The autoimmune bases of infertility and pregnancy loss

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Abstract

Several lines of evidence suggest that autoimmune mechanisms may influence the reproductive life and fertility of both sexes, commonly manifesting as infertility or pregnancy loss. Part of the controversy that characterizes this assumption derives from the overlooked suspect of autoimmune conditions in the absence of symptoms or the limited physician awareness in a gynecological setting. Numerous autoimmune diseases, including but not limited to systemic lupus erythematosus and anti-phospholipid syndrome, may be associated with infertility and pregnancy loss through different putative mechanisms. First, serum autoantibodies such as anti-phospholipid, anti-thyroid, or antinuclear antibodies may be directly associated with infertility, regardless of the presence of a clinically overt autoimmune disease. Second, autoimmunity may affect all stages of fertility, via ovarian failure, testicular failure, implantation failure, and pregnancy loss. Third, infertility may also be secondary to vasculitis associated with other conditions such as systemic lupus erythematosus and diabetes mellitus. This review article will illustrate and critically discuss the available data on the link between the breakdown of tolerance that characterizes autoimmune diseases and the changes in reproductive life that affect patients in real clinical setting and that often constitute the iatrotropic stimulus.

Introduction

Infertility (defined as the failure to conceive after 12 months of regular sexual intercourses) can be estimated to affect approximately 10% of the couples of child bearing age. On the other hand, recurrent pregnancy loss (RPL) is defined as the loss of two (American Fertility Society) or three (European Society of Human Reproduction and Embryology, and Royal College of Obstetricians and Gynaecologists) pregnancies and occurs in approximately 1% of couples. The causes of infertility commonly encompass anovulation, endocrine dysfunctions, mechanical infertility (commonly following pelvic infections), and unexplained causes (idiopathic). Autoimmune diseases are not considered as a major cause of impaired fertility and are thus commonly overlooked despite the fact that several conditions are associated with infertility or pregnancy loss. In general terms, autoimmune conditions may affect all stages of fertility, from ovarian and testicular failures, to implantation failure and pregnancy loss. Although the contribution of autoimmunity to impaired fertility remains controversial, numerous conditions are associated with or directly cause subfertility, as in the case of anti-phospholipid syndrome (APS) [1], type 1 diabetes mellitus (T1DM) [2], and systemic lupus erythematosus [3] while maternal anti-Ro/SSA and anti-La/SSB autoantibodies cause a complete heart block in the newborn. Our group summarized the prevalence of autoantibodies in a cohort of 269 patients referred for infertility, recurrent pregnancy loss [4]. In the subjects with infertility anti-phospholipid antibodies (aPL, odd ratio, OR 5.11, 95% confidence interval, CI 1.2–25.4) and anti-prothrombin antibodies (OR 5.15, CI 2.1–12.7) were significantly more represented compared to controls. Further, anti-Sacchromycetes cerevisiae (ASCA, OR 3.9, 95% CI 1.5–10.6), anti-prothrombin (OR 5.4, 95% CI 2.4–12.5), and aPL antibodies (OR 4.8, 95% CI 1.2–22.2) were more frequently found in patients with repeated pregnancy loss. Within this group of patients, serum anti-prothrombin and aPL antibodies were particularly associated with late compared to early pregnancy loss. Pertinent to the present discussion, we recognize a tendency to utilize immunomodulatory approaches to enhance fertility, particularly using steroids which may lower the number and killing activity of natural killer cells, and intravenous immunoglobulin (IVIg) in cases of recurrent implantation failure following in vitro fertilization (IVF) or for the prevention of pregnancy loss. Similarly, cytokine modulation can also be used acting on Th2 and Th1 molecules, albeit in opposite ways. The possibility of an autoimmune response to steroid hormones presenting with infertility [5] or pregnancy loss [6] should be considered in this scenario.

Section snippets

Ovarian failure

Premature ovarian failure (POF, ovarian failure appearing before the age of 40) may be secondary to genetic aberrations, autoimmune and environmental causes (viral infections, chemotherapy, radiotherapy, and pelvic surgery). In most cases, however, the cause remains idiopathic. Of most interest, it has been estimated that 10–30% of women with POF have a concurrent autoimmune disease, frequently autoimmune thyroid disease, hypoadrenalism, and in some cases myasthenia gravis, systemic lupus

Testicular failure

Autoimmune orchitis often causes male infertility and is characterized, in its primary form, by the presence of specific anti-sperm antibodies (ASA) directed at the basal membrane or the seminiferous tubules. These autoantibodies are found in approximately 10% of infertile couples [20] and may follow specific conditions such as the obstruction of the vas deferens [21], varicocele, mumps orchitis, and spinal cord injury [21] but are found in 40% of men with SLE, albeit with limited sperm

Anti-endometrial antibody and endometriosis

Endometriosis is characterized by the presence of endometrial tissue in the ovaries, pouch of Douglas, and uterosacral ligaments or other ectopic locations within the pelvic cavity including the bladder, ureter and rectum, leading to adhesions, pain, and infertility. Endometriosis is found in 10–15% in women of reproductive age and 20–50% of infertile women [31]. An intense inflammatory reaction with elevated pro-inflammatory cytokines and angiogenic factors, mobilization of fibroblasts and

Anti-trophoblast antibody

It is well established that aPL antibodies affect the adhesion molecules between the elements of the syncytiotrophoblast as the cytotrophoblast cells express phospholipids and aPL may damage the trophoblast independent of the presence of thrombosis, as observed in vitro [40]. Similarly, women with aPL manifest at histology reduced vasculosyncitial membranes, increased synctial knots and premature aging of the villi with necrosis [41], [42], as illustrated in Fig. 2. Anti-phospholipid antibodies

Autoimmunity diseases associated with infertility

Data on parity, fertility, and pregnancy losses are available for most autoimmune and chronic inflammatory conditions and are summarized in Table 1.

Immunomodulation and infertility

Several drugs that modulate the immune function and are commonly used in autoimmune diseases can also be employed, albeit empirically, to treat reproductive dysfunctions, thus indirectly supporting a role for autoimmunity in the pathogenesis of these disturbances.

Conclusions

With few exceptions such as SLE or APS, the impact of autoimmune diseases on reproductive health variables is largely overlooked in clinical practice and in research [94], [95], [96]. First, this is particularly relevant considering that autoimmune diseases affect preferentially women, often during their reproductive age [97]. Second, the risk of reproductive failure may be also secondary to the medical treatments used, as in the case of cyclophosphamide, or to vasculitis phenomena [98]. Third,

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