Etiology Of Recurrent Miscarriage Research Articles

Comparison of the expression of human leukocyte antigen (HLA)-G and HLA-E in women with normal pregnancy and those with recurrent miscarriage

Recurrent miscarriage affects 1% of all couples attempting pregnancy. Immunological factors are postulated to play a role in the aetiology of recurrent miscarriage because the fetus and placenta are immunologically different from the mother. In particular, altered expression of the, non-classical, class I histocompatibility leukocyte antigen (HLA) molecules has been postulated to play a role in the aetiology of recurrent miscarriage as the fetus and placenta are semi-allogenic to the mother. This study was conducted to examine whether altered expression of the non-classical class I HLA molecules, HLA-G and HLA-E, by cells at the maternofetal interface could play a role in the aetiology of recurrent miscarriage. First-trimester placental and decidual biopsies were obtained from 45 women with recurrent miscarriage and 17 gestation-matched normal controls. These biopsies were screened by immunohistochemistry for HLA-G and HLA-E and isotype-matched control antibodies. Staining was analysed by light microscopy and digital image analysis. In both recurrent miscarriage and normal pregnancy, HLA-G was localised to the extravillous trophoblast. There was no difference in the pattern of HLA-G expression between women with recurrent miscarriage and those with normal pregnancies. HLA-E was localised to the syncytiotrophoblast, villous mesenchymal cells, extravillous trophoblast and several decidual cell types, but staining for HLA-E appeared to be confined primarily to the cytoplasm. There was no difference in the pattern of HLA-E expression between women with recurrent miscarriage and those with normal pregnancies.

Recurrent miscarriage: pathophysiology and outcome

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. 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. 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.

An update in recurrent spontaneous abortion

Recurrent spontaneous abortion (RSA) is defined as three or more consecutive pregnancy losses prior to the 20th week of gestation. The etiology of recurrent spontaneous abortion is often unclear and may be multifactorial, with much controversy regarding diagnosis and treatment. Reasonably accepted etiologic causes include, genetics, anatomical, endocrine, placental anomalies, hormonal problems, infection, smoking and alcohol consumption, exposure to environmental factors, psychological trauma and stressful life event, certain coagulation and immunoregulatory protein defects. Detection of an abnormality in any of these areas may result into specific therapeutic measures, with varying degrees of success. However, the majority of cases of RSA remains unexplained and is found to be associated with certain autoimmune (APA, ANA, ACA, ATA, AECA) and alloimmune (APCA, Ab2, MLR-Bf) antibodies that may play major role in the immunologic failure of pregnancy and may lead to abortion. Alteration in the expression of HLA-G molecules, T-helper-1 (Th-1) pattern of cytokines and natural killer (NK) cells activity may also induce abortion. Various forms of treatment like antithrombotic therapies such as aspirin and heparin, intravenous immunoglobulin (IVIg) therapy, immunotherapy with paternal lymphocytes and vitamin D3 therapy are effective mode of treatment for unexplained cause of fetal loss in women with RSA.

Multiple thrombophilic gene mutations rather than specific gene mutations are risk factors for recurrent miscarriage

Recurrent miscarriage is a heterogeneous condition. While the role of acquired thrombophilia has been accepted as an etiology of recurrent miscarriage, the contribution of specific inherited thrombophilic genes to this disorder has remained controversial. We compared the prevalence of 10 thrombophilic gene mutations in 75 patients with a history of recurrent miscarriages with 14 fertile control women.

CD83 +Dendritic Cells in the Decidua of Women with Recurrent Miscarriage and Normal Pregnancy

Immunological factors have been postulated to play a role in the aetiology of recurrent miscarriage as the fetus and placenta are semi-allogenic to the mother. Potent immunostimulatory (CD83 +) dendritic cells have recently been identified in the uterine decidua. This study was conducted to examine whether decidual dendritic cells could play a role in the aetiology of recurrent miscarriage. First trimester placental and decidual biopsies were obtained from 40 women with recurrent miscarriage and 15 gestation-matched normal controls. These biopsies were screened by immunohistochemistry for CD83 +cells. Staining was analysed by light microscopy and digital image analysis. In both recurrent miscarriage and normal pregnancy, CD83 +dendritic cells were localized to the decidua. Individual dendritic cells were present in the decidual stroma or in clusters of 3–4 dendritic cells, in lymphoid aggregates. There were no significant differences in decidual CD83 +dendritic cell density between women with recurrent miscarriage and normal pregnancy when the groups were compared as a whole. However, when segregated by gestational age, decidua from women with recurrent miscarriage at 8 weeks' gestation contained significantly more dendritic cells than gestational age-matched normal controls. This suggests dendritic cells may play a role in the aetiology of some cases of recurrent miscarriage.

The level of preconceptional peripheral blood natural killer cells which expected a successful treatment outcome using low-dose intravenous gamma immunoglobulin (IVIg) infusion in patients with recurrent spontaneous abortion

Objective: Recurrent spontaneous abortion (RSA) occurs in 1–2% of the child bearing population. In the vast majority of cases, the etiology of RSA is unknown and several hypotheses have been made on the basis of available of data. Several studies have been reported that women with RSA manifest an abnormal cellular immune response with marked increase in peripheral blood NK cells with CD56+. Intravenous gamma immunoglobulin (IVIg) infusion is largely used as an effective means for treatment of some immune-related disease. And, some authors reported that elevated peripheral blood natural killer cells are effectively down regulated by IVIg infusion in women with RSA. In this study, we compared the preconceptional peripheral blood NK cells level in successful treatment outcome with that of the treatment failure group and evaluated the level of peripheral NK cells which was expected to successful treatment outcome using our low dose IVIG treatment protocol in patients with RSA.

Immunogenetic determinants in recurrent miscarriage – evidence from genetic‐epidemiological research

Immunological disturbances probably play a major role in the etiology of recurrent miscarriage (RM) – however, a detailed insight in the immunological processes going on is difficult because the most important interactions take place locally in the uterus during pregnancy at the feto–maternal interface. The study of the role of the impact of polymorphic immunogenetic determinants in RM has advantages compared to the study of humoral or cellular immunological factors locally or systemically: genetic polymorphisms can be determined unambiguously using DNA technology, polymorphisms associated with RM are expected to influence immunological processes also locally in the uterus and the finding of an increased prevalence of specific immunogenetic polymorphisms in RM cannot be deduced as a result of RM but may be a cause of the syndrome.We have investigated polymorphisms in the genes coding for HLA‐DR, HLA‐DQ, HLA‐G and mannan‐binding lectin (MBL) in patients with RM and in controls and investigated the impact of RM‐associated polymorphisms on the outcome of future pregnancies. Furthermore, we have investigated the impact of the gender of the first child on future pregnancy outcome in patients with secondary RM.The case–control studies and the prospective studies provide evidence that specific maternal class II HLA alleles or genotypes, specific combinations of HLA‐G alleles in the RM couples, genes coding for low MBL concentrations and male‐specific minor histocompatibility antigens (HY‐antigens) play a role in the pathogenesis of RM.

VEGF, its receptors and the tie receptors in recurrent miscarriage.

The aetiology of recurrent miscarriage (at least three consecutive miscarriages) usually remains unsolved. The vascular endothelial growth factor (VEGF) family of proteins, together with their receptors and the Tie (tyrosine kinase with immunoglobulin and epidermal growth factor homology domains) receptors, are crucial for embryonic development. Therefore, we used immunohistochemistry to analyse the expression of VEGF, the VEGF receptors (VEGFR)-1, -2, and -3, and the Tie-1 and Tie-2 receptors in placental and decidual tissue of women with a history of recurrent miscarriage and missed abortion (MA; n = 12) or blighted ovum (BO; n = 6), and from normal early terminated pregnancies (n = 12). Compared with controls, the MA and BO groups showed: (i) diminished placental trophoblastic VEGF immunoreactivity; (ii) weaker VEGFR-1 and -2 immunoreactivity in decidual vascular endothelium; (iii) reduced placental trophoblastic Tie-1 receptor immunoreactivity; and (iv) reduced decidual vascular endothelial Tie-1 and -2 receptor immunoreactivity. The absence of VEGFR-3 immunoreactivity in decidual vascular endothelium was also noted in all study groups. Interestingly, placental villi from the BO group presented blood vessel-like structures negative for von Willebrand factor, but positive for VEGF, VEGFR-1, -2, -3, Tie-1 and Tie-2 receptor. We conclude that the expression of these antigens may be altered in recurrent miscarriages.

X chromosome defects as an etiology of recurrent spontaneous abortion.

Recurrent spontaneous abortion is a significant problem in women's health, yet it remains a poorly understood phenomenon. Many cases of recurrent spontaneous abortion defy diagnosis, and we predict that a subset of these unexplained cases are caused by previously unknown, recessively inherited genetic causes. Here, we provide background on known genetic factors that contribute to spontaneous abortion and describe a novel X chromosome-based genetic mechanism that may be an important cause of recurrent spontaneous abortion. Recessively inherited defects on the human X chromosome would cause no symptoms in carrier females but would be lethal in utero to male conceptions that receive the defective X. Through investigation of the basic biology of the X chromosome, we propose that the female carriers of such traits can be identified through the molecular finding of skewed X chromosome inactivation. Furthermore, we have observed an association between skewed X chromosome inactivation and recurrent pregnancy loss, supporting the hypothesis that X chromosome defects may be an important, previously unknown cause of recurrent pregnancy loss.

Association of reduced selenium status in the aetiology of recurrent miscarriage.

To determine whether recurrent miscarriage is associated with reduced selenium status. Case-control study. Department of Obstetrics and Gynaecology, Glasgow Royal Infirmary and Glasgow Royal Maternity Hospital. Twenty nonpregnant women with a history of unexplained recurrent miscarriage, and 47 nonpregnant parous women with a history of at least one successful pregnancy and no more than one miscarriage. A 7 mL blood sample from each woman was collected into lithium heparin 'vacutainer' tubes. Samples were centrifuged at 3000 g for 15 minutes, and plasma was extracted and stored at -20 degrees C. Selenium concentrations were measured using a fluorescence spectrophotometer. The selenium concentrations in the two groups were compared and the differences examined using the Student's t test. Plasma selenium concentration (microg/L). The mean selenium concentration for women with a history of unexplained recurrent miscarriage was 67.7 microg/L (SD 16.4). The selenium level for the women with no history of recurrent miscarriage was 70.3 microg/L (SD 12.7). There was no difference in selenium concentrations between the two groups (P = 0.53). In this study there is no association between unexplained recurrent miscarriage and reduced selenium status, implying that reduced selenium status is not a factor in the pathogenesis of recurrent miscarriage. We can find no rationale for a trial of selenium therapy in women with a history of recurrent miscarriage.

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.

Issues in the etiology of recurrent spontaneous abortion

Recurrent spontaneous abortion is seen often. Although many causes of this condition have been identified, there is still a large proportion in which no cause can be found. This review highlights some of the newly described proposed causes. Several reports have linked reproductive inefficiency to hypersecretion of luteinizing hormone (LH) in the follicular phase. It is apparent that the presence of inappropriate elevation of LH, and not the ultrasonographic appearance of polycystic ovaries, is the critical factor in determining the risk of abortion. Consequently, by lowering the LH levels one can expect a better reproductive outcome. This hypothesis awaits testing through clinical trials. The role of ultrasonography in evaluating the luteal phase, by assessing the image of the endometrium, has been studied by many investigators. This non-invasive technique is not yet able to replace the endometrial biopsy. The association between antisperm antibodies in the female serum and recurrent spontaneous abortion requires re-evaluation in light of more recent evidence; however, the role of semen abnormalities, especially severe oligospermia in this disorder, points towards a factor in the male partner that should be identified. Oligomenorrhea has been identified by mathematical modeling as a potential risk factor for recurrent abortion, although the mechanism has not been clearly elucidated. Chromosome heteromorphisms, particularly inv (9)(p11 q12), appear to be associated, more frequently, with recurrent abortion. Similarly, associations were observed with factor-XII deficiency and high titers of immunoglobulin G (IgG) antibody to Chlamydia trachomatis.(ABSTRACT TRUNCATED AT 250 WORDS)

A set of MHC haplotypes found among Finnish couples suffering from recurrent spontaneous abortions.

The role of major histocompatibility complex (MHC) genes in the etiology of recurrent spontaneous abortion (RSA) was studied by analyzing the polymorphism of several, at least 14, immunogenetically important MHC genes either by serological or molecular methods in 56 Finnish RSA couples, and in 29 infants born to these families during the follow-up period of two years after the abortions. The haplotype analysis showed that the RSA couples had significantly increased sharing of MHC fragments, compared to the control families. Furthermore, the MHC risk markers for abortions defined 12 different, extended MHC haplotypes that were found in a significantly higher proportion among persons in the RSA group (45%) than in the controls (11%). However, neither of these observations associated with the reproductive success of the study couples. The results suggest that extended MHC haplotypes, disadvantageous for reproduction, exist in some isolated populations, such as the Finns.