Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction (IID) in IVF: The Controversy!

Dr. Geoffrey Sher - March 20, 2016
Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction (IID) in IVF: The Controversy!

 “Innovators are rarely received with joy, and established authorities launch into condemnation of newer truths; for at every crossroad to the future are a thousand self-appointed guardians of the past.”

 

 

It is an indisputable fact that  thousands of women with “unexplained” infertility/IVF and recurrent pregnancy loss (RPL) have, following selective immunotherapy with Intralipid (IL) or intravenous immunoglobulin (IVIG) in combination with corticosteroids, gone on to have healthy babies. So, why then is there such a “militant obsession” on the part of many, to denounce the entire concept of immunologic factors playing a role in implantation dysfunction?  The most common reason cited is that there are no randomized controlled “gold standard”  studies to support a causal relationship between immunologic implantation dysfunction (IID) and reproductive dysfunction (infertility/failed IVF and early miscarriage)  or the efficacy of immunotherapy to treat the condition. The double standard: But to single out IID for criticism is a clear example of a double standard since there are no reliable randomized controlled (“gold standard”) studies to validate virtually any IVF, outcome-based treatments currently in general use. It has not even been shown that outcome following IVF is superior to alternatives such as gamete intra-fallopian tube transfer (GIFT) or zygote intra-fallopian tube transfer (ZIFT). Yet, no one would dispute the fact that IVF is far more effective than either of the other alternatives, to the extent that both GIFT and ZIFT are rarely performed any longer and have largely been relegated to the pages of history. Similarly, there are no randomized studies that demonstrate a benefit in using commonly used adjunct procedures such as embryo assisted hatching (AH), embryo co-culturing, nuclear cytoplasmic transfer, uterine scratch, embryo vitrification,  intracytoplasmic sperm injection (ICSI) etc. Yet, many highly ethical and competent IVF practitioners confidently tout some or all of these techniques as being efficacious and beneficial without turning a hair. The truth is that as is the case in many other medical specialties, progress has come has through experience gained by longitudinal studies, not through gold standard statistical testing. Background: Ordinarily, upon reaching the uterus, the embryo makes itself invisible to uterine natural killer (NK) cells (the predominating immune lymphocytes in the uterine lining). There, provided that the NK cells do not become activated (NKa) and the embryo has a normal configuration of 46 chromosomes (euploid) and is thus “competent”, it will usually gain acceptance, implant and develop into a viable conceptus. However, in some women, the uterine NK cells become activated (NKa) and go “rogue”, confronting the embryo as a “foreign invader”. In response, they (and other uterine immune T-cells) release an excess of TH-1 cytokines (e.g.  TNF-alpha and interferon-gamma) and attack the embryo’s “root system” (trophoblast)   resulting in failed or dysfunctional implantation (i.e.  Failure to conceive or early pregnancy loss). Uterine NK cells were first identified and described in the mid-90’s and were soon touted as playing a vital role in regulating embryo implantation.  This was soon followed by the determination that under certain conditions, NK cells became activated (NKa) leading to immunologic implantation dysfunction (IID) which could manifest as “unexplained” infertility, “unexplained” IVF failure and recurrent pregnancy loss (RPL). This spawned a lively debate on how to best assess, diagnose and treat the condition. Why is it that until very recently, there has been a singular inability to reliably evaluate data derived from ART-related studies? To answer this question requires a realization that roughly 80% of ART failures are largely due to  chromosomal numerical irregularities (embryo aneuploidy) which until the recent introduction of full embryo karyotyping (using techniques such as comparative genomic hybridization-CHG or next generation gene sequencing- NGS) was not possible to reliably assess. And, to reliably compare results between groups of IVF patients, it is essential that outcome per embryo transferred be computed. To achieve this requires that the “competency” of the embryos transferred be known prior to embryo transfer so that only chromosomally normal (euploid/”competent”) embryos can be transferred to patients of each group. Since virtually no previously reported clinical, outcome based IVF studies took this critical requirement into consideration virtually negates their validity, making them virtually meaningless. How might we in the future, reliably establish value and efficacy of selective immunotherapy in IVF?  In order to be reliable and representative, any study to assess a benefit of immunotherapy in women with IID would require that, demographically and clinically identical NKa positive patients, all of whom would be treated by the same physician using the same stimulation protocols, be randomly assigned to one of two groups. Group 1 would receive the designated immunotherapy regime and Group 2, would not. To be reliable, all variables that could affect outcome, would need to be kept constant. Only “competent” (euploid) blastocysts would be eligible for transfer and results would be reported as viable birth per embryo transferred. Clinical Reproductive immunology is a very complex field which most IVF physicians do not take the time to try and understand. Most, simply follow the party line and dismissively reject the concept out of hand. So, when patients tell me that “My RE does not believe in immunologic factors causing infertility, IVF failure or Recurrent pregnancy loss”,  I advise them, to go back and ask the doctor that gave this answer for a clear explanation as to what it is that he/she does not believe. I submit to you, that in most cases a rational answer will not be forthcoming.


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