Why Knowing Your Immune System is so Important for Fertility Preservation

BRIEFING:  There are over 80 diseases which are already fully recognized as so-called autoimmune diseases (AIDs) and/or inflammatory diseases (IDs) and, undoubtedly, there are many more waiting to be discovered as such. One characteristic they all have in common is their high degree of familial occurrence. Most diseases are, indeed, familial, but the degree of risk one inherits (the “penetrance”) if another member of the family is afflicted can greatly vary, and no group of diseases except so-called single gene diseases or so-called sex-linked disease, where the risk is either 25% (recessive) or 50% (dominant and/or sex-linked), has greater penetrance than autoimmunity. And autoimmunity as well as inflammation have considerable effects on especially female fertility as well as conception, and significantly increase risks for pregnancy. For young women in general and especially for young women planning on delaying pregnancy and considering fertility preservation through egg-freezing, knowing whether they are at risk for autoimmunity and/or inflammation, therefore, is of crucial importance, and this article will explain why that is, how you can find out, and what can be done in protection of reproductive health. 

FOREWORD 

Our immune system has one principal function, which is protection from invaders. In other words, it is our border police and military, all at once. If it malfunctions, bacteria, viruses, parasites, and other foreign agents are free to enter our bodies without meeting resistance. This is, for example, the reason why older people–who have weaker immune systems than younger individuals–are at greater risk for viral infections like COVID or why individuals born with complete immune deficiency used to have to live in complete isolation in “bubbles” (who remembers the movie about David Vetter, nicknamed ‘Bubble Boy,’ born in 1971 with combined immunodeficiency – basically complete absence of an immune system – who until his death at age 12 lived in a sterile plastic bubble?). 

To function properly our immune systems also have to be able to “recognize” when something is “foreign” because, short of this ability, the immune system could and would start attacking normal components of our own bodies. Our immune system, therefore, has an innate ability to distinguish “self” from “foreign.” When this ability malfunctions and the immune system by mistake starts attacking components of our own body, the affected individual demonstrates autoimmunity. And when this malfunction of the immune system leads to clinical symptoms, the individual has an autoimmune disease (AID). The distinction between demonstrating autoimmunity and having an AID is important because individuals with only autoimmunity will mostly be asymptomatic and, therefore, will likely be unaware of their autoimmunity. Adverse effects of autoimmunity on reproduction can, however, already be present at those early stages. In regard to infertility this means that many cases of so-called “unexplained” infertility in reality are cases of autoimmunity.1 This is an important reason why the CHR does not believe in the diagnosis of “unexplained infertility,” which textbooks and many even relatively recent publications still claim to represent at least 15% of all infertility cases.2 

Over 80 AIDs have so far been described in the literature and experts agree that many more likely exist,  still unrecognized in their autoimmune etiology. Table 1 presents the most frequent ones. Roughly one in fifteen people in the U.S. is affected by an AID, women much more frequently than men, though men usually have more severe disease. 

Like most diseases, AIDs are so-called polygenic diseases. In contrast to monogenic diseases, polygenic diseases are not inherited through only one single chromosomal mutation in any one of 46 chromosomes, but by an inheritance pattern that is dependent on the presence of multiple mutations in multiple chromosomes. This kind of polygenic inheritance pattern does not result in exactly predictable inheritance risks (of 25% or 50%), but basically means only the following: (i) The risk of getting the disease is bigger than it would be if no close relative had the disease (how much bigger varies between diseases but is much lower than the 25% in a recessive single-gene inheritance) and is, therefore, also called a “familial”-inheritance pattern; (ii) In cases of autoimmunity where the risk involves many different autoimmune diseases, it also means that the individual at risk, after expressing one AID, will also be at increased risk to develop other AIDs. Moreover, the number of affected close relatives matters since the risk increases with more affected close relatives. A currently widely accepted hypothesis regarding autoimmune diseases suggests that the predisposition toward autoimmunity is inherited in above-described polygenic fashion; but by which individual autoimmune disease(s) an individual may express during her/his lifetime, is then determined by environmental factors she/he was exposed to in utero or after birth. 

THE EFFECTS OF AUTOIMMUNITY ON REPRODUCTION 

Autoimmunity affects the reproductive success of women in several quite distinct ways,3,4 from being closely associated with premature ovarian aging (POA) in young women during their reproductive years and, therefore, with female infertility, to–likely–the implantation process, almost universally an increased miscarriage risk, and increased risk for several pregnancy complications, with premature labor and premature delivery almost representing hallmarks of all AIDs,5 and an increased preeclampsia risk also being highly significant.3,4 

But AIDs demonstrate yet another very typical general characteristic of medical problems in pregnancy,  namely that medical diseases not only affect pregnancy, but that pregnancy–in reverse–also often affects medical diseases. And, once again, AIDs demonstrate this fact probably better than most other diseases because–as yet another almost universal characteristic–they tend to flare peripartum and especially post-partum.6 Peri- and post-partum clinical presentations, from preeclampsia, over premature labor, and peri-as well as post-partum disease flares are, likely, all the results of caseation of immunological tolerance of the fetal-placentals semi-allograft by the maternal immune system and, probably, the best evidence how closely tolerance pathways of “self” and of pregnancy are interwoven .7 

But among all of these associations, what relates to the topic of this communication is only the long-known association of autoimmunity/inflammation with POA, including its end stage, primary ovarian insufficiency (POI).8 Abnormally low age-specific ovarian reserve has been reported with many–if not most–autoimmune diseases.

WHY YOUNG WOMEN SHOULD KNOW THEIR RISK 

And here is why all of this is important information for young women: Approximately 10% of all women–independent of race and ethnic background–end up prematurely aging their ovaries (i.e., will be suffering from POA). Approximately 10% of these women (1% of all women) will experience early menopause (i.e., POI), which is the end stage of POA. 

Unfortunately, POA is usually an asymptomatic disease. In other words, so-affected young women in most cases have no idea that their ovaries are aging prematurely, until they discover that they no longer can conceive. By that point their functional ovarian reserve (i.e., the number of remaining eggs in their ovaries) has already fallen below a certain minimal threshold, thereby preventing them from conceiving. Consequently, they will require fertility treatments, in most cases in vitro fertilization (IVF). And if they waited too long, IVF may also no longer be an option and what is then left is only third-party egg donation. 

And these are exactly the situations which, through this article, we are trying to help young women avoid: It all starts with being conscious as a young woman about one’s risk status for developing POA. In other words, just like young women have become increasingly conscious about the possibility of freezing their eggs, so they should–at even younger ages–become conscious about the importance of finding out if they are among those 10% of all women who are at increased risk for developing POA. And since autoimmunity is highly associated with POA, knowing about one’s family history of autoimmunity is of great importance. 

In a moment we will discuss how a risk assessment for POA can be done at young ages; but before we do so, it is also important to note that finding out whether one is at risk for POA is also extremely relevant for egg-freezing because those at risk are well-advised to freeze their eggs as early as possible. The later in life eggs are frozen, the fewer eggs will be produced in every retrieval cycle and the more cycles of egg-freezing will be necessary (i.e., costs will go up significantly). Moreover, the poorer the quality of obtained eggs will be and egg quality, of course, translates into embryo quality and pregnancy chances once eggs are thawed out. 

One more very important point: Beyond egg-freezing women considered at risk for POA also usually still have an alternative option to egg-freezing: they can simply decide to have children earlier than otherwise was planned, and that may even still be possible without medical help. What makes this such an important discussion, however, is the fact that it offers young women maximal control over their reproductive future. When to start their families remains their decision and is no longer dependent on their genetically inherited baggage for POA. 

HOW IT IS DONE (Advertisement)

“What’s my fertility?”  is a very simple program for which the CHR was awarded a U.S. patent roughly 10 years ago, which allows for the prediction of whether a young woman is likely (a) not at risk for POA; (b) at risk for POA; or (c) already has evidence of POA.37 It is based on a handful of short questions and blood tests. One of the very important questions is whether the young woman has relatives with autoimmune diseases. If the answer is affirmative, it automatically puts her into the “at-risk” group. That’s it; it’s that simple! 

Individuals who are judged not to be at risk don’t have to return for 3-5 years for a repeat evaluation. Individuals judged at risk enter, depending on their risk assessment, into a 6- or 12-month retesting program with an appropriately timed recommendation for egg-freezing. Women already found to show evidence of POA are advised to attempt conception right away or start egg-freezing instantly. If their functional ovarian reserve is already significantly diminished, they are immediately started in preparations for IVF. 

The CHR’s approach to IVF in POA patients significantly differs from what is offered by most other IVF clinics. This is not the moment to summarize all the important differences; therefore, only so much: As noted earlier, autoimmunity is statistically highly associated with POA, and autoimmunity, like POA, can be asymptomatic. Therefore, risk-screening for POA also involves some immune testing. Such testing is not only important for POA screening; if a woman is found to have evidence of subclinical autoimmunity (i.e., immune abnormalities in her blood but without any clinical symptoms of an AID), this denotes that–without proper treatment–she likely would be at increased risk to miscarry once she conceives. And of course, the last thing we would want to happen after conception is a miscarriage that is preventable with proper treatment. 

It should now be crystal-clear why the CHR during every initial consultation with new patients places so much emphasis on obtaining very detailed family histories. And it, moreover, it should also be very obvious why knowing one’s own immune system is so important for young women in general, but especially if considering delaying pregnancy and planning on freezing one’s eggs. 

References 

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37.   https://www.facebook.com/whatsmyfertility/