Immunologic causes and thrombophilia in recurrent pregnancy loss

Certain miscarriages result from immunologic factors, but there is no clear identification of the precise causes of recurrent pregnancy loss (RPL). Miscarriages and RPL can arise from a disruption of maternal–fetal immune homeostasis. Remodeling of the maternal uterine spiral arteries is one of the key steps for normal growth and development of the fetus. An adequate oxygen supply is necessary for correct placentation, and it is accomplished by proper vascular changes. The development of fetal tissues creates a potential immunologic problem since the fetus can express paternal antigens and, in some cases, antigens of a gamete donor. The maternal immune system actively responds to fetal antigens, and dysregulation of this crosstalk could partly explain pregnancy complications such as miscarriages and RPL. RPL resulting from thrombophilia is primarily due to acquired thrombophilia, and therefore screening and treatment should be focused on antiphospholipid antibody syndrome. Certain miscarriages result from immunologic factors, but there is no clear identification of the precise causes of recurrent pregnancy loss (RPL). Miscarriages and RPL can arise from a disruption of maternal–fetal immune homeostasis. Remodeling of the maternal uterine spiral arteries is one of the key steps for normal growth and development of the fetus. An adequate oxygen supply is necessary for correct placentation, and it is accomplished by proper vascular changes. The development of fetal tissues creates a potential immunologic problem since the fetus can express paternal antigens and, in some cases, antigens of a gamete donor. The maternal immune system actively responds to fetal antigens, and dysregulation of this crosstalk could partly explain pregnancy complications such as miscarriages and RPL. RPL resulting from thrombophilia is primarily due to acquired thrombophilia, and therefore screening and treatment should be focused on antiphospholipid antibody syndrome. Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/31782 Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/31782 Human reproduction is a notoriously inefficient process, and even when pregnancy is achieved, losses can still occur. Recurrent pregnancy loss (RPL) may arise from the failure of maternal–fetal immune homeostasis, which normally provides ideal immune conditions for the development of normal pregnancies leading to healthy newborn babies. Technological and scientific advances in the field of assisted reproductive technology (ART) have provided new tools for better understanding of the factors that affect the reproductive outcome, notably by allowing selection of euploid embryos. However, for reasons that have not yet been identified, more than 30% of euploid embryos fail to the implant (1Franasiak J.M. Scott R.T. Contribution of immunology to implantation failure of euploid embryos.Fertil Steril. 2017; 107: 1279-1283Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). Disruption of maternal immune tolerance has been invoked as one possible cause of RPL. The original theory was that immunosuppression was required for the presence of the allogenic fetus to be accepted and not disrupted. Owing to repeated failed ART cycles, including after gamete donation, patient demand for immune tests and immune therapy has increased. Years later, however, the role of the immune system in RPL is still debated (2Alecsandru D. Garcia-Velasco J.A. Immune testing and treatment: still an open debate.Hum Reprod. 2015; 30: 1994Crossref PubMed Scopus (5) Google Scholar, 3Alecsandru D. Garcia-Velasco J.A. Immunology and human reproduction.Curr Opin Obstet Gynecol. 2015; 27: 231-234Crossref PubMed Scopus (15) Google Scholar). Cells of the immune system play an important role in immune defense, as well as in reproduction. During pregnancy, the physiological changes that take place through the remodeling of maternal uterine spiral arteries are among the key steps necessary for the normal growth and development of the fetus (4Tang A.W. Alfirevic Z. Quenby S. Natural killer cells and pregnancy outcomes in women with recurrent miscarriage and infertility: a systematic review.Hum Reprod. 2011; 26: 1971-1980Crossref PubMed Scopus (130) Google Scholar). For the correct development of the placenta, cells of the fetal trophoblast must infiltrate the decidua and transform the spiral arteries of the placental bed during the first weeks of pregnancy. This ensures an adequate supply of oxygen and nutrients to promote normal growth and development of the fetus. Poor arterial transformation can deprive the fetal–placental unit of oxygen and nutrients. This is seen when vascular remodeling is deficient and results in preeclampsia, maternal hypertension, or fetal growth restriction. However, invasion of the uterus by the trophoblast should not be excessive since this can also generate maternal risks (i.e., placenta accreta). Infiltration of fetal tissues creates a potential immunologic problem since the fetus can express paternal or, in the case of oocyte and/or sperm donor ART, donor antigens. In parallel to what happens during organ transplantation, the placenta can be rejected if it is recognized by the maternal immune system as “nonself”(4Tang A.W. Alfirevic Z. Quenby S. Natural killer cells and pregnancy outcomes in women with recurrent miscarriage and infertility: a systematic review.Hum Reprod. 2011; 26: 1971-1980Crossref PubMed Scopus (130) Google Scholar). In order to face the challenge created by the nonself nature of the developing embryo and the risk of rejection, the immune system has been reduced, in the area of reproduction, to one group of cells: the natural killer (NK) cells. NK cells have become a central element in immunologic studies conducted in women suffering from RPL. Originally, studies wrongly identified NK cells as “killers” in charge of rejecting the embryo and associated this function with reproductive failure (5Kam E.P. Gardner L. Loke Y.W. King A. The role of trophoblast in the physiological change in decidual spiral arteries.Hum Reprod. 1999; 14: 2131-2138Crossref PubMed Scopus (173) Google Scholar). In the late secretory phase (luteal days 7–9), profound changes in the distribution of local immune cells are observed in the healthy endometrium. The percentage of uterine NK (uNK) cells dramatically increases to reach 70%–80% of total leukocytes. Meanwhile, the percentage of macrophages is 30%, while T cells decrease to 10% in response to estradiol and progesterone signals. uNK cells proliferate and differentiate in the uterine mucosa. They are not present prior to menarche or after menopause. The dependence of uNK cells on ovarian hormones, primarily progesterone, is shown by the observation of a great surge in proliferative activity after ovulation. This phenomenon is mediated by an increased expression of interleukin 15 from stromal cells in response to progesterone. During pregnancy, the presence of uNK cells in the decidua is at its peak in the first trimester, with declining numbers thereafter. uNK cells are still present at term, but not in abundant numbers (6Trundley A. Moffett A. Human uterine leukocytes and pregnancy.Tissue Antigens. 2004; 63: 1-12Crossref PubMed Scopus (264) Google Scholar). It has been suggested that estradiol and progesterone could regulate the expression of specific chemokines in the endometrium, which, in turn, would partake in the recruitment of NK cells in the uterus (4Tang A.W. Alfirevic Z. Quenby S. Natural killer cells and pregnancy outcomes in women with recurrent miscarriage and infertility: a systematic review.Hum Reprod. 2011; 26: 1971-1980Crossref PubMed Scopus (130) Google Scholar). In addition to differentiating and proliferating during the implantation window, uNK cells populate the decidua immediately adjacent to the infiltrating trophoblast and around the spiral arteries during early pregnancy. The cells that form the barrier between the maternal and fetal compartments are the trophoblast cells. The syncytiotrophoblast is in contact with immune cells circulating in the maternal blood in the intervillous space. The extravillous trophoblast (EVT) cells invade the uterine lining—the decidua—at the implantation site and during placentation to transform the arteries and establish the blood supply of the placenta. In early gestation, the dominant immune cells present in the decidua, the uNK (CD56brightCD16-) cells, have receptors that can bind to ligands on invasive EVT cells. uNK cells are also characterized by the secretion of several factors involved in vascular remodeling and angiogenesis, an action that occurs when EVT invasion begins shortly after implantation (7Chen X. Man G.C.W. Liu Y. Wu F. Huang J. Li T.C. et al.Physiological and pathological angiogenesis in endometrium at the time of embryo implantation.Am J Reprod Immunol (New York, NY: 1989). 2017; : 78Google Scholar). uNK cells are associated with the establishment of normal early placentation through vascular remodeling at the end of the implantation process. This altered vascular conversion and insufficient invasion of the uterine lining by the trophoblast have been considered the primary defects encountered in preeclampsia and are hypothesized to contribute to RPL (8Arck P.C. Hecher K. Fetomaternal immune cross-talk and its consequences for maternal and offspring's health.Nat Med. 2013; 19: 548-556Crossref PubMed Scopus (332) Google Scholar). uNK cells regulate trophoblast invasion and enhance vascular remodeling induced by EVT cells (9Moffett A. Colucci F. Co-evolution of NK receptors and HLA ligands in humans is driven by reproduction.Immunol Rev. 2015; 267: 283-297Crossref PubMed Scopus (91) Google Scholar) and T regulatory (Treg) cells (FoxP3+Treg), ultimately promoting maternal–fetal immune tolerance. Recently, the physiology of the maternal–fetal interface has been further complicated by the description of three different populations of uNK cells (10Vento-Tormo R. Efremova M. Botting R.A. Turco M.Y. Vento-Tormo M. Meyer K.B. et al.Single-cell reconstruction of the early maternal-fetal interface in humans.Nature. 2018; 563: 347-353Crossref PubMed Scopus (486) Google Scholar). In addition to their interactions with EVT cells, uNK1 cells exhibit active glycolytic metabolism, increased expression of the killer immunoglobulin-like receptor (KIR), LILRB1 genes, and cytoplasmic granules (10Vento-Tormo R. Efremova M. Botting R.A. Turco M.Y. Vento-Tormo M. Meyer K.B. et al.Single-cell reconstruction of the early maternal-fetal interface in humans.Nature. 2018; 563: 347-353Crossref PubMed Scopus (486) Google Scholar). Simultaneously, human trophoblast cells express an array of immune inhibitory molecules predominantly targeting T cells (CD4+ or CD8+), such as Fas ligand and indoleamine 2,3-dioxygenase, which are potent inducers of T-cell apoptosis. This is known to be a protective mechanism for maternal–fetal tolerance. The interaction between trophoblast human leukocyte antigen (HLA)-G dimers and leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1) receptors expressed by macrophages and dendritic cells also promotes maternal–fetal tolerance. The interactions between members of the KIR family expressed by uNK cells binding to trophoblast HLA-C molecules are of particular interest for allorecognition. Both maternal KIR and fetal HLA-C genes are highly polymorphic. This means that there are different maternal–fetal genetic combinations in each pregnancy. The variability in the KIR gene family is both at the level of the presence or absence of a gene and the level of the individual allelic variability at each KIR locus. Placentation is regulated by interactions between maternal KIRs expressed by uNK cells and fetal HLA-C molecules expressed by EVT cells. Hiby et al. (11Hiby S.E. Regan L. Lo W. Farrell L. Carrington M. Moffett A. Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage.Hum Reprod. 2008; 23: 972-976Crossref PubMed Scopus (219) Google Scholar) showed that invading EVT cells are the principal site of HLA-C expression in the decidua basalis and that both maternal and paternal HLA-C allotypes encounter KIRs. Insufficient invasion of the uterine lining by the trophoblast and vascular conversion of the decidua are thought to be the primary defects encountered in preeclampsia, fetal growth restriction, and RPL. Several studies conducted in natural pregnancies by Hiby and Moffett (12Alecsandru D. Garrido N. Vicario J.L. Barrio A. Aparicio P. Requena A. et al.Maternal KIR haplotype influences live birth rate after double embryo transfer in IVF cycles in patients with recurrent miscarriages and implantation failure.Hum Reprod. 2014; 29: 2637-2643Crossref PubMed Scopus (34) Google Scholar) showed that women who have a KIR AA genotype (two KIR A haplotypes) are at risk for preeclampsia and other pregnancy disorders when the fetus has more HLA-C2 genes than the mother and when additional fetal HLA-C2 alleles are of paternal origin. These authors also reported that protection from preeclampsia is likely mediated by activating KIR2DS1 (B haplotype), which also binds HLA-C2. Thus, it appears that trophoblast cell invasion is regulated by the type KIR–HLA-C interactions. ART-derived pregnancies differ from natural pregnancies. ART patients may receive more than one embryo per transfer, and in certain cases, albeit rare, donor oocytes or even donor embryos may be used. In ART, a double embryo transfer results in the expression of more than one paternal HLA-C per trophoblast cell. In case of oocyte donation cycles, an increasingly requested approach in women of advanced age, the interaction between the oocyte and maternal HLA-C, which is genetically different from the mother’s receptor, behaves like the interaction with paternal HLA-C. Ultimately, this results in more nonself HLA antigens being presented to the mother’s KIRs than is the case in naturally occurring or ART-induced pregnancies. Invasion by the embryo requires specific immune activation at the maternal–fetal interface, mediated by interactions between the mother’s uNK cell receptors, KIRs, and the embryo’s ligand HLA-C, expressed by EVT cells. Absence of this maternal immune activation, which is observed in KIR AA (inhibitory receptor) carriers, is associated with poor embryo invasion and poor placentation. This is particularly the case when the fetus has more HLAC2 genes than the mother and when additional fetal HLAC2 alleles are of paternal or oocyte donor origin (11Hiby S.E. Regan L. Lo W. Farrell L. Carrington M. Moffett A. Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage.Hum Reprod. 2008; 23: 972-976Crossref PubMed Scopus (219) Google Scholar, 12Alecsandru D. Garrido N. Vicario J.L. Barrio A. Aparicio P. Requena A. et al.Maternal KIR haplotype influences live birth rate after double embryo transfer in IVF cycles in patients with recurrent miscarriages and implantation failure.Hum Reprod. 2014; 29: 2637-2643Crossref PubMed Scopus (34) Google Scholar, 13Hiby S.E. Apps R. Sharkey A.M. Farrell L.E. Gardner L. Mulder A. et al.Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2.J Clin Invest. 2010; 120: 4102-4110Crossref PubMed Scopus (316) Google Scholar). A recent study observed increased miscarriage rates and decreased live birth rates in patients with KIR AA genotypes (transmitting inhibitory immune signals) than in patients with KIR AB or BB genotypes (14Alecsandru D. Barrio A. Garrido N. Aparicio P. Pellicer A. Moffett A. et al.Parental human leukocyte antigen-C allotypes are predictive of live birth rate and risk of poor placentation in assisted reproductive treatment.Fertil Steril. 2020; 114: 809-817Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). Interestingly, the percentage of KIR AA was higher in an RPL cohort than among Spanish white women (Basque country 16.9%, Cantabria 31.3%, and Granada 26% [allelefrequencies.net]) and European white women. Autoimmune connective tissue diseases, notably rheumatoid arthritis, systemic lupus erythematosus, antiphospholipid antibody syndrome, and systemic sclerosis (primary Sjogren’s syndrome and inflammatory myositis) predominantly affect women, with a female–male ratio of 9:1. Moreover, these disorders most often occur during the reproductive years. The degree of activity of these autoimmune disorders can have a negative impact on reproductive outcomes (15Marder W. Littlejohn E.A. Somers E.C. Pregnancy and autoimmune connective tissue diseases.Best Pract Res Clin Rheumatol. 2016; 30: 63-80Crossref PubMed Scopus (28) Google Scholar, 16Andreoli L. Tincani A. Beyond the “syndrome”: antiphospholipid antibodies as risk factors.Arthritis Rheum. 2012; 64: 342-345Crossref PubMed Scopus (24) Google Scholar). Planning embryo transfers according to the clinical stability of the autoimmune disease could minimize pregnancy risks. An emphasis on preconception counseling and strict disease control in the months prior to conception are essential for managing the desire for pregnancy (notably by ART) and autoimmune diseases (17Andreoli L. Fredi M. Nalli C. Reggia R. Lojacono A. Motta M. et al.Pregnancy implications for systemic lupus erythematosus and the antiphospholipid syndrome.J Autoimmun. 2012; 38: J197-208Crossref PubMed Scopus (63) Google Scholar). Routine metabolic screening of all RPL patients is not yet recommended, but this classic recommendation may change in the future. Impairments of glucose metabolism are typically screened for during pregnancy. Less is known, however, about the usefulness of such screening in the preconception period, notably in cases of prior miscarriages and RPL. A recent study by Conway et al. recommended that a fasting glucose test be performed in obese women, in lean women of advanced age (>40 years) with polycystic ovary syndrome, and in women with a personal history of gestational diabetes or a family history of type 2 diabetes mellitus (18Conway G. Dewailly D. Diamanti-Kandarakis E. Escobar-Morreale H.F. Franks S. Gambineri A. et al.The polycystic ovary syndrome: a position statement from the European Society of Endocrinology.Eur J Endocrinol. 2014; 171: P1Crossref PubMed Scopus (352) Google Scholar). Approximately 5% to 14% of patients with a diagnosis of type 2 diabetes mellitus have diabetes-associated autoantibodies. Hence, screening for these antibodies in cases of RPL may be an interesting area of study, as little is known about their incidence in women suffering from RPL. Thrombophilia is a term used to describe a group of disorders that result in an increased risk of abnormal coagulation and consequently of venous and arterial thromboembolism. Thrombophilia is associated with a variety of adverse pregnancy outcomes, but the relationship between RPL and specific thrombophilias is often misunderstood (19American College of Obstetricians and Gynecologists' Committee on Practice Bulletins–ObstetricsACOG Practice Bulletin No. 197: Inherited Thrombophilias in Pregnancy.Obstet Gynecol. 2018; 132: e18-34Crossref PubMed Scopus (24) Google Scholar). Thrombophilias can be inherited or acquired during one’s lifetime, and patients may be unaware of their presence. Physicians who care for women at risk for RPL should have a good understanding of the pathophysiology, screening, diagnosis, and management of thrombophilias in early pregnancy. 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It is debated whether inherited thrombophilias result in adverse pregnancy outcomes, and the results of studies are mixed on whether there is an association with RPL (27Dizon-Townson D. Miller C. Sibai B. Spong C.Y. Thom E. Wendel G. et al.The relationship of the factor V Leiden mutation and pregnancy outcomes for mother and fetus.Obstet Gynecol. 2005; 106: 517-524Crossref PubMed Scopus (193) Google Scholar, 28Silver R.M. Zhao Y. Spong C.Y. Sibai B. Wendel G. Wenstrom K. et al.Prothrombin gene G20210A mutation and obstetric complications.Obstet Gynecol. 2010; 115: 14-20Crossref PubMed Scopus (106) Google Scholar, 29Silver R.M. Saade G.R. Thorsten V. Parker C.B. Reddy U.M. Drews-Botsch C. et al.Factor V Leiden, prothrombin G20210A, and methylene tetrahydrofolate reductase mutations and stillbirth: the Stillbirth Collaborative Research Network.Am J Obstet Gynecol. 2016; 215: 468.e1-468.e17Abstract Full Text Full Text PDF Scopus (13) Google Scholar). 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Diagnosis requires the presence of antiphospholipid antibodies (in particular, the standardized assays for anticardiolipin antibodies, and/or lupus anticoagulant antibodies, and/or anti–2-glycoprotein I antibodies) measured on two occasions 12 weeks apart. In addition to this laboratory criterion, clinical criteria consisting of either thrombosis or pregnancy morbidity must also be present. With regard to RPL, pregnancy morbidity refers to three or more unexplained consecutive spontaneous pregnancy losses before 10 weeks of gestation. Several theories have emerged regarding the pathophysiology of antiphospholipid antibody syndrome resulting in RPL. Initially, the thought was that thrombosis and infarction of the placenta resulted in early fetal loss, but evidence suggests that placental thromboses are equally common in women with and without antiphospholipid antibody syndrome (39Sheppard B.L. Bonnar J. 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