The relevance of autoimmunity to infertility and of infertility to autoimmunity
By Norbert Gleicher, MD, Medical Director and Chief Scientists of the Center for Human Reproduction (CHR) in NYC. He can be reached through the editorial office of The Reproductive Times or directly at ngleicher@thechr.con or at ngleicher@rockefeller.edu
Briefing: A recent article in Human Reproduction asked the question whether having received fertility treatments (as an infertile woman) affects the likelihood of – later – being diagnosed with an autoimmune disease in comparison to not having undergone infertility treatments. The article below is an edited and somewhat expanded version of an article soon appearing in the January-February CHR newsletter, the VOICE
So, here is an interesting question: How much does infertility treatment affect the later onset of systemic autoimmune diseases in women who give birth? A recent paper by Canadian investigators in Human Reproduction attempted to answer this. The answer was somewhat surprising: Women who experienced infertility but did not use fertility treatment had a higher incidence of later autoimmune diseases—up to nine years after delivery—than those who did not experience infertility, even after accounting for higher rates of preeclampsia, spontaneous preterm birth, and stillbirth.
The study included 568,053 singleton births among 465,078 women aged 18–50 years without known pre-existing autoimmune diseases, using all 2012-2021 data from the Canadian province of Ontario. Here are some important details: The median follow-up was 6.5 (4–9) years. The incidence of autoimmune diseases was 9.3 per 10,000 person-years in women without infertility, 12.5 per 10,000 person-years in those with infertility and no fertility treatment, 10.9 per 10,000 person-years following non-invasive fertility treatment, and 10.9 per 10,000 person-years after invasive fertility treatment (1). Infertility without treatment was associated with an elevated risk, even after accounting for adverse pregnancy outcomes. Neither non-invasive nor invasive fertility treatments were associated with increased autoimmunity.
What Do These Findings Mean?
The authors suggest that infertility, in the absence of fertility treatment, may be an important risk marker for the development of autoimmune diseases in the future in women who give birth. Though this conclusion may seem obvious and, therefore, should not be underestimated in its importance, we feel that this paper highlights some additional significant issues. One is the mere fact that female infertility appears to be highly associated with autoimmunity. Doesn’t this represent an even more important conclusion of this paper?
That autoimmune findings in infertile female populations are more frequent than in non-infertile female populations has been claimed by several authors for decades—including investigators at the CHR (2). But we are unaware of any study that has documented this fact as clearly as this study did. Doesn’t this suggest a strong pathophysiological and, therefore, etiological connection between autoimmunity and infertility?
So much for those who still believe that the female immune system has nothing to do with female infertility!
The Role of Fertility Treatments
And last but not least, shouldn’t we ask the question: Why and how do fertility treatments apparently reduce the risk of autoimmune diseases? Isn’t this, likely, the most important issue raised by this paper?
Unfortunately, the paper addresses none of these issues in depth and, indeed, raises serious questions about its overall validity. One of the issues noted by the authors themselves is that neither non-invasive nor invasive fertility treatments were associated with the occurrence of autoimmune diseases. So which treatments did? The association between untreated infertility and later autoimmune diseases only persisted in analyses restricted to women under age 38 and those without endometriosis or other autoimmune diseases.
The incidence of autoimmune diseases was 12.5 per 10,000 person-years with untreated infertility and 9.3 per 10,000 person-years in controls without infertility. Though statistically significant due to the large study size, one must ask whether this is clinically relevant. We, frankly, doubt it. The authors also pointed out other limitations and reasons for caution. For example, the study used published algorithms in health administrative data with unknown or imperfect sensitivity and specificity. Data on individual-level social and lifestyle factors, as well as underlying causes of infertility, were not available and, therefore, not included in the analysis.
In short, this is a potentially interesting study but of questionable clinical value. Its principal benefit may, after all, be a strong reemphasis of the connection between autoimmunity and female infertility.
A Related Study on Early Menopause and Autoimmunity
And finally, somewhat related, a recent study in BMC Rheumatology linked early menopause before age 45 with an increased risk for rheumatoid arthritis. Based on a meta-analysis from 11 observational studies (and we don’t favor many meta-analyses, as our readers by now well know), they found that: (i) postmenopausal women experienced more rheumatoid arthritis than menstruating women, and—more interestingly—women with early menopause (before age 45) had an even greater risk [OR 2.97, 95% CI 1.73-4.22] (3). Again, not a surprising but interesting finding because, after all, autoimmune diseases increase with age, and autoimmunity is, of course, one of the most prominent associations with primary ovarian insufficiency.
References
1. Scime et al., Hum Reprod 2025;40(1):157-166
2. Gleicher N, Hum Reprod Update 1998;4(2):169-176
3. Namavari et al., BMC Rheumatology 2024;8:48