Endometriosis and recurrent pregnancy loss: two manifestations of the same underlying dysfunction?

Endometriosis is a common benign gynecological condition with wide-ranging effects that continue to be elucidated. In the current issue of Fertility and Sterility, Boje et al. (1Boje A.D. Egerup P. Westergaard D. Mathilde Friis Bertelsen M.L. Nyegaard M. Hartwell D. et al.Endometriosis is associated with pregnancy loss: a nationwide historical cohort study.Fertil Steril. 2023; 119: 826-835Abstract Full Text Full Text PDF Scopus (1) Google Scholar) have further contributed to our understanding of the impact of endometriosis on recurrent pregnancy loss (RPL) in their recently published nationwide cohort study on 29,563 women with endometriosis and 295,630 controls. They demonstrated an association between RPL and endometriosis with an increased association seen with higher number of pregnancy losses. This association has been previously demonstrated, but the breadth of this cohort strengthens the known association. Their cohort did not demonstrate an association between endometriosis and recurrent second-trimester losses or stillbirth, which have been previously reported, for example, a meta-analysis (2Breintoft K. Pinnerup R. Henriksen T.B. Rytter D. Uldbjerg N. Forman A. et al.Endometriosis and risk of adverse pregnancy outcome: a systematic review and meta-analysis.J Clin Med. 2021; 10: 1-39Crossref Scopus (21) Google Scholar) including eight cohort studies showed an association between endometriosis and stillbirth (odds ratio [OR] 1.27, 95% confidence interval [CI] 1.07–1.51). This discrepancy prompts further investigation into late-gestation complications and their potential association with endometriosis. The powerful sample size inherent to their cohort study unfortunately results in a loss of more granular elements of data. The diagnosis of endometriosis is made based on the International Classification of Diseases-8 and International Classification of Diseases-10 codes, and therefore, not all patients were diagnosed via a pathological diagnosis and conversely, the control group is not a group established to be free from endometriosis, which is notoriously under-diagnosed. Similarly, the study notes that 14.1% of those with endometriosis-achieved pregnancy via assisted reproduction and only 4.4% of the control group used assisted reproduction but did not analyze whether those with endometriosis continue to have a higher rate of RPL for in vitro fertilization (IVF) pregnancies. As those with severe endometriosis were not found to have higher rates of RPL, but perhaps are more likely to undergo IVF due to anatomic distortion and tubal damage associated with severe endometriosis, this analysis is essential. Additionally, there is inherently a rate of spontaneous conceptions that is unrecognized but ends in pregnancy loss. Both the pathophysiologic origins of endometriosis and the mechanism of RPL have been attributed to immune dysregulation, and the finding of an increase in presumed euploid losses further promotes this hypothesis. By selecting subgroups of patients with higher likelihood of euploid pregnancy losses (i.e., patients with RPLs, pregnancy losses at <30 years of age, pregnancy losses during the second trimester, and stillbirth), the authors showed an association between endometriosis and euploid losses. Several immunological abnormalities in women with endometriosis would explain immunosurveillance evasion, implantation, proliferation, and angiogenesis of the ectopic endometrial tissue. Decreased T cell reactivity and natural killer cell cytotoxicity, polyclonal activation of B cells and increased antibody production, increased number and activation of peritoneal macrophages, and changes in inflammatory mediators have been described (3Riccio L.D.G.C. Santulli P. Marcellin L. Abrao M.S. Batteux F. Chapron C. Immunology of endometriosis.Best Pract Res Clin Obstet Gynaecol. 2018; 50: 39-49Crossref PubMed Scopus (139) Google Scholar). Although impairments in many factors, such as egg quality, ovulation, and ovarian function, can be implicated in early pregnancy loss, RPL has been hypothesized to have multiple immunologic defects at its origin. Dysfunctional maternal immunotolerance can have wide-ranging implications for inflammatory sequela from decreased endometrial receptivity to poor oocyte quality. Women with endometriosis express an inflammatory state both locally and systemically. Patients with endometriosis are noted to have peritoneal infiltration of immune cells, such as macrophages and neutrophils, inflammation with the secretion of pro-inflammatory cytokines, including but not limited to interleukin-1 (IL-1)[-α and -β], IL-6, IL-8, or tumor necrosis factor-α, and the production of chemokines that amplify immune cell recruitment, thus leading to adhesion and growth of endometriotic lesions. Maternal immunomodulation is a key step in early pregnancy - successful implantation requires a transient increase in pro-inflammatory cytokines (T helper [Th] 1 bias), followed by switching to an anti-inflammatory state (Th2 profile). Recurrent pregnancy losses have been linked to a dysregulation in T cell function with an imbalance in Th1/Th17/Th2/T regulatory (Treg) cells as seen by increased Th1/Th17 immunity (pro-inflammatory), while the Th2/Treg cell profile is decreased. Interestingly, an adaptative immune response involving Th1/Th17/Th2/Treg cells has also been shown in endometriosis. Chronic inflammation may also have dramatic effects on gene expression and may impact decidualization and embryo implantation, thus leading to early pregnancy losses. Nuclear factor- κB is a transcription factor activated by several cytokines (tumor necrosis factor-α and IL-1) and has been shown to be increased in endometriosis. This decreases the expression of progesterone receptors and leads to progesterone resistance. This process may alter the expression of key factors, such as homeobox A10, and may negatively impact endometrial decidualization. As a result, the implantation process may be compromised. Autoimmunity (another indication of immune imbalance) is a common trait between endometriosis and RPLs. A cross-sectional survey involving n = 3,680 patients diagnosed surgically with endometriosis showed a strong association between autoimmune diseases and endometriosis. Similarly, Hashimoto's thyroiditis showed a 6.4-fold increase in the endometriosis group versus the control group. Furthermore, a strong association has also been shown between patients not adequately treated for clinical hypothyroidism and pregnancy losses. The main finding of the study further complicates the treatment dilemmas facing patients with endometriosis and their providers. Many of the medical therapies presented for the treatment of endometriosis-related pain prevent conception through hormonal suppression. Treatment of endometriosis-associated infertility necessitates the cessation of these medical therapies, and the comparative (or additive) efficacy of medical and surgical treatment for endometriosis-associated infertility is not fully understood. For patients with such obstacles and high stakes associated with every attempt at conception, an increased likelihood of loss holds even greater weight. Further cementing this association, the study by Boje et al., in its concluding remarks and analysis, demands that we explore the root of this association. Strengthening the association between endometriosis and recurrent pregnancy loss has wide-ranging treatment implications, starting with the diagnostic management of patients with RPL. Many common symptoms of endometriosis are often overlooked, and many patients with endometriosis have very few or even none of the typical symptoms associated with endometriosis. Therefore, patients with RPL deserve access to further imaging studies, surgical diagnosis and treatment of endometriosis, and immunologic testing. Our understanding of the impact of different severities of endometriosis on fertility will also be greatly advanced by the standardization of endometriosis surgical staging such as the AAGL (Elevating Gynecologic Surgery Worldwide) classification system released last year. From a treatment perspective, there is limited evidence to suggest that surgery for endometriosis specifically prevents miscarriage. Using live birth as an endpoint, a recent systematic review and meta-analysis published in this journal reported the effectiveness of surgery for endometriosis in improving fertility outcomes in women with infertility. The studies included a total of 26 trials reporting on 2,245 women with endometriosis-related infertility. The authors found that surgery for endometriosis was associated with higher odds of pregnancy compared with placebo (OR 1.63, 95% CI 1.13–2.35) (4Hodgson R.M. Lee H.L. Wang R. Mol B.W. Johnson N. Interventions for endometriosis-related infertility: a systematic review and network meta-analysis.Fertil Steril. 2020; 113: 374-382.e2Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). There is evidence to suggest that immunological treatments may be effective in preventing RPL. In a recent systematic review (5Christiansen O.B. Kolte A.M. Krog M.C. Nielsen H.S. Egerup P. Treatment with intravenous immunoglobulin in patients with recurrent pregnancy loss: an update.J Reprod Immunol. 2019; 133: 37-42Crossref PubMed Scopus (24) Google Scholar), the authors found that the use of immunological treatments was associated with an increase in live birth rates compared with the placebo if the treatment commenced before conception. The relative risk for live birth in patients who received intravenous immunoglobulin before conception versus those who received placebo was 1.69 (95% CI 1.33–2.14, P<.0001). The authors also noted that the optimal timing and dosage of immunological treatments for recurrent miscarriage are not well-established and that more research is needed to determine the most effective strategies. As with infertility, miscarriage is often kept within a realm of silent suffering. Pregnancy loss is rarely discussed, and when patients present with pregnancy loss, only repeated events prompt investigation. The standard workup for RPL investigates only a limited number of potential causes, and the default treatment approach is often IVF with genetic testing of embryos. However, for many patients without genetic causes of pregnancy loss who are able to spontaneously conceive, this approach does not eliminate all pregnancy losses. Sadly, for a patient with a history of three losses, the likelihood of a fourth is 60%. Optimistically, as more is learned about the underlying causes of RPL, more clinicians will feel empowered to offer more clinical attention to these patients. Those with RPL should be evaluated for endometriosis as the underlying cause, and conversely, pregnant patients with a history of endometriosis should be managed as high risk for pregnancy loss and obstetric complications. Ultimately, advancements in reproductive immunology hold great potential to inform our management of both patients with endometriosis and those with RPL. Endometriosis is associated with pregnancy loss: a nationwide historical cohort studyFertility and SterilityVol. 119Issue 5PreviewTo study whether endometriosis is associated with pregnancy loss and recurrent pregnancy loss (RPL). Full-Text PDF