Good News for Infertile Women with Autoimmunity

Immuno-suppressive biologics may be on the horizon

Steady readers of the VOICE, of course, know by now that, when assessing new patients and when initiating treatments, CHR takes the immune system very seriously, if autoimmune abnormalities were diagnosed during initial diagnostic evaluations. This is a very specific feature that differentiates CHR from many, if not most, other IVF centers, where immunology is unfortunately, still, viewed with considerable distain.

Part of that disdain was well deserved because, as so often is the case, many among those who claimed to be “experts” in reproductive immunology failed the rest of the IVF field, when exaggerating their knowledge by finding almost everything a reason to recommend autoimmune testing and autoimmune treatments. Once those exaggerations became obvious, those “experts” had lost all credibility and, with it, much of the reproductive immunology field lost its apparent relevance for many fertility specialists.

Today we, however, understand the importance of the immune system for normal pregnancy much better. For example, most experts no longer believe that autoimmunity causes implantation failure and/or miscarriages, as was widely perceived 20 years ago because of associations between those two conditions and presence of autoimmune findings in infertile women. At least “directly” autoimmunity, likely, has absolutely nothing to do with implantation failure and/or miscarriages.

What really appears to be happening is that autoimmunity (as do inflammation and allergies) interferes with the normal immune processes that allow an embryo to implant.

Here is a little detail to better understand this point: Everything starts with every embryo being genetically 50% paternal. Therefore, a normally functioning immune system in a woman will always naturally reject any embryo trying to implant. The to the exterior exposed endometrium must, indeed, be especially adept in rejecting invaders because, otherwise, a woman would constantly face infections and parasitic invaders attacking her endometrium. Yet, in a normal pregnancy, a woman with a normal functioning immune system allows this 50% “foreign” parasite, called an embryo, to invade the endometrium without any evidence of an allogeneic immune response against it. The question is, how can that be?

Here is how we see it at CHR: Blastocyst-stage embryos, before implantation, spend ca. 48 hours in the endometrial cavity, swimming in its mucous microenvironment. There is now increasing evidence that during that time period the embryo establishes communications with the maternal immune system, basically saying, “I am here” and “please open the gate.” In response, the maternal immune system and, indeed, the endometrium with it, carefully assess the embryo, determining whether this stranger should be allowed in. If by sniffing the embryo out, the embryo is judged to be “bad,” the gate never opens. If the embryo, however, is judged to be “good,” it is not only welcomed but embraced.

In practical terms this means that, once an embryo has passed muster, the maternal immune system reprograms itself by inducing certain tolerance pathways and, therefore, no longer mounts an allogeneic immune response against the implanting embryo. Instead, it welcomes the embryo, and the endometrium literally embraces the embryo, as British colleagues recently demonstrated in a number of well-designed studies. As a consequence, the rapidly growing semi-allograft of pregnancy survives for nine months in an, otherwise, potentially very hostile environment because the maternal immune system established above noted new tolerance pathways.

And here is where autoimmunity (inflammation and allergies) comes into play: There is evidence in the literature that hyper-active immune systems (i.e., immune systems with autoimmunity, inflammation and allergies) do not induce tolerance pathways well. In such women, the implanting embryo is, therefore, still viewed as “foreign” and, therefore, attacked, leading to implantation failure and miscarriages. The association, therefore, is not between autoimmunity (inflammation and allergies) and these two medical problems but between poor levels of tolerance induction and implantation problems as well as miscarriages. The immune attack against the embryo is, therefore not autoimmune, as used to be believed for decades (and some still do) but an allogeneic immune response, almost the equal to how our immune systems would reject a solid organ transplant without appropriate immunosuppression of the recipient. Yet, if these allogeneic immune responses are to be kept to a minimum, the mother’s hyper-active immune system must be tamed.

Here at CHR we are using immune-suppressive treatments quite frequently. Treatment has, however, not changed in over 20 years and encompasses, depending on severity of lab findings, prednisone and intravenous gammaglobulin (IV-Ig) (we are not big fans of Intralipid), anti-inflammatory drugs, like aspirin, plaquenil and, most recently, the newly over-the-counter available Conflam-Forte, which a recent patient with fibromyalgia at our center recently noted “changed her life after nothing else had helped for years.

Meanwhile colleagues in rheumatology and organ transplantation have made significant progress in developing and applying new generations of drugs with much more specific immunosuppressive effects. One of those was Certolizumab pegol, an antibody to Tumor Necrosis Factor (TNF)-Alpha, which is widely used in the treatment of Crohn’s disease, rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis.

Now to the good news: A group of investigators from Duke University just published a study of 528 pregnancies exposed to this drug and report no adverse effects on offspring. This is truly great news because it creates the opportunity to cautiously start using this drug in women with hyper-active immune systems and high TNF-Alpha levels who fail to conceive and/or still have miscarriages with more standard treatment. Moreover, it suggests that in the near future we may have available a much broader set of so-called biologics to intervene when the maternal immune system isn’t playing ball with the implanting embryo.

This is a part of the May 2018 CHR VOICE.

Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned reproductive endocrinologist, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.