Role In Recurrent Miscarriage Research Articles

Inhibition of BCAT1 expression improves recurrent miscarriage by regulating cellular dysfunction and inflammation of trophoblasts.

Sustained or chronic inflammation in the placenta can result in placental insufficiency, leading to adverse reproductive outcomes such as pregnancy loss. Branched-chain amino acid transaminase 1 (BCAT1) expresses in the placenta and is involved in the pathological inflammatory response, but its role in recurrent miscarriage (RM) has not been fully investigated. In the present study, we delved into the effects of BCAT1 on trophoblast inflammation induced by lipopolysaccharide (LPS) and a mouse model of pregnancy loss induced by LPS. In vitro, after the HTR-8/SVneo cells were treated with LPS and BCATc inhibitor 2 (a selective BCAT inhibitor), the cell apoptosis was verified by TUNEL assay, and the activity of caspase-3 and caspase-9 was detected. Real-time PCR, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence (IF) were used to determine the expression of inflammatory cytokines (TNF-α, IL-6, and IL-1β) and inflammasomes (NLRP3 and ASC) in LPS-treated trophoblast cells. Western blot analysis was performed to verify the expression of phospho-IκBα (p-IκBα) in cells and NF-κB p65 in the nuclei. IF staining was used to detect the nuclear translocation of NF-κB p65. The DNA binding activity of NF-κB was detected by an electrophoretic mobility shift assay (EMSA). The results demonstrated that inhibition of BCAT1 reduced trophoblast apoptosis, suppressed the release of proinflammatory cytokines, and prevented NLRP3 inflammasome activation in response to LPS. Additionally, BCAT1 inhibition blocked the activation of the NF-κB pathway in trophoblasts. This study highlights the potential therapeutic role of targeting BCAT1 in preventing adverse reproductive outcomes associated with chronic placental inflammation.

Inflammation in recurrent miscarriage - a comprehensive perspective from uterine microenvironment and immune cell imbalance to therapeutic strategies.

Recurrent miscarriage, poses a significant challenge for many couples globally, the causes of which are not fully understood. Recent studies have shown the intricate link between uterine inflammation and recurrent miscarriages. While inflammation is essential during early pregnancy stages, especially in embryo implantation, an imbalance can lead to miscarriage. Key inflammatory mediators and an imbalance in immune cells can significantly alter and contribute to recurrent miscarriages. Lifestyle factors like smoking and obesity exacerbate inflammatory responses, increasing miscarriage risks. Understanding the interaction between the uterine environment, immune cell imbalances, and recurrent miscarriages is essential for devising effective treatments. This paper presents the latest data on inflammation's role in recurrent miscarriage, emphasizing the significance of diagnosing chronic endometritis and immune imbalances, offering practical recommendations for treatment and diagnosis.

The Association between Histidine-Rich Glycoprotein rs10770 Genotype and Recurrent Miscarriage in Iranian Women.

Recurrent miscarriage (RM) is a significant reproductive concern affecting numerous women globally. Genetic factors are believed to play a crucial role in RM, making the histidine-rich glycoprotein (HRG) gene, a topic of interest due to its potential involvement in angiogenesis. This study is aimed at investigating the association between the HRG rs10770 genotype and RM. Blood samples were collected from a total of 200 women at the beginning of the study. Subsequently, a comparative analysis was conducted between the blood samples of 100 women with a history of RM (case group) and the blood samples of another 100 healthy women (control group). HRG rs10770 genotyping was performed through polymerase chain reaction restriction-fragment length polymorphism (PCR-RFLP), followed by statistical analysis to evaluate the relationship between HRG rs10770 genotype and RM. The results indicated a significant statistical difference between the C/C genotype (OR = 3.32, CI: 1.22-9.04, p = 0.01) and the C/T genotype (OR = 1.24, CI: 0.67-2.30, p = 0.47) in both the case and control groups. Additionally, a significant correlation was observed in the C allelic frequency among RM participants compared to the control group (OR = 1.65, CI: 1.06-2.58, p = 0.02). The study highlights the importance of HRG rs10770 in understanding RM, shedding light on its implications for reproductive health. Furthermore, it became evident that women carrying the homozygous C/C genotype exhibited increased susceptibility to the risk of RM.

Role of genetic factors in recurrent miscarriages - A review.

Recurrent miscarriage is classically defined as three or more consecutive pregnancy losses in about 1-5% of couples trying to conceive. However, several researchers have amended this to two or more because of the recent increase in childless miscarriages. Recurrent miscarriage is a clinical challenge for clinicians because there are many possible causes, and diagnostic testing is expensive and time-consuming. Established causes of recurrent miscarriage are antiphospholipid antibodies, uterine anomalies, and abnormal chromosomes in either partner, particularly translocations. Uterine anatomical abnormalities, endocrine abnormalities, infections, immunologic factors, environmental factors, metabolic or hormonal disorders, sperm quality, and maternal and paternal age have each been linked. Among them, the genetic factor plays a significant role in recurrent miscarriage. Approximately 70% of miscarriage conceptions with sporadic spontaneous miscarriage reveal some chromosome abnormality. Specifically, recurrent miscarriage can be caused by a structural or numerical defect in the parents' or fetus' chromosomes. Recurrent miscarriage has been linked to several genes, including those involved in oxidative stress, angiogenesis, clotting, and inflammation. Despite several well-known etiologic factors, the etiology of recurrent miscarriage is unknown in over half of all instances. The current review aims to analyse the role of the genetic basis of recurrent miscarriages.

The Circ-CYP24A1-miR-224-PRLR Axis Impairs Cell Proliferation and Apoptosis in Recurrent Miscarriage.

AimRecurrent miscarriage (RM) is associated with numerous clinical factors. However, some RM occurred without specific factors. It has been revealed that some molecules such as hormones, miRNAs, and transcription factors are involved in RM by regulating proliferation, apoptosis, etc. However, the mechanism of RM has yet to be identified clearly. Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs that often act as sponges for miRNAs or binds to proteins involved in biological processes. However, the functional role of circRNAs in the uterine decidua of patients with early RM is still unclear. In this study, we aimed to investigate the mechanisms of circ-CYP24A1 in RM.MethodsThe Dual-Luciferase Activity Assay was designed to analyze the bonding between circ-CYP24A1 and miR-224, and miR-224 and prolactin receptor (PRLR) mRNA 3′UTR. In situ hybridization (ISH) and immunohistochemistry (IHC) were used to observe the expression of circ-CYP24A1 and PRLR in the decidua. Rescue experiments were performed to investigate the regulating effects of circ-CYP24A1, miR-224, and PRLR. Western blotting was conducted to test the expression level of PRLR. The proliferation and apoptosis-related markers in Ishikawa cells were analyzed using CCK8, immunofluorescence staining, and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay.ResultsIn this study, based on the microarray analysis data, we identified a high level of circ-CYP24A1 and PRLR in the decidua of patients with early RM. Based on the bioinformatics prediction, the binding relationship between circ-CYP24A1 and miR-224, as well as miR-224 and PRLR, were verified. Functional experiments demonstrated that circ-CYP24A1 regulated proliferation and apoptosis by binding to and inhibiting miR-224, resulting in increased PRLR expression. Taken together, this study provides new insights into the mechanism of RM.ConclusionIn this study, we found that circ-CYP24A1 plays a role in RM by impairing the balance of cell proliferation and apoptosis by sponging miR-224, thereby regulating PRLR.

Evaluation of the role of CD56 cells in unexplained recurrent spontaneous abortion

Objective: To determine whether peripheral natural killer (NK) cells play a role in recurrent miscarriage by evaluating the percentage of these cells using flow cytometry and comparing it with the percentages in normal multiparous women and women who experienced miscarriage only once. Methods: This case-control study was carried out on a total of 108 women. The study participants consisted of two groups of cases: unexplained recurrent miscarriage cases (n=36) and explained recurrent miscarriage cases (n=36). Additionally, a control group of normal multiparous women or women with only one previous miscarriage (n=36) was included. Detailed clinical assessments, laboratory investigations, and flow cytometry analysis were conducted to collect relevant data. Flow cytometry was used to determine the percentage of CD56+ NK cells in peripheral blood samples. Results: The mean age of the participants ranged from 26.72 to 28.33 years, with no significant difference among the three groups. Parity showed a statistically significant difference, with a higher proportion of nulliparous women in the unexplained abortion group. The number of previous abortions did not differ significantly between the unexplained and explained groups. Among the causes of abortion, endocrine and immunological factors were prominent.

The Prevalence and Impact of Polycystic Ovary Syndrome in Recurrent Miscarriage: A Retrospective Cohort Study and Meta-Analysis

Background: The use of different definitions and diagnostic approaches of polycystic ovary syndrome (PCOS) and recurrent miscarriage (RM) has led to a wide range of prevalence rates in the literature. Despite the persistent controversy about the factual prevalence of PCOS in RM, a vast number of studies have revealed evidence about their association with each other. The goals of this study were to evaluate the prevalence of polycystic ovarian morphology and PCOS within the RM population, performing meta-analyses with the obtained data from this study, together with previous reports on this topic and evaluating reproductive outcome in women with RM and PCOS. Methods: A retrospective cohort study with 452 women with RM and a meta-analysis were conducted. The main outcome parameter was the prevalence of PCOS in RM patients. Results: In the retrospective study, the prevalence of PCOS in RM was 9.5%. Negative results for the selected risk factors for RM were present in 283 patients (62.6%). From all evaluated possible underlying causes for RM, only the presence of thrombophilic disorders was significantly associated with PCOS (PCOS: 20.9% versus no PCOS: 7.8%, p = 0.010). In the meta-analysis of three studies on PCOS in RM patients, which used the revised Rotterdam criteria for defining PCOS, an estimated pooled prevalence of 14.3% (95% CI: 6.2–24.9) was found. In the retrospective data set, women in the PCOS group revealed significantly higher luteinizing hormone (LH), testosterone, and Anti-Mullerian hormone (AMH) levels than age- and body mass index (BMI)-matched controls with RM negative for the selected risk facotrs (p < 0.05). The rate of further miscarriages was significantly higher in PCOS women than in controls (71.4% versus 53.6%, respectively; p = 0.031). Conclusions: The prevalence of PCOS seems slightly increased in women with RM. Women with PCOS suffering from RM showed a significantly higher risk for further miscarriage and decreased chances of having a life birth of about 18% which did not reach statistical significance. Therefore, we assume that PCOS plays a moderate role in RM.

FasL on decidual macrophages mediates trophoblast apoptosis: A potential cause of recurrent miscarriage.

Macrophages can induce Fas ligand (FasL)-mediated apoptosis, and the deregulation of apoptosis is known to be associated with recurrent miscarriage (RM). The aim of the present study was to investigate the possible involvement of FasL in macrophage-mediated trophoblast apoptosis and its potential role in RM. Human decidual and placental villous tissues were collected from 81 women (21 for the RM group, 26 for the spontaneous abortion group and 34 for the control group) at 7-9 weeks of gestation. The distribution changes of macrophages and the expression of FasL on macrophages were evaluated by immunohistochemical, immunofluorescence and western blot analyses. A macrophage and trophoblast co-culture model was used to determine the effects of FasL on the apoptosis of trophoblasts. The results indicated that CD86+ macrophage populations in decidual tissues were significantly increased, accompanied by reduced CD163+ macrophages in the abortion and RM groups. Furthermore, the distribution of CD68+ macrophages was also significantly altered in specimens from the abortion and RM groups, and they were observed to have infiltrated into the trophoblast cells. In addition, elevated expression of FasL on CD68+ and CD86+ macrophages in the decidua was observed in the spontaneous abortion and RM groups of patients, and FasL was demonstrated to mediate the induction of trophoblast apoptosis by macrophages in co-culture. These results indicate that the aberration of macrophage-induced FasL-mediated apoptosis may represent one of the causes of RM.

Expression of ERK and Akt proteins in women with unexplained first-trimester recurrent miscarriage

Abstract Objective: Recurrent miscarriage (RM) is one of the most common clinical problems in reproduction. The aims of the current study were to evaluate the expression of ERK and Akt proteins in human trophoblastic tissue and to assess the significance of MAPK and PI3K-Akt signal pathways in the progression of unexplained recurrent miscarriage. Study design: A case-control study. Setting: Women Health Hospital, Assiut, Egypt. Materials and methods: All pregnant women presented with first-trimester inevitable miscarriage with a history of RM, defined as three or more spontaneous consecutive first-trimester miscarriages before 12 weeks’ gestation, were included in the study (RM group). Age-matched healthy women who had at least one normal pregnancy with no history of miscarriage were included as a control group at the time of delivery. A sample of trophoblastic tissue was taken for Western blot test to evaluate the level of phospho-ERK and Akt (active forms) proteins in trophoblastic tissue. Results: The study included 20 women in each group. There were non-significant differences between both groups as regards maternal age, BMI, passive smoking and family residence. There were significantly lower levels of p-ERK and p-Akt in the RM group as compared to the control group ( p = 0.001). Conclusion: The activation of ERK and Akt pathway plays a significant role in RM. The data suggest that decreased expression of p-ERK and p-Akt occurs less frequently during RM may play a role in this process. This suggests that p-ERK and p-Akt may be markers of RM.

The Effects of Intravenous Immunoglobulins in Women with Recurrent Miscarriages: A Systematic Review of Randomised Trials with Meta-Analyses and Trial Sequential Analyses Including Individual Patient Data.

BackgroundImmunological disturbances are hypothesised to play a role in recurrent miscarriage (RM) and therefore intravenous immunoglubulins (IVIg) have been tested in RM patients.ObjectivesThe objectives were to investigate the benefits and harms of IVIg versus placebo, no intervention, or treatment as usual in women with RM.Search StrategyWe searched the published literature in all relevant databases.Selection CriteriaRandomised trials investigating IVIg versus placebo, no intervention, or treatment as usual in women with RM.Data Collection and AnalysisWe undertook meta-analyses of aggregated data and individual patient data using a two-step approach, and we conducted bias domain assessments and trial sequential analyses to assess the risks of systematic and random errors.Main ResultsWe identified 11 randomised clinical trials. No significant difference in the frequency of no live birth was found when IVIg was compared with placebo or treatment as usual (RR 0.92, 95% CI 0.75–1.12, p = 0.42). Trial sequential analysis showed that the required information size of 1,008 participants was not obtained. IVIg compared with placebo seems to increase the risk of adverse events. Subgroup analysis suggests that women with RM after a birth (secondary RM) seemed most likely to obtain a potential beneficial effect of IVIg (RR for no live birth 0.77, 95%CI 0.58–1.02, p = 0.06), however, trial sequential analysis showed that insufficient information is presently accrued.ConclusionWe cannot recommend or refute IVIg in women with RM. IVIg should therefore be assessed in further randomised clinical trials with positive outcomes before any clinical use is considered.

The effects of immunotherapy with intravenous immunoglobulins versus no intervention, placebo, or usual care in patients with recurrent miscarriages: a protocol for a systematic review with meta-analyses, trial sequential analyses, and individual patient data meta-analyses of randomised clinical trials.

BackgroundRecurrent miscarriage is generally defined as three or more miscarriages before gestational week 20. Recurrent miscarriage affects 1% of all women and the condition can only be explained by parental chromosome abnormalities, uterine malformations, or endocrine or thrombophilic disturbances to a limited extent. Immunological disturbances are hypothesised to play an important role in recurrent miscarriage and, therefore, various types of immunologically-based therapies have been tested in recurrent miscarriage patients including intravenous immunoglobulins. So far, at least eight randomised placebo-controlled trials, with opposing results, investigating intravenous immunoglobulins with a total of 324 recurrent miscarriage patients have been published.Methods/DesignWe will include randomised clinical trials irrespective of publication date, publication type, publication language, and publication status investigating infusions with immunoglobulins in relation to pregnancy compared to placebo, no intervention, or treatment as usual for assessments of benefits and harms. The relevant published literature will be searched using the following databases: Cochrane Central Register of Controlled Trials, Medline, Embase, WHO International Clinical Trials Registry Platform, and Ovid Medline In-Process and Other Non-Indexed Citations databases. Two review authors will independently extract data and assess risk of bias. We will undertake meta-analyses according to the recommendations stated in the Cochrane Handbook for Systematic Reviews of Interventions. Further, we will conduct trial sequential analyses and individual patient data meta-analyses.DiscussionA miscarriage results in great sorrow, loss of life quality, and personal concern. In particular, recurrent miscarriage is extremely stressful and burdensome. It is, therefore, very important to conduct research in this area. There is currently no evidence-based treatment for women with recurrent miscarriage which significantly improves their ability to give live birth. Therefore, a comprehensive up-to-date systematic review is needed. By using individual patient data, it will be possible to provide new knowledge about the benefits and harms of intravenous immunoglobulins and try to identify the subgroup in which the treatment will have the highest impact.This systematic review protocol was registered within the International Prospective Register of Systematic Reviews (PROSPERO) as number CRD42014007112.

Assessment of sperm antigen specific T regulatory cells in women with recurrent miscarriage

Background and aimsThe prevalence of recurrent miscarriage (RM) is about 1–3% of women; the pathogenesis of RM is not fully understood yet. This study aims to assess the sperm antigen specific regulatory T cells (Treg) in women with RM. MethodsA group of women with RM was recruited into this study. The sperm antigen was extracted from the semen samples of each woman's husband. The sperm antigen specific T cell response was assessed by flow cytometry. ResultsLow frequency of sperm specific Tregs and high frequency of T helper (Th)1 cells were detected in RM women as compared with women without RM. The sperm specific Tregs in RM women expressed less Ubc13. Knockdown of Ubc13 from Tregs converted the Tregs to effector T cells. ConclusionsImmune deregulation may play an important role in RM.

Soluble TRAIL is elevated in recurrent miscarriage and inhibits the in vitro adhesion and migration of HTR8 trophoblastic cells

What is the potential physiopathological role of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in recurrent miscarriage (RM), characterized by at least three consecutive pregnancy losses. The levels of serum TRAIL immediately after miscarriage in RM patients are significantly elevated with respect to that in first-trimester normal pregnant women, and recombinant TRAIL inhibits the adhesion and migration of HTR8 trophoblastic cells in vitro. Both TRAIL and its trans-membrane receptors (TRAIL-R1, TRAIL-R2, TRAIL-R3and TRAIL-R4) have been documented in the placenta, but their physiopathological role is incompletely understood. The study populations consisted of RM patients (n = 80) and first-trimester normal pregnant women (n = 80). Blood samples were obtained within 24 h after abortion (RM) or at gestational 12-week (normal pregnant women). As additional controls, third-trimester normal pregnant women (n = 28) were examined before (within 72 h) and after (within 24 h) partum. The concentrations of TRAIL were analysed in serum samples by ELISA. In parallel, the effect of soluble recombinant TRAIL (0.1-1000 ng/ml) was analysed on the survival of primary extravillus trophoblasts (EVTs) and on the survival, proliferation, adhesion and migration of trophoblastic HTR8 cells. The circulating levels of TRAIL in RM women (median: 52.5 pg/ml; mean and SD: 55.5 ± 24.4 pg/ml) were significantly higher with respect to first-trimester normal pregnant women (median: 44.9 pg/ml; mean and SD: 47 ± 15.1 pg/ml) and third-trimester normal pregnant women, as assessed before (median: 45.1 pg/ml; mean and SD: 46 ± 12.4 pg/ml) and after partum (median: 35.4 pg/ml; mean and SD: 38 + 17.5 pg/ml). Both primary EVT and HTR8 cells expressed detectable levels of TRAIL death receptors, but exposure to soluble recombinant TRAIL did not induce cell death of trophoblastic cells. On the other hand, TRAIL dose-dependently inhibited the adhesion of HTR8 cells to decidual endothelial cells (DEC) as well as the migration of HTR8 in transwell assays using either fibronectin or DEC. Although this study suggests that TRAIL might have a pathogenic role in RM by inhibiting both the adhesion and migration capabilities of first trimester trophoblastic cells, there is a possibility that the elevated serum levels of TRAIL in RM are not cause but rather the result of RM. Our current findings together with data of other authors suggest that circulating TRAIL should be further analysed as a potential important biomarker in different physiopathological settings. This study was funded by FIRB projects (RBAP11Z4Z9_002 to Giorgio Zauli and RBAP10447J_002 to Paola Secchiero). The authors have no competing interests to declare.

The involvement of inflammatory cytokines in the pathogenesis of recurrent miscarriage

ObjectiveTo investigate the inflammatory cytokine expression pattern in trophoblastic tissue from women with unexplained recurrent miscarriage (RM). Study designTrophoblasts were obtained during uterine evacuation from 11 women with RM and from 20 healthy pregnant women undergoing elective termination of pregnancy, who served as controls. The array was performed using GEArray Q Series Human Inflammatory Cytokines & Receptors Gene Array HS-015 membranes. Data were confirmed by quantitative real-time PCR. The Mann–Whitney U test was performed for statistical analysis. ResultsMicroarray analysis identified three genes that were differentially expressed between RM patients and controls. We observed significant downregulation of Transforming Growth Factor beta 3 (TGF-β3) and Interleukin 25 (IL-25) (5-fold reduction and 2.5-fold reduction, respectively) and significant upregulation of CD-25, also known as Interleukin 2 receptor alpha (IL-2RA) (7-fold increase) in women with RM compared with controls.The median ΔCt of TGF-β3 was 8.2 (interquartile range, 7.67–8.9) in RM patients vs. 5.85 (interquartile range, 5.3–6.09) in controls; the median ΔCt of IL-25 was 5.18 (interquartile range, 4.46–5.76) in RM patients vs. 3.85 (interquartile range, 3.6–4.51) in controls, and the median ΔCt of CD-25 was 9.62 (interquartile range, 7.81–12.42) in RM patients vs. 12.44 (interquartile range, 11.02–13.86) in controls. DiscussionOur results suggest that the immunological and inflammatory regulation mechanisms of the placental environment play a key role in recurrent miscarriage. The observed trophoblast cytokine expression pattern at the maternal–fetal interface confirms the immunotrophic theory, as demonstrated by a switch from a T-helper-1 (Th1) profile to a T-helper-2 (Th2) profile in women who experience recurrent miscarriages.

Thyroid Autoimmunity and Recurrent Miscarriage

To investigate the role of antithyroid autoantibodies (ATA) in recurrent miscarriage (RM). In this case-control study, a total of 160 women with RM and 100 healthy women were investigated for the presence of serum ATA directed against thyreoglobulin (TG-Ab), thyroid peroxidase (TPO-Ab) and TSH receptor (TSHr-Ab), which were determined by either chemiluminescence or radioimmunoassay. Antithyroid autoantibodies were detected in 46 (28.75%) women with RM and in 13 (13%) women of the control group (P < 0.05). The frequencies for TG-Ab and TPO-Ab were higher in RM than in control women. Among the women of RM group, 91.3% of ATA+ women were positive also for other autoantibodies. The majority of study women were euthyroid. Antithyroid autoantibodies, particularly TG-Ab, are associated with RM and could be an expression of a more general maternal immune system abnormality leading to RM. ATA could have a role in RM irrespective of thyroid hormone status.

The presence of HLA-antibodies in recurrent miscarriage patients is associated with a reduced chance of a live birth

Anti-paternal HLA-antibodies are considered a harmless phenomenon during most pregnancies, whereas their role in recurrent miscarriage (RM) patients is disputed. In contrast to primary RM, patients with secondary RM have carried a fetus to term pregnancy prior to a series of miscarriages, which increases the chance that allogeneic fetal cells appear in the maternal circulation. This study investigates the frequency of HLA-antibodies in secondary RM, primary RM patients and parous controls and analyzes whether the presence of HLA-antibodies in early pregnancy is associated with pregnancy outcome. Sera from women with secondary RM (n=56), primary RM (n=13) and parous controls (n=24) were tested for HLA-antibodies using an ELISA assay and complement dependent cytotoxicity. Samples were taken at gestational week 4-5 in 62 (90%) of the patients. HLA-antibodies were significantly more frequent in secondary RM patients with a boy prior to the miscarriages (62%) compared to secondary RM patients with a firstborn girl (29%, p=0.03), primary RM patients (23%, p=0.02) and parous controls (25%, p=0.005). Forty-one percent of HLA-antibody positive pregnant RM patients had a live birth compared to 76% of HLA-antibody negative RM patients, p=0.006 (adjusted OR: 0.22 (0.07-0.68), p=0.008). In conclusion, HLA-antibodies are significantly more frequent in secondary RM patients with a firstborn boy than in other RM patients and controls. The presence of these antibodies in early pregnancy is associated with a reduced chance of a live birth. Further exploring this association may increase our understanding of maternal acceptance of the fetal allograft.

The impact of anti-HY responses on outcome in current and subsequent pregnancies of patients with recurrent pregnancy losses

Women pregnant with a male fetus often generate cellular and humoral immune responses against male-specific minor histocompatibility (HY) antigens-however, the importance of these responses for pregnancy outcome is unclear. Epidemiologic studies have shown that the birth of a boy compared with a girl prior to a series of miscarriages significantly reduces the chance of a subsequent live birth and pregnancies with boys have an increased risk of placental abruption. This paper aims to review the current knowledge about the impact of anti-HY immunity on pregnancy outcome in terms of miscarriage and placental abruption. Our knowledge primarily comes from studies of the impact on pregnancy outcome of HLA class II alleles known to restrict CD4 T cell mediated anti-HY responses among 358 secondary recurrent miscarriage (SRM) patients and 203 of their children born prior to the miscarriages and investigation of these HLA alleles in 8 patients with recurrent severe placental abruptions. The chance of a subsequent live birth in SRM patients with firstborn boys compared to firstborn girls was significantly lower in women with HY-restricting HLA class II alleles [OR: 0.17 (0.1-0.4), p=0.0001]. Most patients with recurrent placental abruptions had firstborn boys and significantly more of these patients carried HLA haplotypes with HY-restricting class II alleles compared with controls (p=0.009). These findings are strongly indicative of aberrant maternal immune reactions against fetal HY antigens playing a role in recurrent miscarriage and placental abruption. We propose pathogenetic pathways for these conditions that in our view best explain the findings.

Thyroid antibody titer and avidity in patients with recurrent miscarriage

Objective: To determine whether the titer and avidity of the thyroid peroxidase antibody differs between pregnant women in their first trimester who have a history of recurrent miscarriage and whose pregnancies continue to term and those whose pregnancies fail again later in the first trimester. Design: Controlled clinical study. Setting: Healthy volunteers in an academic research environment. Patient(s): Pregnant women in their first trimester who had a history of recurrent miscarriage (≥3 miscarriages) and who were known to be positive for the thyroid peroxidase antibody. Intervention(s): None of the patients received any medication. Main Outcome Measure(s): Thyroid peroxidase antibody titer and avidity (i.e., the net binding strength between antibody and antigen). Result(s): At the time of presentation, thyroid peroxidase antibody titer and avidity was significantly higher in those women who later miscarried compared with those whose pregnancies continued. In those whose pregnancies continued to term, titer and avidity declined as the pregnancy progressed. Conclusion(s): Autoimmunity plays a role in recurrent miscarriage. Among a group of patients who had had recurrent miscarriages, there appeared to be differences in the humoral response to the pregnancy between those whose pregnancies continued to term and those whose pregnancies failed again.

Is the expression of classical HLA class I antigens on trophoblast of importance for human pregnancy?

Human leukocyte antigen (HLA)-C and possibly also HLA-B seem to be expressed on the extravillous trophoblast. These antigens carry epitopes that function as ligands for natural killer (NK)-cell-inhibitory receptors. Antitrophoblast cytotoxicity mediated by decidual NK cells might be involved in miscarriage. We thus found it relevant to elucidate whether parental HLA-C and -Bw polymorphism play a role in recurrent miscarriage (RM). HLA-C and -Bw investigations by DNA-based techniques were undertaken in 35 couples with unexplained RM and in 30 couples with normal fecundity. The number of HLA-C- and -Bw-related supertypic specificities that can bind NK-cell-inhibitory receptors was evaluated in selected couples. The proportions of couples with RM and control couples carrying four HLA-C alleles with the same NK-cell-inhibitory supertypic specificities were equal. In 46% of studied couples with RM, all four HLA-B alleles carried the HLA-Bw6 supertypic specificity, which was significantly higher than the corresponding frequency (17%) in the control couples (P < 0.02). The expression of polymorphic HLA-C on trophoblasts does not seem to play a role in RM. Assuming that HLA-B is expressed on trophoblasts, we may suggest that the revealed predominance of HLA-Bw6 expression (which excludes the presence of HLA-Bw4-protective antigens) may predispose a particular couple to the RM phenomenon.