Infertility with a concomitant diagnosis of INFLAMMATION
By Norbert Gleicher, MD, Medical Director and Chief Scientist at The Center for Human Reproduction in New York City. He can be contacted through The Reproductive Times or directly at either ngleicher@thechr.com or ngleicher@rockefeller.edu.
Briefing: Inflammation is an extremely common occurrence in humans, so it is unsurprising that inflammation frequently coexists with infertility and pregnancy. As a component of what can be considered to represent a “hyperactive” immune system, inflammation is something the CHR does not like to see in women undergoing infertility treatments because hyperactive immune systems are closely associated with increased miscarriage risk and—with less evidence to this point—implantation failure. As one of the most prominent reproductive immunologists in the country and building on over 40 years of research and clinical practice in this arena, the author of this article objectively points out how little is still known about the interdependence of pregnancy and the maternal immune system and, on purpose subjectively, summarizes how the CHR has come to view subspecialty area in infertility care that is unfortunately still widely unexplored.
Everybody has, of course, heard the word “inflammation,” and everybody has an opinion about what it means to have inflammation; but whatever we may believe inflammation is, in reality it is much more. It is pervasive, since every human being at any given moment may, indeed, have inflammation somewhere in the body, often without even knowing. On the other hand, inflammation may manifest itself as fever, pain, swelling, and local heat production of an inflamed area of the body. And at the same time normal physiological processes can be dependent on occurrence of inflammatory processes, among those several in reproduction, such as ovulation, implantation, labor, and others.
At the same time inflammation is also a normal defense mechanism in abnormal circumstances. When one gets injured, the body is invaded by bacteria, viruses, chemicals, etc., and yes, under certain circumstances by the fetus. It may be symptomatic or not at all, just as an inflamed tooth may hurt or not. And even just an inflamed tooth—as the diagnosis already gives away—is, of course, also an inflammation.
In other words, inflammation can be good in defending us and it can be bad in attacking our bodies. It can be acute or chronic. It can be caused by as trivial a thing as an inflamed tooth, or it may be the consequence of a life-threatening autoimmune disease. In short, inflammation is everywhere and nowhere, it is essential for many important physiological processes, but inflammation can also kill us. It is an almost all-encompassing term and, therefore, has only limited value as a primary diagnosis.
Reaching a diagnosis
As already noted, inflammatory processes are omnipresent. When acute, they are simple to suspect and usually easy to diagnose. They can cause discoloring of an inflamed area or flushed skin in a local area of inflammation, with or without tenderness in the area or mild pain (and not elsewhere) or can cause swelling, for example after a knee injury. But inflammation can also be local without localized symptoms, as it can be systemic with and without symptoms. And then, inflammation can be chronic, as in cases of autoimmunity, inflammatory bowel disease, cardiovascular disease, and even in certain cancers. Even mental/psychiatric diseases have now been associated with inflammation and, certainly neurodegenerative diseases, like Alzheimer’s disease. It has been estimated that inflammatory diseases account for more than half of all death in the world.1
How a laboratory diagnosis is established, of course, depends on the underlying diagnosis. At the CHR the search for inflammation is part of every patient’s initial basic work-up and includes several standard inflammatory markers, all routine medical tests: A white blood cell count (WBC) in a CBC with differential, an erythrocyte sedimentation rate (ESR), a C-reactive protein (CRP), and an interleukin-6 (IL-6). We also look for thyroid autoimmunity, obtain an antinuclear antibody (ANA) panel, and antiphospholipid antibody (APA) panel. In addition, we look at total immunoglobulin levels in IgM, IgG, IgE, and IgA and – if the patient has a past history or family history of autoimmunity – we may go into more detail in our initial evaluation, with the principal goal not being the discovery of a previously unknown inflammatory and/or autoimmune disease (that happens only very rarely), but to determine whether the female infertility patient demonstrates evidence of a hyperactive immune system.
The hyperactive immune system
And this is the point where the CHR approach to the immune system in infertile women significantly diverts from how many of our colleagues treat immune patients: Though it matters, of course, what kind of inflammatory and/or autoimmune condition a patient suffers from, over many decades of research the CHR has come to the conclusion that this is not the central question in treating infertile women with immune problems. The really important question is whether a patient shows signs of a hyperactive immune system.
If she does, she is definitely at increased risk of miscarriages and likely at increased risk of failure to implant (the latter is less well-established than the miscarriage risk).
In other words, we do not chase after individual markers (because there are too many nowadays) and, therefore, also do not run up diagnostic testing costs thousands of dollars because patient only very rarely have an undiagnosed, specific disease. Patients who do have a specific disease are usually already diagnosed. A large majority of infertile women with hyperactive immune systems do not know that they have a hyperactive immune system, and secondly, have only selected laboratory abnormalities and not really enough for a specific disease diagnosis.
The CHR, therefore, performs only a limited “checklist” of above noted immune parameters (unless a couple’s history asks for more) to determine the likelihood of a hyperactive immune system. This, for example, does not include the investigation of NK cells (as many colleagues do) – and not only because peripheral NK cells in blood have nothing to do with endometrial NK cells which can only be obtained by endometrial biopsy – but because what determines the treatment offered to affected patients is not NK cells or APAs but the question of whether a patient has a hyperactive immune system or not. Once she is determined to have evidence of a hyperactive immune system, the severity of noted laboratory findings then determine the degree of treatment the patient will receive.
Having an abnormal immune system in pregnancy
Pregnancy has a unique relationship with the maternal immune system, with the principal reason being that every embryo trying to implant in the mother’s uterus is either a so-called semi-allograft (50% genetically from mother and father, respectively) or even a full 100% allograft when egg and sperm are genetically distinct from the woman carrying the pregnancy [i.e., either a pregnancy established with an egg donor or where a couple uses a gestational carrier (GC) for their embryos].
It is, however, one of the ground rules of our biological existence that our immune systems’ primary function is to defend us from being invaded by genetically foreign organisms. Based on this ground rule, every embryo trying to implant into a uterus should be immediately rejected by the maternal immune system, even more so in donor eggs and GC carrier pregnancies. And, yet, in an overwhelming number of cases, this does not happen.
Why that is, has not been fully established yet, even though certain local mechanisms – including local endometrial Treg cells – have been identifies as important local contributors to the implantation process.2 While these local mechanisms may at least partially explain the initial development of maternal tolerance toward an implanting embryo, they do not explain the tolerance of a solid organ transplant growing with logarithmic speed (called the fetal-placental unit) by the maternal immune system.
How the maternal immune system tolerates such a massive “tumor” is still unexplained, though certain features appear obvious: (i) Local immune processes may help in implantation; but the embryo – in successful implantation – buries into the endometrium for at least 10 days completely independent of any maternal input and unaffected by a maternal immune response3 even though the endometrium, in principle, must be hostile to any penetration, since women would otherwise be steadily infected by transvaginal invaders. (ii) Such an uncontested invasion is only explainable by the maternal immune system having made the invading embryo immunologically “invisible” by reprogramming itself from being hostile to being tolerant of this embryo. Data suggest that this reprogramming through induction of tolerance pathways occurs in response to certain messages received by the endometrium from the embryo.
It is this reprogramming process leading to the induction of tolerance pathways that malfunctions in women with hyperactive immune systems, whatever the cause. Consequently, women with hyperactive immune systems are at increased risk for miscarriages and also, likely, implantation failure, because if tolerance pathways are not properly induced, the implanting embryo remains at least partially immunologically visible and, therefore, is attacked by the maternal immune system. A first intervention in suppressing such unwanted maternal immune responses, therefore, must be in place, ideally before the embryo enters the endometrial cavity.
The appropriate treatments
As is so often the case in medicine, there is no one treatment for all women with hyperactive immune systems. Here we return to the different etiologies of hyperactive immune systems: A woman whose immune system is hyperactive because of autoimmunity will have to be treated differently from a woman whose immune system hyperactivity is primarily inflammatory in nature, or is both autoimmune and inflammatory. And treatment will also vary based on the severity of laboratory abnormalities.
At a very basic level, corticosteroids will be first line of drugs in cases of autoimmunity, while anti-inflammatory medications, like Plaquenil, will be first choice in women with primarily inflammatory conditions. Because autoimmune diseases almost uniformly also have inflammatory components, both drugs may be used in unison (systemic lupus erythematosus, SLE, is a good example). Also considered a rather automatic treatment in both conditions is low-dose aspirin (mostly at a dose of 81mg daily) which has also become vogue in the prevention of preeclampsia during pregnancy, where it usually is prescribed in slightly higher dosing. These are, indeed, the three Level I medications at the CHR for women with hyper-active immune systems. Based on a recent systematic review,4 the CHR no longer automatically uses anticoagulation, unless a patient has a diagnosed thrombophilia.
Where patients require longer-term anti-inflammatory pretreatment before IVF cycle starts, patients at the CHR are often placed on an anti-inflammatory multi-component non-prescription supplement. An example is Conflam-Forte, soon to be relaunched Ovaterra by Fertility Nutraceuticals, LLC, in NYC, to the CHR’s specifications; this supplement contains a multitude of anti-inflammatory compounds and does not have the potential side-effects on eyes that Plaquenil has, requiring an eye exam every six months.
In more severe cases, additional medications are added. The CHR’s Level II medications are Intralipid and intravenous gamma globulin (IV-Ig), with IV-Ig greatly preferred over Intralipid. Fortunately, Level I and II medications will be sufficient for an overwhelming number of patients with hyperactive immune systems but, on occasion, patients may need even more (Level III). This is when so-called “biologicals” come into play, with this term indicating that these drugs were made from living organisms or their products. They are currently our most powerful weapons for stopping inflammation. Among the most well-known examples are Humira (adalimumab) (by AbbVie) and Enbrel (etanercept, by Amgen and Pfizer). Another level III medication at CHR, indeed, the longest one in use is granulocyte colony stimulating factor (GCSF).
None of these drugs has, however, been specifically studied in pregnancy and the CHR, therefore (except for GCSF), consider these drugs as still experimental if used during pregnancy. From post-marketing studies of women who conceived on these drugs often unintentionally, there is, however, increasing evidence that their use in pregnancy is safe.
References
1. https://my.clevelandclinic.org/health/symptoms/21660-inflammation
2. Lindau et al., J Reprod Immunol 2021;146:103330
3. Deglincert et al., Nature 2016;533(7602):251-254
4. Tamiris Barbosa Dias et al., JBRA Assist Reprod 2021;25(1):10-27