Immunomodulation in Recurrent Miscarriage

There are many etiological factors responsible for recurrent abortions. However, no explanation can be identified in approximately 40–50 % of women with recurrent miscarriage (RM). Several studies demonstrated that successful pregnancy is dependant on shifting of maternal immune response from (proinflammatory) Th1 toward (anti-inflammatory) Th2 phenotypes. It was suggested that unexplained RM might be due to immunologic factors. Recently, there is improved understanding regarding the role of the different immune cells and proteins that are important at each stage of a normal pregnancy. Various immune-based therapies with variable clinical evidences have been reported in women with RM with variable efficacy. Still there is lack of information about the mode of action and possible adverse effects of the treatment and a reliable marker for patient selection for immunopotentiation. Adequately powered placebo-controlled studies are required to study and treat couples with the so-called idiopathic recurrent miscarriage.     

How does variability of immune system genes affect placentation?

Formation of the placenta is a crucial step in mammalian pregnancy. Apart from its function in ensuring an optimal supply of nutrients and oxygen to the fetus, the placenta is also the interface at which allo-recognition of invading trophoblast cells by the maternal immune system can potentially occur. We summarise here the “state of the art” on how variability of immune system genes that code for major histocompatibility complex (MHC) molecules and natural killer receptors (NKR) may impact on human placentation. MHC and NKR are the most polymorphic human genes. Our recent reports point out that specific combinations of fetal MHC and maternal NKR genes in humans correlate with the risk of pre-eclampsia, recurrent miscarriage (RM) and fetal growth restriction (FGR). Research in this field is still at an early stage and future studies in mouse and humans will be needed before the results can be translated to clinical applications. We discuss our recent work, as well as the opportunities offered by mouse genetics, to understand the cellular and molecular mechanisms underlying immune interactions at the maternal-fetal interface.     

Do uterine natural killer (uNK) cells contribute to female reproductive disorders?

The most abundant immune cells in the uterine decidua around the time of implantation and early placental development are the uterine natural killer (uNK) cells. Altered numbers of uNK cells have been associated with several human reproductive disorders, including recurrent miscarriage, recurrent implantation failure, uterine fibroids, sporadic miscarriage, fetal growth restriction and preeclampsia. Understanding of the function of uNK cells in non-pregnant and pregnant endometrium is now increasing; the potential contribution of altered numbers and function of uNK cells to reproductive disorders is the focus of this review.     

双胎妊娠介入性产前诊断不同取样方法术后流产风险评估及相关因素分析

目的:探讨介入性产前诊断不同取样方法应用于双胎妊娠的术后流产风险,并分析影响术后流产风险的相关因素.方法:回顾性分析2015年1月至2019年3月广东省妇幼保健院产前诊断中心行介入性产前诊断的452例双胎妊娠的临床资料.按照介入性产前诊断不同取样方法分为3组:绒毛取材组(33例)、羊膜腔穿刺组(376例)、脐血取样组(...     

Immune modulation of i.v. immunoglobulin in women with reproductive failure

Background

The mechanism of maternal immune tolerance of the semi‐allogenic fetus has been explored extensively. The immune reaction to defend from invasion by pathogenic microorganisms should be maintained during pregnancy. An imbalance between the immune tolerance to the fetus and immune activation to the pathogenic organisms is associated with poor pregnancy outcomes. This emphasizes that the immune mechanism of successful reproduction is not just immune suppression, but adequate immune modulation.

Methods

In this review, the action of i.v. immunoglobulin G (IVIg) on the immune system and its efficacy in reproductive failure (RF) was summarized. Also suggested is the indication of IVIg therapy for women with RF.

Main findings (Results)

Based on the mechanism of the immune regulation of IVIg and following confirmation of the immune modulation effects of it in various aberrant immune parameters in patients with RF, it is obvious that IVIg is effective in recurrent pregnancy losses and repeated implantation failures with immunologic disturbances.

Conclusion

The authors recommend IVIg therapy in patients with RF with aberrant cellular immunologic parameters, including a high natural killer cell proportion and its cytotoxicity or elevated T helper 1 to T helper 2 ratio, based on each clinic's cut‐off values. Further clinical studies about the safety of IVIg in the fetus and its efficacy in other immunologic abnormalities of RF are needed.     

Immunologic associations of keloids.

The mechanisms underlying the pathogenesis of keloids have not been fully characterized despite extensive past and present research. Results of past and present studies have shown that the immune system is actively involved in the development of these lesions. Future investigations into the biochemistry and immunologic factors of keloids are anticipated and expected to produce additional insight. The inability to identify cellular (fibroblast) abnormalities has led most investigators to focus on the humoral regulators of wound healing, that is, biochemical substances, immunologic mediators and growth factors. Future studies are needed to confirm or refute the presence of AFA. AFA, if they exist, may prove to be useful as immunologic markers of keloids and may help distinguish keloids from hypertrophic scar in the early stages of wound healing. The influence of immunologic mediators may be more impressive early in the development of scars. "Young" or "early" is defined as less than two years of age, whereas "old" or "late" keloids are more than two years of age. We suggest that future studies stratify keloids into early versus late and also measure the rates of collagen synthesis of fibroblasts derived from the normal and abnormal specimens from the same patient. Analysis of the leukocyte factors will clarify the role the immune system has in the regulation of collagen synthesis. Preliminary investigations have shown that immunotherapy may be of value in the treatment of keloids. The role of fibroblast heterogeneity needs to be investigated. It is not known which aspects of fibroblast heterogeneity are responsible for the localized and accelerated rates of collagen synthesis of keloid fibroblasts.     

Immunological abortion: the thyroid factor

Spontaneous miscarriage (SM) is a multifactorial problem involving several couples. Recent studies investigated the correlations between the presence of antithyroid antibodies (ATA) and pregnancy loss, and found that many women with a previous history of recurrent miscarriage, showed high levels of ATA circulating in their blood. Further-more, the thyroid function disorder may also affect the course of pregnancy. Basically, two theories can explain the reasons of the spontaneous termination of pregnancy in presence of ATA: the first theory suggests that the hypofertlity or infertlity of these subjects may be due to a subtle degree of hypothyroidism which is difficult to detect by routine serum hormone determinations; the second theory supports that the presence of thyroid antibodies reveals a more generalized underlying abnormal stimulation of the immune system. Therefore, the thyroid function should be tested before conception and during pregnancy to avoid the pregnancy loss and neuropsychological deficits in infants. Actually, some papers suggest that treatments reserved to women with thyroid antibodies could decrease the miscarriage rate. Unfortunately, there is not agreement about the most effective therapy. We need more large, randomised, placebo controlled, double blind studies.     

Thrombophile Gerinnungsstörungen als Risikofaktoren für habituelle Aborte

Recurrent spontaneous abortions – three or more consecutive miscarriages of the same couple – are traditionally associated with genetic, anatomic, immunologic, endocrine, and questionable infectious factors. However, there is growing evidence that changes in the haemostaseologic maternal pathway may play a role in the development of pregnancy complications. Maternal thrombophilic disorders, whether hereditary or acquired, can be associated with a significantly elevated risk for miscarriage. Besides hereditary changes of the coagulation system (e.g. factor V Leiden mutation, prothrombin mutation, protein S deficiency), it is the acquired thrombophilic disorder of the antiphospholipid syndrome that especially symbolizes a major risk factor for recurrent miscarriages; however, it can be treated adequately with combination anticoagulant therapy. This review summarizes the current knowledge concerning the diagnosis and therapeutic options in patients with recurrent abortions and maternal thrombophilic disorders.     

Recurrent miscarriage: pathophysiology and outcome

PURPOSE OF REVIEW: This article reviews new concepts in the aetiology of recurrent miscarriage, presents new outcome data and evaluates new modalities of treatment for unexplained recurrent miscarriage. RECENT FINDINGS: Preimplantation genetic diagnosis has been considered an option for couples who have structural chromosomal abnormalities or unexplained recurrent miscarriage. The association between thrombophilias and adverse pregnancy outcome is further reviewed. In relation to this, there is increasing support for the use of thromboprophylaxis in improving pregnancy outcome in women with inherited thrombophilias. Nonrandomized studies have shown that the reduction in insulin levels with metformin in insulin-resistant individuals may reduce miscarriage risk by restoring normal haemostasis and improving the endometrial milieu. With respect to immunological concepts there is now evidence to suggest that, in addition to a suppression of maternal cell-mediated immunity, some elements of the innate immune system are activated in successful pregnancies. SUMMARY: With the exception of aspirin and heparin for the prevention of recurrent miscarriage in women with the antiphospholipid syndrome, no other suggested therapies for this heterogeneous group of patients have been evaluated in randomized controlled trials. These include thromboprophylaxis for inherited thrombophilias and use of insulin sensitizers in women with insulin resistance and/or polycystic ovarian syndrome. The role of the innate immune system in pregnancy was recently highlighted, and use of nonspecific therapies to suppress the maternal immune response to pregnancy should be reassessed.     

Immune testing in fertility practice: truth or deception?

PURPOSE OF REVIEW: Much attention has been paid to the role of immunology in reproductive success or failure. Every step in the establishment of normal pregnancy has been implicated as a possible site of immune-mediated reproductive failure. The widespread testing of antiphospholipid, antinuclear, antithyroid, and antisperm antibodies, as well as generalized immune testing, have thus been employed to diagnose patients with otherwise unexplained infertility or recurrent pregnancy loss. Controversial data surrounding the widespread and variable use of immune testing in current fertility practice is reviewed to determine which tests are warranted based on sound scientific evidence. Because it is postulated that early miscarriage, when occult, could represent a failure of embryo implantation indistinguishable from unexplained infertility, this analysis of immune testing includes a discussion of patients with recurrent pregnancy loss. RECENT FINDINGS: Despite the increased prevalence of abnormal immune testing associated with early reproductive failure, the most rigorous studies have not proven a cause and effect between these phenomena. There is wide variation and inconsistency regarding this association, depending upon which test(s) are employed, the study methodology used, and the patient population under study. The significance of selected immunological test abnormalities associated with early reproductive failure is uncertain. SUMMARY: Great variability exists in identifying candidates for immune testing, determining which tests to order, interpreting the test results, and offering immunologic treatments. This review argues that the use of widespread immune testing in clinical practice can not be supported by existing data. The resulting therapies are similarly of unconfirmed benefit and may cause harm.     

Antiphospholipid antibodies and the investigation of recurrent miscarriage

Recurrent miscarriage (three or more consecutive miscarriages) affects 1% of the female population and this causes severe psychological morbidity in both the sufferer and their partner. For many years the aetiology of recurrent miscarriage in the majority of cases has remained unclear. Treatment regiments to improve pregnancy outcome were based on poorly-designed studies, often without control cohorts, which have subsequently been shown to be of no proven benefit. Over the past 15 years accumulating evidence has implicated the presence of antiphospholipid antibodies (APAbs) in the aetiology of recurrent miscarriage. APAbs can be found in 15% of the recurrent miscarriage population, and are associated with first and second-trimester miscarriages as well as other obstetric complications. Aspirin and subcutaneous heparin administration are of clinically-proven benefit in lowering the miscarriage rate in women with this condition. Maternal side effects of aspirin and heparin are rare but include thrombocytopenia and osteoporosis. No direct teratogenic effects of aspirin and heparin have been demonstrated but pregnancies complicated by APAbs need to be monitored closely for evidence of pre-eclampsia and intrauterine growth restriction.     

Immunologic abnormalities in infants infected with human immunodeficiency virus

The spectrum of HIV-related immunologic dysfunction in children and adults is very broad. Recent advances in our understanding of the molecular basis for this disease has led to insights into the pathophysiologic mechanisms responsible for the immunologic deterioration characteristic of HIV infection. It is clear that CD-4 positive T cells are the pivotal cells of the immune system. HIV infection results in a selective CD-4 cells. However, equally important is a demonstrable qualitative defect in proliferative responses to antigens and in lymphokine production. A number of HIV-related defects in cellular immunity can be attributed to macrophage dysfunction, which appears to occur both through direct infection by HIV as well as by failure of CD-4 T cells to generate lymphokines with macrophage-activating activity. In a similar fashion, the humoral immune system is dysfunctional, because of interaction of B cells with virus or viral products, and as a result of diminished specific production of B cell growth and differentiation factors. From a more practical perspective, few of the many in vitro assays that have been described are easily accessible or provide information directly relevant to patient care. We do find the assessment of skin-test reactivity and periodic enumeration of T cells, in particular CD-4 positive T cells, as useful indicators of disease status. In addition, the assessment of T cell numbers for quantitative abnormalities in ill young infants may be very useful if persistent maternal antibody to HIV precludes the use of routine assays for HIV antibody to confirm a diagnosis of HIV infection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Toll样受体与子宫内膜及子宫内膜异位症

子宫内膜异位症（EMs）发病机制尚未完全阐明。大量研究表明,免疫因素在EMs的发病机制中起重要作用。EMs免疫应答异常主要是巨噬细胞数量和活性增加及其分泌产物,如生长因子、细胞因子和血管生成因子的改变。Toll样受体（TLRs）识别特异性的病原体相关分子模式,启动和介导免疫应答,在固有免疫中发挥重要作用,并诱导产生适应性免疫反应。TLRs在正常子宫内膜中的生理作用以及在EMs中的相关研究已逐步开展,对其深入认识和研究将为EMs诊断、治疗和预后判断提供新思路和手段。     

Miscarriage and its associations

Despite many years of study, abnormal chromosome number remains the most common and well-documented cause of miscarriage. Nonchromosomal factors that have been associated with miscarriage are many and include endocrine abnormalities, anatomic abnormalities, inherited and acquired thrombophilia, environmental exposures, immunologic factors, and others. This article attempts to provide a brief overview and critique of the frequently reported factors. In addition, we call attention to the fact that, to be most helpful, modern studies of miscarriage need to provide details about the sonographically determined gestational age and fetal anatomic development prior to or at the time of pregnancy loss. Such information will be critical in helping to sort out which miscarriage-associated factors are more relevant at which stage of fetal development.     

Successful pregnancy in a patient suffering from recurrent mid-trimester miscarriage with C9 deficiency after receiving cervical cerclage followed by clindamycin and progesterone: a case report

Complement component 9 (C9) deficiency is relatively common, especially in Japan. Here we present the case of a 27-year-old Japanese woman whose obstetric history involved three mid-trimester miscarriages (at 22 weeks', 18 weeks' and 21 weeks' gestation) and one early spontaneous miscarriage. Her fifth pregnancy was successfully managed by cervical cerclage at 13 weeks' gestation, followed by clindamycin administration (600 mg/day for 7 days) and progesterone injections (250 mg/week). She gave birth to a healthy 3326-g male infant at 40 weeks and 1 day gestation after natural onset of labor. After delivery, the serum complement components were analyzed. C9 protein and activity were undetectable in the patient's serum. We suggest that an immunologic disorder such as C9 deficiency should be considered as a potential complication of undiagnosed recurrent miscarriages.     

NLR家族Pyrin域蛋白3炎症小体与妊娠的研究进展

炎症小体是人类天然免疫系统的重要组成部分,参与包括妊娠在内的多种炎症反应,其中NLR家族Pyrin域蛋白3(NLRP3)炎症小体是目前研究最广泛的炎症小体,是宿主防御反应的重要因素,其能够对固有免疫进行调控,各种环境剌激物、多种微生物、内源性或外源性危险信号、病原体和不同的病原相关分子模式(PAMPs)/损伤相关分子模...     

Placental growth factor (PlGF): a key to optimizing fetal growth

Abstract

The needs of the uterus and the fetus for the provision of nutrients and oxygen, supplied by the blood flow, are understandably extremely high, with the circulatory system playing the most important role in this action. Abnormal vascular growth and transformation that create a high vessel resistance network have been associated with various pregnancy pathologies, including miscarriage, small for gestational age (SGA) fetuses with or without preeclampsia and intrauterine growth restriction (IUGR). Placental growth factor (PlGF) has a major role in vasculogenesis and angiogenesis in human placenta. Low concentrations of PlGF and high concentrations of its inhibitor-soluble Fms-like tyrosine kinase-1 (sFlt-1) are linked with impaired angiogenesis and placental development, leading to the above pregnancy complications. The activity of vascular endothelial growth factor (VEGF), which is the most potent of all angiogenic mediators, is partly modulated by PlGF. Although the mechanisms via which PlGF exerts its various effects are still under investigation, we herein discuss the known actions exerted by this major mediator together with its results on fetal growth.     

The molecular basis of embryo implantation in humans

The implantation of the human embryo is a double paradox, immunological and biological. The immunological paradox is that it consists of a heterologous graft in which the uterine immune system (via the cytokines) and the embryo's antigenicity (HLAG) collaborate to make possible both implantation and the maintenance of the pregnancy. The biological paradox arises because several different mechanisms must be successively implemented for these two epithelia to fuse and then for one to allow invasion by the other (that is, the for the endometrium to be decidualized by the trophoblast): preparation of the endometrium throughout the menstrual cycle under the influence of estrogens and then progesterone, with the involvement of growth factors (EGF, TGF and IGF), neoangiogenesis (estradiol, FGF and VEGF), recognition by the trophoblastic cells of the various components of the decidua and of the extracellular matrix (integrins and cadherin) and the progressive invasion of the decidua, to the depth of the spiral arteries (by the trophoblastic secretion of metalloproteases). A defective or excessive trophoblastic invasion can result in complications of pregnancy: early spontaneous miscarriage, preeclampsia and growth retardation of vascular origin in the case of defects, placenta accreta or percreta in the case of excess.     

Multiple pregnancy at 11+0 - 13+6 weeks

Chorionicity, rather than zygosity, is the main factor determining pregnancy outcome. In monochorionic twins the rates of miscarriage, perinatal death, preterm delivery, fetal growth restriction and fetal abnormalities are much higher than in dichorionic twins. High mortality confined to monochorionic pregnancies is the consequence of severe early-onset TTTS. Death of a monochorionic fetus is associated with a high chance of sudden death or severe neurological damage in the co-twin. Sonographic examination provides reliable distinction between dichorionic and monochorionic pregnancies. Reduction of the excess fetal loss in twins, can only be achieved through early identification of monochorionic pregnancies by ultrasound examination at 11+0 - 13+6 weeks, close surveillance and appropriate treatment in those that develop severe TTTS. In multiple pregnancies, compared to singletons, prenatal diagnosis of chromosomal abnormalities is complicated because, firstly, the techniques of invasive testing may provide uncertain results or may be associated with higher risks of miscarriage and, secondly, the fetuses may be discordant for an abnormality.     

子宫内膜异位症的免疫机制研究进展

子宫内膜异位症(endometriosis,EMs)是以慢性盆腔痛、痛经、性交痛及不孕为主要症状的妇科常见病,目前该病的发病机制尚不清楚。研究表明腹腔微环境的异常免疫反应对异位内膜细胞的黏附、侵袭及血管生成至关重要。异位内膜的生长聚集大量多样性的免疫细胞,引发强烈的炎症反应,其中促炎因子、生长因子和血管生成增加。几乎所有类型的免疫细胞在EMs患者中都表现出了异常的免疫功能,如T细胞反应性和自然杀伤(NK)细胞毒性降低,B细胞的多克隆激活和抗体产生增加,腹腔巨噬细胞的数量和活化增加以及炎性介质的变化。进一步的探讨异位内膜细胞介导的免疫系统稳态失衡的机制,深层次了解异位内膜引发的免疫逃逸机制,可能成为新型非激素治疗的目标,从而制定出更全面的治疗EMs的方法。