Trying to Conceive? Questions from Patients and the Public

28 years old; I had 3 miscarriages in a row, and now can’t get pregnant for over 18 months. My gynecologists says I’m too young to worry; but I do worry. 

Your gynecologist is, unfortunately, very wrong and you, fortunately, are very right in worrying: It, of course, is impossible to reach a diagnosis for you simply based on the little we so-far know about you; but three consecutive miscarriages fulfill even the criteria for “repeated pregnancy loss.” This means that, simply for this reason, you should have had a diagnostic work-up because there, likely, is a reason behind your repeat miscarriages. 

Without testing, in most cases it is impossible to say what the underlying cause may be; but as you describe your history, we already have a strong suspicion which, of course, will have to be confirmed.. 

You also pointed out a second very important circumstance, - namely that you now for over 18 months have been unable to conceive. This, even at your still very young age, defines you as a so-called secondary infertility patient, which means that you became infertile after initially being fertile. The occurrence of secondary infertility after prior repeated miscarriages in almost all cases is a presentation typical for so-called immunologic pregnancy loss.  

The natural history of immunologic pregnancy loss is, indeed, characterized by women, first, experiencing (often more than one) pregnancy loss(es) and then, at some point, no longer can get pregnant. When at that point undergoing a diagnostic investigation, these women often demonstrate evidence for what is called premature ovarian aging (POA), by some also called occult primary ovarian insufficiency (oPOI). This means that they have fewer eggs left in their ovaries than ca. 90% of women their age. And, like repeated miscarriages, POA is also closely associated with immune problems. 

Your diagnoses, therefore, likely, are (i) repeat-immune aborter and, already at relatively young age, (ii) POA, a diagnosis that affects ca. 10% of all women. We, therefore, recommend that you see a fertility specialist who also has expertise with immunologic infertility.  

Experts in the latter are called reproductive immunologists and there are really only relative few such experts around. The CHR is lucky in that its Medical Director and Chief Scientist, Norbert Gleicher, MD, is one of the best-known reproductive immunologists in the country and, indeed, is known as one of the fathers of reproductive immunology in the country. He in 1979 was among the founders of the American Society for Reproductive Immunology (and the society’s first VP) and, for ca. 20 years, was also the editor-in-chief of the society’s official journal, the American Journal of Reproductive Immunology (AJRI). 

POA is unfortunately a progressive condition which we have not yet learned to arrest. Time, therefore, may not be on your side and we recommend that you don’t waste time in seeing somebody with appropriate qualifications. Remember, simply based on your history we can only suspect your multiple diagnoses. They now must be confirmed with a few simple tests which do not have to cost a fortune. Because of your young age, with a little help you, likely, should still have no problems conceiving and, with proper treatments, should also have no problems in avoiding yet another miscarriage.1

References

Sung et al., J Reprod Immunol 2021;148:103369 

My husband and I are older. We got married when I was 42 and he 53. We want a child- but now are scared of having one with Down’s syndrome or autism 

We hear you and, almost daily, many others with similar fears. A little information is sometimes more dangerous than no information and your question is a good example for this. We hope that the source of your information was not a physician because physicians, even if not in reproductive medicine, should know better. So here is a little bit of information which, hopefully, will reduce your concerns about having a baby with chromosomal abnormalities at your current ages. 

Let’s start with warranted concerns: It is true that chromosomal abnormalities in eggs increase with advancing female age (though not with advancing male age) and, therefore, chromosomal abnormalities in parallel also increase in embryos. This, however, does not mean that chromosomal abnormalities in parallel also increase in pregnancies and the reason is simple: nature is smart, and nature does not want us to have “abnormal” offspring. Nature, therefore, has built in three well-working defenses as women get older: The first is that a large majority of human embryos with significant chromosomal abnormalities are not allowed to implant. Only a relatively small number of chromosomal “abnormal” embryos slips through this first line of defense and do implant. But that “defeat” of nature’s defense usually does not last very long before the second defense kicks in and that is a usually a quite early miscarriage before fetal heart, either as a so-called chemical pregnancy (before a pregnancy becomes visible on ultrasound) or an early clinical pregnancy (visible on ultrasound but before fetal heart). Only relatively recently discovered,1 there, indeed, exists also a third natural mechanism in early-stage embryos that prevents birth of chromosomal-abnormal embryos and that is the ability of embryos at to “self-correct.” What that means is that embryos at those early stages can get rid of chromosomal-abnormal cells, which allows them to continue to develop as chromosomal-normal euploid fetuses.    

Because of these three defenses nature puts up against abnormal pregnancies, when one looks at the risk of, for example, having an ongoing pregnancy with Down’s syndrome (the most frequent human chromosomal abnormality) is at age 20 only 1/1667 and only 1/526 for all chromosomal abnormalities combined, - and even at age 40 it is only 1/106 (less than 1%) and for any chromosomal abnormality 1/66 (1.51%) 

These numbers are based on miscarriage assessments of products of conception. For several reasons, especially miscarriage assessments, mostly performed after cell cultures were established from trophoblast (extraembryonic cell lineage) lead to somewhat exaggerated assessments of aneuploidy since, in contrast to the embryonic cell lineage that forms the fetus, the extraembryonic cell lineage does not have the same capability to self-correct from aneuploidy.1    

The risk of an ongoing, chromosomal abnormality, therefore, with advancing maternal age goes from incredibly low only to very low. Moreover, so called non-invasive prenatal blood testing (NIPT) in very early pregnancy detects even those small risks in over 90% of cases and in 99.9% of cases with a little later performed chorionic villous biopsy (CVS) or amniocentesis.  

The story with advanced male age is quite different. As already noted, male age does not affect the risk of chromosomal abnormalities. Advanced male age is, however associated with increased autism risk. Unfortunately, a reliable way of testing a pregnancy for autism does not exist. But once again, the increase in risk is small: In absence of a known risk in a pregnancy for the fragile X syndrome (a rare condition in offspring that can be diagnosed), the risk of having a child with autism to parents in their 20s has been reported in the literature at about 1.5%; the risk to parents in their 40s (mostly representing paternal age risk) in comparison will be only ca. 1.6%. 

In summary, while at your older ages your risks to have a child with a chromosomal abnormality and/or autism is, indeed, higher than at younger ages, we don’t see it as substantial enough a risk not to have children with your own eggs and semen at your ages. To reduce your risk, you, of course, have the option of working with young donor eggs and/or young donor sperm; but we do not believe that the risks outlined here really warrant such a decision. 

References 

Yang et al., Nat Cell Biol 2021;23:314-321 

I was diagnosed with systemic lupus erythematosus (SLE) and have been in full remission since age 32.  Now 35, I have been unable to conceive for over two years and have failed 2 IVF cycles. Could there be a link with my history of SLE? 

Coincidentally you are addressing in your question a very important issue in reproductive medicine, - the close link between female fertility and autoimmunity, which is also the subject of our Case Report of The Month below. After this answer to your question we, therefore, suggest you also read the below presented case report which demonstrates in more detail how autoimmunity often mingles with female fertility/infertility. Since you are a patient diagnosed with a classical autoimmune disease (SLE), even though you apparently are in remission from your disease, this does not mean that your autoimmunity no longer affects your fecundity (i.e., ability to conceive). It, indeed, very likely still does and it, moreover, also still, likely, increases your miscarriage risk once you do conceive. Autoimmunity and pregnancy have one very important thing in common: they are very dependent on each other, - though on an inverted scale. 

Both are dependent on immunologic tolerance of the host; The human’s immune system must be tolerant to “self” (i.e. all biological structures making up our bodies). Every time this tolerance is broken, our immune system will start reacting against components of our own bodies, in most severe cases causing autoimmune diseases, for example including SLE and rheumatoid arthritis (RA). In pregnancy, the maternal immune system must be initially tolerant to the implanting embryo and, later in pregnancy, to the complete fetal-placental unit. In absence of such tolerance, and because pregnancy is a semi-allograft (like an organ transplant or nowadays with use of donor-oocytes even a full 100% allografts), pregnancies would in very early stages be destroyed by the maternal immune system if it had not developed tolerance toward the products of conception. 

The induction of tolerance pathways by mothers in pregnancies must be similar to the pathways that guarantee in most people immunological invisibility for “self” antigens because, once the initial risk of rejection of a new pregnancy is overcome, starting in the second trimester of pregnancies many autoimmune diseases, including SLE and RA, actually clinically tend to improve.1 The explanation for this observation is that tolerance pathways induced to protect fetus and placenta also protect from immune responses to “self”-epitopes. In other words, whatever helps to prevent rejection of pregnancy by the maternal immune system, also weakens existing immune responses against “self.” 

Overall, autoimmune diseases, including SLE and rheumatoid arthritis (RA), are, however, not a good thing in pregnancy because, especially at the beginning and end of pregnancy, autoimmune disease flares are common. They, indeed, rise by ca. 60% over non-pregnant periods.2 At the beginning, such flares are, among several other conditions, associated with miscarriages, at the end of pregnancy they are associated with premature labor/delivery and preeclampsia/ eclampsia. The by far largest risk of autoimmune flares, however, exists in the immediate postpartum period and up to 5 months postpartum, when autoimmune diseases often are also for the first time diagnosed. 

Whether SLE is specifically associated with female infertility is unclear; but autoimmunity in general very clearly has such an association. Moreover, SLE and other autoimmune diseases are often also associated with other autoimmune diseases. Individuals who develop an autoimmune disease, therefore, lifelong are at increased risk for other autoimmune diseases. That you were diagnosed with SLE, clearly demonstrates that you have a hyperactive immune system and such an immune system, even when you are in remission from active SLE, still means increased flare risks at the beginning and end of pregnancy, including the postpartum months, likely increased miscarriage risk, increased risk for premature labor and delivery, increased preeclampsia/eclampsia risks, higher chances of a Cesarean section delivery, and other later pregnancy complications. 

You, moreover, should not only receive treatment at a fertility clinic that also has special expertise in managing women with autoimmune diseases, but you should also maintain an ongoing relationship with a rheumatologist throughout pregnancy and into the postpartum period, preferably with admitting privileges at the same hospital where you are planning on delivering. Similarly, you should also choose an obstetrician and/or perinatologist to take care of you during your pregnancy who also understands the close interplay between pregnancy and autoimmunity. Now please switch to the Case Report for some additional explanations. 

References

Adams Waldorf KM, Nelson JL. Immunol Invest 2008;37(5):631-644 

Merz et al., Dtsch Ärtzte Bl Int 2022;119(9): PMC9201458