before the development of the embryo’s supportive system as a placenta.

Autoimmune diseases

Speaking of autoimmune diseases and immunological infertility, the first trimester should be carefully checked along with the early stages of implantation. Currently, more than 80 autoimmune diseases are known in humans and are also more common in women than in men.
Depending on the organ or system of the body affected, autoimmune diseases can be classified as follows:

  • One target – these are specific pathologies of an organ, i.e. they only affect a specific organ. For example, celiac disease is a type of autoimmune disease that affects the small intestine.
  • Systemic – these diseases can affect any organ, or affect multiple organs or systems at once (Rheumatoid arthritis)

Why do autoimmune diseases occur? It is believed that they occur for the following reasons, mainly because there is a genetic predisposition for the development of autoimmune diseases. These diseases are not generic, they are not inherited, but there are combinations of genes that produce an increased risk of developing an autoimmune disease. Depending on the genes that are affected, there will be a predisposition towards one or the other disease. On the other hand, environmental factors can also play a role, since they are necessary to trigger the activation of the immune system. These include hormonal changes, tobacco, alcohol, vaccines, infections, nutrition, eating disorders, weather, etc. Some autoimmune diseases are more common in some races and ethnic groups. For instance, type 1 diabetes is more common among white people, while lupus is more severe in African Americans and Hispanics.

Implantation

Implantation is described as a crucial period in IVF treatment that includes the preparation and stimulation of the ovaries receiving the oocytes (or oocyte donation) and the preparation of embryos. After transferring the embryos into the uterus, blastocyst opposition and adhesion should take place. It is very important to mention that during such a period, the pain of implantation is a condition that is not always properly assessed as it is known to alter the whole cycle.

To analyze if a body is set for conception, a series of tests will be needed to check the immune factors as these are responsible for the spiral endometrial arteries’ development for the proper implantation as there is evidence that the NK cells (Natural Killer Cells) have a role in recurrent miscarriages.

  • Recurrent Miscarriages (defined as three successive miscarriages if aged less than 35 years, two successive miscarriages, if aged over 35 years old)
  • Repeated IVF failure (defined as two or more unsuccessful fresh IVF cycles)

Now it is known that the NK cells (Natural Killer Cells) are divided into the uterine and the peripheral blood and NK cells. However, there is no clear indication, that women undergoing uNK cell testing should understand that there is, as yet, no proven effective treatment for those with what may be considered abnormal results, although preliminary data suggests a possible positive effect of immunological treatment.

The immune system is critical in establishing the relationship between the mother and the fetus that allows both to flourish.

Therefore, the immune testing that has been performed these days includes:

  • Immunological tests
  • NK cells
  • Autologous antibodies
  • HLA
  • IVIG (Uterine biopsy)
  • Intralipids
  • Prednisone

Strategies to test maternal KIR and Fetal HLA-C genes have already been developed. However, according to the Scientific Society, this subject is still controversial due to early clinical interventions. However, for patients with a problematic medical history who have been tested and recommended assessing their key receptors, the test is performed as well.

Intralipids – what is it and how can they help?

In terms of the treatment:

  • Intralipids deactivate natural killer cells in a woman’s body, which may prevent embryos from implanting and growing properly in the uterus. Initial studies show comparable efficacy for the deactivation of natural killer cells and pregnancy rates. Intralipids are well tolerated by patients with few side effects and are created synthetically, unlike IVIG which is a blood product. It is a mixture of high-calorific natural fats containing soybean, oil, egg yolk phospholipids, glycerine, and water.
  • IVIG – Intravenous immunoglobulins is a product made up of antibodies that can be given intravenously. Antibodies are proteins that your body makes to help you fight infections.
    IVIG is prepared from the blood donated by thousands of people, to make a super concentrated and very diverse collection of antibodies against many possible infectious organisms the human body might encounter.

Risks and side effects of IVIG:

  • performing certain blood tests before the IVIG is started
  • keeping well hydrated
  • giving the infusion more slowly
  • dividing a large dose into several smaller doses that are given over several days
  • prescribing pain-relieving medications before your infusion
  • the risk of getting a viral infection from IVIG is considered exceedingly low. Methods used to purify the IVIG will destroy the agents
  • cause temporary changes in the human body (21–28 days)

For better preparation, it is recommended to transfer the euploid blastocyst in the cycles when immunological treatment is going to be performed. Also, it is important to highlight that performance needs to be done during the window of implantation (The time frame when endometrium has maximum receptivity). It is assessed by performing electronic microscopy tests, which are done in the artificial cycle.

Genetically certified oocyte

What is a genetically certified oocyte? They are genetically screened eggs that have been found to have normal chromosomal constitutions. It is recommended to test embryos before treatment. It’s also important to remember that the rate of genetic abnormalities increases with age.

Unexpalained infertility generally means the phisicians failed to find the true cause of your infertility.  – Dr Norbert Gleicher.

Related reading:

- Questions and Answers

How long do intralipids take to work?

In comparison to the medications given by pills, which are still existing intravenous, either intralipids or immunoglobulins are acting immediately. That means as soon as this medication is getting into the blood. The NK cells and the immune system, in general, work differently, so it takes out from the central organ all the NK cells so just mechanism of action and all these NK cells they are going into the periphery to fight with the structure with the molecules which came together with these medications. We are getting the central organs, which include the uterus, being free from the high levels of the intestines. It is how the mechanism works. It’s valid for 21 to 28 days, it’s very individual, and we need to consider each patient individually, and the treatment should be individualized in terms of prescribing the dosage the frequency of the immunoglobulins. It’s easier to predict in patients who’ve been treated with any kind of immunological treatment before that treatment cycle, however, it’s as easy for those who’ve been unsuccessful. It’s hard to say, but some patients are losing their pregnancies just because we haven’t repeated the IVIG in this particular period. It happens because, for example, these medications are not used in some countries, and if patients visited Ukraine for the treatment and they’ve got their injections, it would be okay. However, they fly back home, and there is no possibility to repeat it after the positive pregnancy is achieved, even if the heartbeat is confirmed, we need to repeat it, but if there is no opportunity, the result could be different. They will come for the next pregnancy, or we will think about how to get the medications in their country or where to go, so it’s still very temporary action for the immune system by receiving the immunological treatment, and it needs to be checked, and we need to remember that.

At what pregnancy week is it recommended to stop intralipids, and usually, how often do they need to be administered?

They need to be administered every 3 to 4 weeks. This is what we know from the mechanism of action. For most of the patients, I would say for 80% of patients, we stop prescribing IVIG and intralipids after the first injection, and as soon as the clinical pregnancy is confirmed, so 6 weeks of the pregnancy on first ultrasounds scan if they see the heartbeat and if there is no haematoma. However, sometimes it starts very rapidly, and this is very common for immunological issues, today everything was fine, we checked the pregnancy on the ultrasound and in 2-3 days, there was intense heavy bleeding, and that’s it. That’s why for most of the patients, we recommend keeping injections until the first trimester of the pregnancy is completed. The first trimester of the pregnancy is when the placenta is developing properly. The placenta is responsible for this crosstalk between the mother’s body and the fetus, and it supports a lot of the fetus’s development once it is completely developed. The first trimester is when we can think about it, and mostly we stop the IVIG treatment. Since the embryo transfer until the end of the first trimester, we have 3, sometimes, 4 injections of the intralipids every 3 to 4 weeks.

Is there any exam to evaluate the effect of intralipids? Do you consider normal any special range of NK cells? Blood NK cells or uterine natural killer (uNK)?

As I said during my presentation, we still rely on both tests. All patients are tested, however, we also consider the previous anomalies of the patient, and we are discussing the treatment plan with the patient, we go ahead with immunological treatment, immunological testing and treatment or some other way of treatment and then the strategy for the treatment cycle. We know and agree that uterine NK cells are more certain and more predictive in terms of the treatment, and we base the treatment mostly on those tests. However, our previous experience until we started to analyse uterine NK cells, also the peripheral blood, but mostly the anamnesis works well and helps us decide and be successful with the treatments. We do not perform any confirmation that immunological treatment worked, the best confirmation for this is the clinical pregnancy and the development of the pregnancy.

Would you connect hematoma in early pregnancy, a consequence of immunological factors?

I cannot say that haematoma is always the prediction of immunological infertility. However, if we are talking about proper early pregnancy development, we should avoid having haematomas. If they are present, especially for the patients for whom we initiated immunological treatment, if we see any risks for the first-trimester development, we would consider repeating IVIG treatment or any immunological treatment just to prevent the risk of losing that pregnancy.

How much is each intra-lipid infusion in Ukraine?

It depends on the dosage and the volume of the infusion, which is recommended. However, the average dosage of 10% of IVIG would be 200, again it depends on the patient, but from 200 to 500 millilitres and the costs we would need to double-check with the coordinators. I think it’s about 800 EUR, but it’s better to write to us and to get this confirmed by email.

What causes an imbalance of natural killer cells?

We need to talk about each case individually for the causes. The NK cells can be evaluated in an autoimmune disorder, which may be found in humans, and as we said, we are talking about more than 80, these are just known diseases. I’m sure that with development, we will get more factors. It’s a very hard question to explain.

What kind of dose of Prednisolone would you prescribe for high cytokines?

We use between 4 and 40 milligrams per day of Prednisolone. However, the individual dose is the individual prescription, also about high cytokines, we need to talk specifically about the case.

Do you recommend medical mushrooms for immune issues? E.g., Mesima and Coriolus?

No, unfortunately, I have no experience in that. Even the medications we are talking about right now have no evidence, and if we are talking about up-to-date and the coherent database, etc. They are not level A as a recommendation, but considering the risks and the benefits, we decide to recommend those. However, I don’t know these medications, and I have no practice using them.

Do you use Enoxaparin in these cases?

Yes, for any kind of heparins like Clexane or even low dosage Aspirin, we previously check the factors of the coagulation and thrombotic factors, and after that, we decide about the prescription of that medication in the cycle.

I was told that at 8 weeks the embryo (not PGS tested) was measuring 5 days behind in terms of size. Would you consider that a consequence of immunological factor or more likely a problem with the embryo itself?

The question would be, what was the problem. If there was a miscarry or the embryo stopped its development, have you done the histological evaluation to consider also the genetics of the embryo, it’s really hard to say. However, it is more likely that the embryo itself was a factor than the immunological factors. The immunological factors mostly play their role in the implantation itself. This is either a very early term of the pregnancy or the absence of the implantation in general.

Is biochemical pregnancy linked to the immunological issue?

Mostly yes. However, the embryo factor should be checked. If this is an issue with the euploid embryo, this is an issue of the implantation. If this is an issue with the implantation, we should be looking for the immunological factors.
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Authors
Picture of Uliana Dorofeyeva, MD

Uliana Dorofeyeva, MD

Dr Uliana Dorofeyeva is a Director of International Cooperation at IVMED, Ukraine, and a Medical Director at OVOGENE Egg Donor Bank. She is a multi-talented, engaging and results-oriented fertility specialist with significant experience in ART. She is trained in all aspects of andrology and reproductive endocrinology with exceptional knowledge in the areas of laboratory quality control, vitrification of oocytes, cryopreservation of gametes, embryos and unique ovarian tissue, micromanipulation of gametes including Intracytoplasmic Sperm Injection and Assisted Hatching. Worth mentioning that Dr Uliana is a member of ASRM and ESHRE (American and European Society of Reproductive Medicine).
Event Moderator
Picture of Caroline Kulczycka

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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