Immunologic Implantation Dysfunction (IID): A common Cause of Repeated, “Unexplained” IVF Failure
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):
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).
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.
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. To date 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).