Immunologic Implantation Dysfunction (IID): A common Cause of Repeated, “Unexplained” IVF Failure
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The financial and emotional cost associated with unexplained infertility or repeated IVF failures can be devastating. So, to advise couples who have failed one or more attempts that all it would take to ultimately succeed would be to keep on trying over and over again, is both overly simplistic and disingenuous.
About seven to eight days after fertilization, the embryo’s root system begins communicating with the immune cells (lymphocytes) in the uterine lining (endometrium) through an interchange of growth factors known as cytokines. It is upon the integrity of this communicative process (known as the “cytokine network”) that regulated intrusion of the embryo’s root system (that will eventually develop into the placenta) is predicated.
Thus a dysfunctional immunologic interaction between the developing conceptus and the mother can cause all kinds of reproductive problems ranging from failed implantation (presenting as “unexplained” infertility or repeated IVF failure) and miscarriage, to intrauterine growth retardation, stillbirth, fetal loss, and reduced post-birth neurologic and physical development.
It follows that proper implantation is not only a prerequisite for embryonic survival, it is also a major factor in determining intrauterine growth and development of the baby and perhaps most importantly it ultimately can influence the very quality of life after birth.
There are basically two categories of Immunologic Implantation Dysfunction (ID):
Autoimmune ID:
This is by far the most common variety. It is believed to be implicated in >90% of cases of immunologic implantation dysfunction and occurs when an immunologic reaction is produced by the individual, to his/her body’s own cellular components. The most common antibodies that form in such situations are:
a) Anti-phospholipid antibodies (APA)
b) Antithyroid antibodies (ATA)
c) Antiovarian antibodies.
But, it is only when specialized immune cells in the uterine lining known as Natural Killer (NK) Cells, become activated (NKa) and start to release “toxins” that attack the root system of the embryo, that implantation potential is jeopardized. Diagnosis of such NK cell activation (Nka) requires highly specialized blood and/or endometrial tests that can only be performed in a handful of reproductive immunology laboratories in the United States.
Since Autoimmune ID is often genetically transmitted, it is not surprising that it is more likely to exist in women who have a family (or personal) history of primary autoimmune diseases such as Lupus Erythematosus (LE), Scleroderma, clinical or subclinical hypothyroidism, Rheumatoid Arthritis etc. Reactionary (secondary) autoimmunity can occur in conjunction with any medical condition associated with widespread tissue damage. One such gynecologic condition is endometriosis.
Autoimmune ID is usually lethal to the implanting embryo. This is because it destroys the embryo’s root system from the get-go. Accordingly, it most commonly presents as “unexplained infertility” or “unexplained (often repeated) IVF failure” rather than as a miscarriage. Autoimmune ID is readily amenable to reversal through timely, appropriately administered, selective immunotherapy (see below).
Alloimmune ID:
This is relatively uncommon, accounting for less than 10% of cases of ID. Alloimmune ID is associated with a reaction to cell components (e.g sperm antigens) derived from another member of the same species (e.g., sperm). Thus, it is the sperm contribution to the embryo (i.e. the paternal antigen) that makes the embryo an allograft. It is quite remarkable therefore, that an embryo which in the vast majority of cases is immunogically “different” to the mother, thrives in her uterus. This paradoxical arrangement came about through magnificent evolutionary adaptations that allowed this to take place. Uterine immune cells (especially NK cells and T-cells) play a pivotal roll in this accommodation. They do so through a balanced release of growth factors (cytokines).
So it is that in less than 10% of IVF cases that are associated with ID the embryo (through the contribution made by the sperm) shares too many genetically similar characteristics with the host (the mother). When this happens, repeated exposures to such an embryo will over time evoke an imbalance in the cytokines released by the uterine immune cells. This is characterized by activation of uterine NK cells (Nka). In such cases the “root system” of the embryo” can be compromised and the the embryo may be destroyed immediately but most often will instead “limp” along only to miscarry when its supply of nutrients and oxygen is outstripped by demand.
Thus alloimmune ID usually does not destroy the embryo immediately. Rather, after sustained erosion of its reserve, the conceptus will miscarry.
We diagnose alloimmune ID by testing the male and female partners for shared of genetic markers known as of as DQa and HLA. A sufficient degree of matching clinches the diagnosis. We also test the embryo recipient for Nka in an attempt to measure the relative severity of the problem. This is because once the NK cells in the uterine lining are activated and the cytokine balance is disrupted, the situation is grave and will remain so (or worsen) unless the NKa cells are medically deactivated (down-regulated) at least 1 week in advance of the embryo(s) reaching the uterus.
It usually takes repeated exposures of uterine NK cells to an alloimmune matching embryo for these cells to become activated (NKa). Until this happens a pregnancy can be established and even proceed to a normal birth inspite of the ID. Subsequently over time, with repeated exposures of matching embryos to the mother’s uterus, NK cells will become activated and the couple will find themselves miscarrying. Eventually the NKa will become permanently established and the couple will fail to conceive. It is thus not unusual to find such couples going from having a baby together through a stage of repeated miscarriages to one of secondary infertility.
Unfortunately, immunotherapy for alloimmune ID is not as likely to be as successful as with the treatment of autoimmune ID. Selective immunotherapy is simply not invariably curative in the case of the former. While selective immunotherapy significantly improves the chances of success, in cases of alloimmune ID, it cannot assure a successful outcome.
Heparin and Aspirin Therapy
There is compelling evidence that the subcutaneous administration of regular heparin twice daily or low molecular heparin (Clexane, Lovenox) once daily, (starting with the onset of ovarian stimulation) significantly improves IVF birth rates in women who test positive for APAs.
Aspirin on the other hand, has little if any value and in my opinion. The reason for this is because it increases the potential to bleed. This effect can last for up to a week and could add bleeding risk to the egg retrieval procedure and resulting in intrauterine bleeding at the time of embryo transfer, potentially compromising IVF success.
IVIG and Intralipid Therapy
The main objective of selective immunotherapy for immunologic ID is to down-regulate (reduce toxicity) of Nka. In the past, the only effective and allowable way to accomplish in the U.S was through the intravenous infusion of a blood product known as immunoglobulin-G (IVIG). However, the administration of a blood product raised understandable concerns about the transmission of viral infections such as HIV and hepatitis.
To make matters worse, competing IVF clinics capitalized on all this bad press by raising red flags and sometimes going as far as to caution infertile couples against seeking IVF services from those who dared to offer access to IVIG. This created “a herd mentality” that severely harmed the practices of those of us who recommended selective IVIG therapy.
Notwithstanding this, we were not willing to be dissuaded by prejudice or malice from doing what we knew was the right thing and the reward for taking this stance which came in the form of thousands of babies (that otherwise would never have been born) now brightens the lives of an equivalent number of couples that otherwise would have remained childless.
In 2006, reports began to surface regarding a product called Intralipid (IL), a synthetic product which, upon being administered intravenously prior to embryo transfer, would elicit a similar regulatory effect on Nka as IVIG had achieved. In 2007 we began administering IL to patients with NKa. At first this treatment was confined to those who needed IVIG but for diverse reasons refused the treatment. Later we expanded the trial to other IVF patients with NKa. Todate we have treated more than 200 women with IL with impressive results (soon to be published). Against this background, SIRM physicians have all but abandoned IVIG, supplanting it with IL.
Compared to IVIG which costs about $4000-$5000 per infusion and can evoke unpleasant and potentially dangerous side effects, IL, when used as recommended by SIRM, is virtually devoid of risk and/or side effects and costs less than $400 per infusion (i.e. 1/10th of the cost of IVIG).
Corticosteroid Therapy (Prednisone, Prednisilone and Dexamethasone)
Steroid therapy is a mainstay in most IVF programs. Some programs prescribe daily oral methyl prednisilone while others prescribe prednisone or dexamethasone, commencing with the initiation of ovarian stimulation with gonadotropins, and continuing until after the ultrasound the diagnosis of pregnancy.
Any seed, if it is to thrive and develop into a healthy plant, requires that it be placed in a fertile soil. So also does a successful pregnancy require that an optimal seed (embryo)/soil (endometrium) relationship be established.
In about 70% of cases, reproductive failure is due to poor embryo “competency” issues, while in 30% of cases, a non-receptive endometrium is the reason for failure. It follows that with IVF, focusing entirely on embryo (seed) quality will not reduce the risk of failure in patients with endometrial receptivity (soil) problems.
The evaluation for immunologic dysfunction as well as for other factors that can affect implantation should form part of the evaluation of patients preparing to undergo IVF, and especially so in women with recurrent pregnancy loss (RPL), women with a personal or family history of autoimmune conditions, and women with “unexplained” infertility or IVF failure(s).
24 Responses to “Immunologic Implantation Dysfunction (IID): A common Cause of Repeated, “Unexplained” IVF Failure”
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Dr. Sher,
Is it possible to find these immunologic dysfunctions in patients who already have children? Is that possible?
Thanks,
Amanda
Very definitely…yes. Especially alloimmune problems.
Geoff Sher
Dr. Sher,
I tested positive for this and also have an auto immune disorder. I am currently on Heparin injections via this IVF cycle.
From your past experience, are my chances still better on Heparin injections or does the Intrilipid infusion show a better success rate?
Thanks,
Susan
It very much depends on the type of IID you have. As an example , if it is alloimmune, heparin wont help. Nor will it help if there is increased NK cell activation.
Geoff Sher
Dr. Sher, I tested negative for immune issues 9 years ago. I've given birth to 2 healthy children, before and after this testing. My husband fathered both, as well as one other child in a previous relationship. Could I still need the immune testing after all this?
I have had 2 consecutive blighted ovems. I have stage IV Endometriosis (treated in 2010 w CO2 excision) , borderline APA, low AMHormone and low progesterone. My current RE doesn’t seem to be very knowledgeable about ALLO or autoimmune implantation dysfunction or rather he is slow to accept it; and I would hate to have to go through the emotional and physical toil of yet another miscarriage before I really figure out what’s wrong.. do you believe I should come to your facility in Dallas to get treated?
Indeed, if you live in close proximity to SIRM-Dallas and you want an in-person consultation, contact that office and meet with Dr Saleh.
However, if you live outside the area you can have a telephone of audio-visual consultation with me by calling 800-780-7437.
Geoff Sher
Dr. Sher,
I am currently doing mini-IVF, although after reading through your site am finding my clinic’s procedure a bit different. I miscarried years ago and have unexplained fertility but no one has ever thought to ask me about a history of auto immune or tested for that. Is is possible to take heperin even if I have not been tested for this type of problem? I am supposed to have embryos transferred in a few days and would hate to learn after wards that taking heparin would have resulted in a positive outcome. Also, is it possible to use frozen embryos at another clinic if this transfer does not work? I am feeling some regret after reading how thoroughly it appears you approach this and treat each patient that I am not already working with you.
Thank you!
Ideally you should have been tested in advance of the cycle. Heparin is not my major concern, but if there is in addition an underlying NK cell activation (by the K-562 target cell test) , you would have needed intralipid, 7 days prior to the ET. Indeed the blastocysts can be cryobanked (vitrified) and transferred bat another center , later.
I wish I could advise you how to proceed.
Geoff Sher
Dear Dr Sher,
I have had 4 early pregnancy losses and after some general testing my RE concluded that there is no problem on general blood, genetic, sperm, uterin cavity testings and that the issue is probably the quality of my egg. He put me on clomid for one cycle and now suggests that I do injections for super ovulation with IUI. I am relatively fertile as shown by my 4 losses in the last 9 months (all losses biochemical between week 4 and 6). My immunologist (who I saw for hives I get during these pregnancies) ran a more comprehensive test and found I have anticardiolipin IgM of 45 and prolonged ATPP test but no antilupus antico antibody. My immunologist diagnosed me with APS and said I should go on heparin as soon as I have a positive test. My RE is not worried about this and thinks I should only take baby aspirin (I was on baby aspirin during two losses). I have postponed the injectable cycle for this month as I didn’t feel confident that my RE has a proper game plan to keep me pregnant should it occur and didn’t want to spend 5000 dollars just to have another biochemical pregnancy. I know you can’t diagnose me without seeing and testing but unfortunately I am in Canada and would love to hear your advice on what to do. I feel like I need a second opinion on this.
Thank you in advance for your help!
Respectfully, anticardiolipin being raised alone is in my opinion not of concern. More important would be if you have activated uterine natural killer cells (see the articles below).Might I recommend that you go to the home page on this site, find a “search bar” in the upper right hand column and type in the following subjects into the bar and it will take you to all the relevant articles I posted there.
“Recurrent pregnancy loss”)
“Immunologic Implantation Dysfunction” (posted on May, 10th and on May 16th respectively.
“Embryo Implantation………” (Part-1 and Part- 2—-Posted August 2012)
“Traveling for IVF from Out of State/Country– The Process at SIRM-Las Vegas” (posted on March, 21st 2012)
“A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)
You might consider calling 800-780-7437 or 702-699-7437 to arrange a video conference (or Skype) consultation (free of charge to those who reside in the United States or Canada). If need be, someone from SIRM-Patient Relations can contact you in advance of the consultation and assist you in setting this up through your computer. Such audiovisual interaction it is much more personable than a discussion by telephone. However, if you prefer the latter, this too can be arranged.
Geoff Sher
Dear Dr. Sher,
I am currently in the process of a frozen embryo transfer cycle with cgh tested embryos. We had 7 of our 8 embryos make it to blast, all being fairly high quality. We have had 1 prior fresh transfer of a single blast which failed to implant. We then did a frozen transfer of 2 blasts which also failed. From what I have read I am pretty certain I have endometriosis although I never had symptoms prior to the IVF cycles. I now get incredibly intense cramps during the progesterone initiation phase of my cycles. My Dr. recommended depot lupron as a treatment, but from what I have read this treatment seems almost barbaric especially because I only have problems when cycling.
I know it is too late to do anything with this cycle, which is part if the reason I elected to only transfer one of our four embryos. However, if this doesn’t work I really want to look into this testing. Would I be able to do treatment with your clinic if necessary and still do the transfer with my embryos at my home clinic? I really feel that I have implantation issues and I don’t want to waste Amy more embryos. Thanks for any advice you can provide.
It sounds very much as if there is an underlying implantation dysfunction (possibly immunologic) that needs to be flushed out before you proceed any further. Unfortunately, I cannot be involved with evaluations while you are under the care of another RE.
Good luck!
Geoff Sher
Dr. Sher,
I truly appreciate your attention to those who have asked for your guidance. I have a healthy son born in 2009. I had no issues getting pregnant at that time and no health issues, other than my asthma. Once I stopped breast feeding a year later, I developed Chronic Urticaria (rendering me extremely allergic to all NSAIDS). After an almost 2 year journey, it has been found that I am hypothyroid and have Sjogren’s…the medicines prescribed for these significantly helped with my hives. I got pregnant in July of this year (after learning of all my autoimmune issues) and lost the baby in week 5. Now, (because of unbelievable pains in my abdomen to the right that has no apparent cause) I find that I have a small fibroid in my uterus, am anemic, and have another cyst on my right ovary (had a burst cyst last August on that same ovary). I am deeply concerned that my AI diseases have now impacted my ability to maintain a pregnancy. I was hoping you could provide some information/guidance on what steps I should take to increase fertility/full term pregnancy? No one seemed to take much consideration or show concern to the fact that it could all be related. Does my future seem as though it may hold fertility treatments/planned pregnancies with dr’s aid in it?
Thank you very much for your time,
Lindsay
Hi Lindsay,
Sorry to learn of your tribulations. I agree with you that your autoimmune state might be playing a role in your recent reproductive problems. You need to have your blood sent to a Reproductive Immunology Laboratory (I recommend Reproductive Immunology Associates in Van Nuys, CA or Reprosource in Boston, MA) for the following tests: ANA; APA; antithyroglobulin and antimicrosomal antibodies; Immunophenotype and a K-562 Target cell test for natural killer cell activity (NKa).
I also suggest that you go to the home page of http://www.IVFauthority.com and when you get there, look for the “search bar” in the upper right hand column. Type in the following subjects into the bar and it will take you to all the relevant articles I posted there.
“Immunologic Implantation Dysfunction” (posted on May, 10th and on May 16th respectively.
“Embryo Implantation………” (Part-1 and Part- 2—-Posted August 2012)
“Traveling for IVF from Out of State/Country– The Process at SIRM-Las Vegas” (posted on March, 21st 2012)
“A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)
“IVF success: Factors that influence outcome”
Once having reviewed these articles, consider calling 800-780-7437 or 702-699-7437 to arrange a telephone or Skype consultation (free of charge to those who reside in the United States or Canada). While an audiovisual (Skype) interaction is much more personable and preferable than a discussion by telephone, either will suffice.
Geoff Sher
Thank you for your response. I will look into everything you have suggested.
Thanks again,
Lindsay
You are most welcome Lindsay.
Geoff Sher
You are most welcome Lindsay!
Geoff Sher
Hi,
Yesterday my husband and I got the news that our first round of IVF was not successful. I have hashimoto’s disease and was placed on prednisone after our egg retrieval. My fertiliy specialist put me on it as my anti-bodies were still too high for his liking but upon speaking with my endocronologist he told my fertility doctor to go ahead. Anyways, I was on 5mg of apo-prednisone and at the time of retreival and transfer I was on 112 of synthroid. 3 Days after my embryo transfer my endocronologist adjusted my thryoid medication to 125 because my antibodies had not changed since he tested them last in July. My question to you is do you think that my antibodies attacked my embryos? We go back to our fertility doctor November 27th to discuss our next plan of action. We are desparate to have a child and age is also a factor. I will be 40 in January.
Fifty percent of women who have thyroid antibodies will have an autoimmune implantation dysfunction associated with uterine natural killer cell activation. It is quite possible that byou are one of those and if so, no regulation of your thyroid hormones or even prednisone treatment will solve t he problem. You will need Intralipid +m steroid in the proper format to overcome this. You need your blood tested for NKa by the K-562 target cell test. There are only about 4 reproductive immunology laboratories in the U.S that can do this properly.
Please go to http://www.IVFauthority.com and when you get to the home page find the “search bar” in the right hand column. Type in the following subjects into the bar and it will take you to all the relevant articles I posted there.
“Autoimmune Thyroid disease and IVF”
“Immunologic Implantation Dysfunction” (posted on May, 10th and on May 16th respectively.
“Embryo Implantation………” (Part-1 and Part- 2—-Posted August 2012)
“Traveling for IVF from Out of State/Country– The Process at SIRM-Las Vegas” (posted on March, 21st 2012)
“A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)
“IVF success: Factors that influence outcome”
Consider calling 800-780-7437 or 702-699-7437 to arrange a telephone or Skype consultation (free of charge to those who reside in the United States or Canada). While an audiovisual (Skype) interaction is much more personable and preferable than a discussion by telephone, either will suffice.
Geoff Sher
Hi Dr. Sher,
My husband and I have 1 child who is 6, and we have been trying to conceive a second child for 5 years. We have tried 7 IUIs, one that resulted in a pregnancy, but at the 6 week ultrasound (due to spotting) revealed that there was no fetus. I was soon diagnosed with Hashimoto’s, which has been treated now for 3 years. Recently, I found out that I have anti-sperm antibodies (17%). My husband’s blood test also revealed anti-sperm antibodies, but was not considered positive because the percentage was only 10%. Through genetic testing, I found out that I am also have MTHFR (both genes mutated). I am on Folbee for this.
I was wondering if IVF with ICSI is even a good option for us. I am 38 years old, which I know also lowers our success rate and increases our risks. I did not know if the success rate would be high enough to even consider doing IVF, considering the autoimmune issues that I have. If IVF is a possibility, should intralipids be considered?
Thank you for any information. It is truly appreciated.
Hi Mindy,
I might be able to be of help. You need to know that 50% of women who have autoimmune hypothyroidism (Hashimoto’s disease) also have autoimmune implantation dysfunction that prevents reproductive success (see below).Please go to http://www.IVFauthority.com and when you get to the home page find the “search bar” in the right hand column. Type in the following subjects into the bar and it will take you to all the relevant articles I posted there.
“Thyroid autoimmune disease and IVF”
“Immunologic Implantation Dysfunction” (posted on May, 10th and on May 16th respectively.
“Embryo Implantation………” (Part-1 and Part- 2—-Posted August 2012)
“Traveling for IVF from Out of State/Country– The Process at SIRM-Las Vegas” (posted on March, 21st 2012)
“A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)
“IVF success: Factors that influence outcome”
Consider calling 800-780-7437 or 702-699-7437 to arrange a telephone or Skype consultation (free of charge to those who reside in the United States or Canada). While an audiovisual (Skype) interaction is much more personable and preferable than a discussion by telephone, either will suffice.
Geoff Sher
Dear Dr Sher,
I am getting ready for a new ivf round and my RE will do some testings before. I see he wants to test me for APA but I am more concerned about the Nka test. Will the APA test provide any answer about the Nka too or do I have to do a specific blood test for Nka?
Thank you!
Lucy
There are specific blood and endometrial tests for NK cell activity. Also only a handful of Reproductive immunology labs in the country can do them adequately. The blood test is called a K-562 Target cell test band the uterine test is a “cytokine analysis”
Feel free to call 800-780-7437 or 702-699-7437 to arrange a Skype consultation (free of charge to those who reside in the United States or Canada) with me so we can discuss your case in detail
Geoff Sher