Understanding Immunologic Implantation Dysfunction Part 1: Setting the Stage for Selective Immunotherapy with Intralipid and IVIg

10 May
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It is an unfortunate reality that many IVF programs attach little importance to factors that affect embryo implantation in general, and immunologic implantation dysfunction (IID) in specific (see below). Perhaps the lack of attention given to evaluating IVF patients for factors that adversely affect the receptivity of the uterine lining (endometrium/decidua) is due to the fact that in humans, IVF failure and miscarriage are both four times more likely to be due to embryo “incompetence” than to dysfunctional implantation.Thus, a high measure of IVF success can still be achieved in spite of ignoring less common (and more complex) factors such as IID.

But for the 20% of IVF patients with problems relating to lack of endometrial receptivity, it becomes a different matter altogether. For them, the emotional, physical and financial roller coaster ride goes on and on. Often after “spinning their wheels” and enduring repeated IVF failures, many of them will be advised to move on to egg donation…only to fail there as well. Optimal implantation is not only important for embryo survival; it is also a major factor in determining normal intrauterine growth and development. As such, it is a major determinant of the very quality of life after birth.

Immunologic acceptance of the implanting embryo by the uterus of the mother is both highly complex and magnificent. Not only is it essential for pregnancy to occur, but it also sets the scene for our body’s own cells, tissues and organs to be shielded from attack by our own immune systems. For a moment, consider how, when confrontedby foreign proteins (bacteria, viruses, foreign tissue grafts/transplantation), the body’s immune system goes on the attack, but yet an embryo that is derived from proteins that come from another individual (the sperm or paternal antigen), usually safely implants in the pre-pregnancy uterine lining and then grows into a healthy baby.This phenomenon has come to be referred to as the “immunologic riddle” of pregnancy.

For such a complex arrangement to be foolproof would be without precedent in human biology. To argue that this system can never fail is in my opinion, an absurdity, bordering on arrogance. It can and does go wrong in about 15-20% of women with reproductive failure.When it does, it presents either as failed implantation (presumed by the patient to be infertility), as miscarriage, or (much less frequently) as placental failure and compromised fetal development or intrauterine death. It all depends on the timing, nature and severity of the immune assault.

It is well known that the reason the implanting normal embryo thrives in the womb is that unique immunologic adjustments convert the pre-pregnancy uterine lining (decidua) into a “privileged site” where the embryo and the fetus come to be regarded as the “body’s own” and as such are protected from immune attack. This initial acceptance of the embryo as “self” or “friend” rather than “non-self” or “foe” (in spite of it being composed partially of the father’s “foreign” cells), is one of the miraculous adaptations of nature, and is in large part responsible for our survival as a species.

As soon as implantation begins, the paternal genetic contribution to the embryo (so called DQ alpha genes) initiates asignal to the pre-pregnancy decidual immune system which thereupon determines whether the embryonic “allograft” should be welcomed as “friend” or be rejected as “foe” through immune attack. The process is referred to as “alloimmune recognition.”Given that with the exception of monozygotic twins, interpersonal differences in genotype are inevitable, it follows that maternal and paternal DQ alpha gene combinations will usually also differ in the vast majority of cases. Thus, preservation of the human species required that in spite of such immunogenetic dissimilarities, the immune system of the pre-pregnancy endometrium (decidua) evolutionarily adapt and recognize the embryo as friend rather than foe.

Upon reaching the uterine environment, the genetically “competent” embryo hatches and within 12-24 hours starts sending its root system (trophoblast) into the decidua. The trophoblast has both a villous (root-like) and an extravilous (diffuse) component. The extravilous trophoblast which diffusely permeates the decidua, expresses several so-called “major histocompatibility complex” (MHC) class-1 genes (e.g. histocompatibility leukocyte antigen [HLA]-C, E & G)].These HLA genes, (mainly HLA-G) regulate primarily two types of lymphocytes present in the decidua.These are: a) uterine natural killer cells (NK) and b) cytotoxic lymphocytes (CTL). NK cells comprise approximately 75% of decidual lymphocytes and CTL comprise about 10%. They both play a vital role in regulating the normal implantation process by controlling the penetration and functioning of the trophoblast.

The recognition of proteins as self (“friend”) or non-self (“foe”) is propagated by highly specialized immune lymphocytes known as Regulatory T-cells. These so called Treg cells can “turn-off” immune reactions even once they have been started by conventional immune cells. They play a pivotal role in the immune system’s ability to prevent rejection of an embryo whether due to an autoimmune or alloimmune response. Other immune cells known as “dendritic cells” introduce antigenic proteins to these Treg cells, whose concentration increases when the antigen is recognized as “friend” and decreases when recognized as “foe.” MHC (primarily HLA-G) signaling, through the Treg lymphocyte mechanism working in combination with other regulatory proteins, influences the production and release of so-called cytokines by the NK and CTL cells.

There are 3 varieties of cytokines, two of which play defining roles in the maintenance of implantation:The first is TH-2 cytokines, which encourage growth and expansion of the trophoblast and promote proliferation of blood vessels (angiogenesis). TH-1 cytokines promote destruction (cytolysis) of trophoblastic cells and also cause blood to clot (procoagulant effect).A balance between TH-1 and TH-2 cytokines is essential for normal implantation and development of the placenta (placentation). Over-activity (dominance) of TH-1, the hallmark of NK cell and CTL activation, leads to damage of the trophoblast, implantation dysfunction and reproductive failure.

Part 2 of this post will discuss the diagnosis and treatment of immunologic implantation dysfunction.


  • JS says:

    I am 45 y/o and after 3 failed IVF rounds, we opted for donor egg. We did PGS and had 3 genetically normal embryos and froze them. I got pregnant with the first one but miscarried at week 6 for no particular reason, we even saw the heartbeat. It was devastating. Months later, I just had a negative preg test two weeks after a FET, again it was a genetically normal embryo. We now have one embie left so very fearful that we won’t be successful … or maybe the 3rd time is the charm. Before we take the leap and spend our last embie, is there testing that I should have done? Our clinic has a good reputation in the DC metro area and we have gone through all of the normal testing. After our miscarriage, our doc tested me for lupus, anticardiolipin and glycoprotein and all were negative. Desperate for help.

    • Geoffrey Sher says:

      Thank you for connecting! I am updating my entire blog, so kindly-go to http://goo.gl/4hvjoP and re-post your question/comment there, and I will respond promptly. Henceforth I will be responding on that site.

      Thank you.

      Geoff Sher

  • Mary says:

    I’ve done 2 ivf cycles. First cycle was a fresh semen cycle 1 embryo second cycle was a frozen cycle 2 embryos. Both cycles ended in a miscarriage with low hcg just wondering why embryos are implanting but then dying after they implant

    • Geoffrey Sher says:

      It could be that by chance both were abnormal and incompetent or that the implantation was dysfunctional due to anatomical or immunologic reasons.

      Please go to the home page of this blog, http://www.IVFauthority.com . When you get t there, find the search bar and type in the following subjects into the bar, click and this will take you to all the relevant articles I posted there.

      1. “Unexplained IVF Failure”

      2. Recurrent Pregnancy Loss (RPL)”

      3. An individualized Approach to Ovarian stimulation” (posted on November 22nd, 2010)

      4. “Immunologic Implantation Dysfunction” (posted on May, 10th and on May 16th respectively.

      5. “Thyroid Autoimmune Disease and IVF”

      6. “Embryo Implantation………” (Part-1 and Part- 2—-Posted August 2012)

      7. “Traveling for IVF from Out of State/Country– The Process at SIRM-Las Vegas” (posted on March, 21st 2012)

      8.“A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)

      9. “IVF success: Factors that influence outcome”

      10. “Use of the Birth Control Pill in IVF”

      11.”Staggered IVF”

      12.“Embryo Banking”

      13.“Array CGH versus metaphase CGH in IVF patients….’

      14.“Egg Donation”

      15. “Intrauterine Insemination (IUI): Setting the Record Straight on when it is to be considered”.

      16. “Gestational Surrogacy”

      Consider calling 800-780-7437 or 702-699-7437 to arrange a Skype with me so we can discuss your case in detail.

      Finally, perhaps you would be interested in accessing my new book (recently released). It is the 4th edition (and a re-write) of “In Vitro Fertilization: The ART of Making Babies”. The book is available through “Amazon.com” as a down-load or in book form. It can also be obtained from most bookstores.

      Geoff Sher

      P.S: Please go to http://www.youtube.com/watch?v=Vp3GYuqn2eM&feature=youtu.be
      To view a video-tutorial by Linda Vignapiano RN, Clinical Manager at SIRM-Las Vegas.

      I Will be hosting a 2 hour a webinar on our website (www.haveababy.com ) on the evening of January 29th,. The topic will be “Management of Immunologic Implantation Dysfunction as a Cause of IVF Failure and Recurrent Pregnancy Loss”. I urge you to enroll on this website or to contact Tom Anderson at toma@sherinstitute.com ASAP to enroll as it is filling up rapidly.

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