Recurrent Fetal Loss Research Articles

Proteomics of Serum Samples for the Exploration of the Pathological Mechanism of Obstetric Antiphospholipid Syndrome.

Obstetric antiphospholipid syndrome (OAPS) is a multisystem disorder characterized by thrombosis or recurrent fetal loss. In this study, we aim to explore the pathological mechanism of OAPS. Herein, we carried out data-independent acquisition (DIA) mass spectrometry quantitative proteomic analysis of serum samples from OAPS patients and healthy controls. A set of 93 differentially expressed proteins was identified, including 75 upregulated and 18 downregulated proteins compared with the levels in controls. Those proteins are enriched in KEGG pathways related to autoimmune diseases, allergic diseases, and pathogen infection. Interestingly, metabolic pathways such as fatty acid degradation and type I diabetes were enriched, indicating that OAPS is metabolic disease related. The significantly increased triglyceride also supported this idea. The differentially expressed proteins insulin-like growth factor-binding protein-1 (IGFBP-1), C-reactive protein (CRP), and ferritin light chain (FTL) were validated by ELISA. Our study presented a deep serum proteomics of OAPS and advanced our understanding of OAPS pathogenesis.

Unmet Needs of Immune Thrombotic Thrombocytopenic Purpura (iTTP)-Specific Pregnancy Counseling, Care and Outcomes in Women with Ittp

Unmet needs of iTTP-specific pregnancy counseling, care and outcomes in women with iTTP INTRODUCTION: Pregnancy is a known trigger for an initial episode or relapse of immune thrombotic thrombocytopenic purpura (iTTP) and outcomes of pregnancy in women with iTTP have historically been suboptimal with high rates of recurrent iTTP, fetal loss, preeclampsia and HELLP syndrome. More recent data suggest that prophylactic immunosuppression to normalize ADAMTS13 levels before conception, and ADAMTS13 monitoring and prophylactic steroids or plasma exchange during pregnancy can improve maternal and fetal outcomes. However, it is not clear whether women with iTTP are routinely counseled regarding these options. We conducted this study to understand the experiences of women with iTTP with reproductive healthcare, how iTTP has impacted their reproductive decisions, and outcomes of pregnancy. METHODS: We developed a web-based (RedCap) survey focused on the reproductive healthcare experiences of women with iTTP with in three major sections: (1) counseling and education around pregnancy that was provided to them, (2) the impact of iTTP on their reproductive decisions, and (3) outcomes of any pregnancies they had experienced. The survey was distributed through social media and email mailing lists of a patient advocacy organization and was kept open for one month (January 2023). Survey data were summarized using counts and percentages. The focus of the analysis was to identify gaps in patient education and care where efforts could be focused on educating clinicians or providing information to patients though patient advocacy groups. RESULTS: Seventy-five females with iTTP responded to the survey. The median age of the respondents was 44 years (range 23 - 65). Sixty-five (74.7%) identified as White, 13 (14.9%) as Black, 6 (6.9%) as Asian and 3 (3.4%) identified as other/prefer not to say. Nearly all (94.6%) were followed by a hematologist or hematologist-oncologist and 82.9% reported being monitored regularly for iTTP. Only 26.7% (20 of 75) reported that their doctor talked to them about measures that may help achieve a successful pregnancy. These included ADAMTS13 monitoring (n=15), plasma exchange treatments (n=10), rituximab (n=10), and aspirin (n=3) (options are not mutually exclusive so total is > 20). Moreover, 30.0% (21 of 70) reported that they were advised by their doctor to not get pregnant due to their iTTP. Some patients (36.0%) avoided pregnancy out of fear of the consequences of iTTP and 28.4% (21 of 74) responded that their iTTP diagnosis has affected their ability to get into a relationship, which impacts their quality of life (Figure 1). Fifty-three patients reported that they had had at least one pregnancy. Of these, 35 had pregnancies before iTTP diagnosis, 10 with the initial presentation of iTTP, and 8 women had a total of 11 pregnancies following the diagnosis of iTTP. Consistent with prior reports, there was a high rate of maternal and fetal complications in pregnancies that occurred in the setting of a first iTTP episode complicating pregnancy, or pregnancies after an iTTP diagnosis (Table 1). iTTP relapse occurred in 27.3% (3 of 11) pregnancies in women with prior iTTP. Fetal loss occurred in 30% of pregnancies with first TTP diagnosis and 9% of pregnancies after iTTP. In both groups, approximately 20% were small for gestational age. Preeclampsia or HELLP syndrome occurred in 50% and 18.2% of pregnancies complicated by initial TTP diagnosis or after iTTP diagnosis, respectively. CONCLUSION: Though pregnancy in women with iTTP is high risk, close monitoring and prophylactic interventions can improve outcomes. While many women with iTTP are counseled regarding the risks of pregnancy, few receive counseling regarding their options to potentially improve pregnancy outcomes. This limits their reproductive choices and impacts their relationships. Educating clinicians and providing information to patients though patient advocacy groups may help address these healthcare gaps.

Effect of Anti-TNF Biologic Exposure During Pregnancy on Villitis of Unknown Etiology Diagnoses in Patients with Autoimmune Disease.

Tumor necrosis factor-α (TNF-α) antagonists are highly effective in controlling autoimmune diseases. This has led to speculation that they might also be useful in treating inflammatory placental conditions, such as chronic villitis of unknown etiology (VUE). VUE affects 10-15% of term placentas and is associated with recurrent fetal growth restriction (FGR) and pregnancy loss. We aimed to evaluate outcomes in patients with autoimmune diseases with and without anti-TNF-α biologic exposure during gestation. This retrospective cohort study compared pregnant women with autoimmune disease taking anti-TNF-α biologics (n = 89) to pregnant women with autoimmune disease but not taking a biologic (n = 53). We extracted data on all patients meeting our inclusion criteria over a 20-year period. Our primary outcome was the diagnosis of VUE by histology. Our secondary outcomes were maternal and neonatal complications such as preeclampsia, FGR, and neonatal intensive care admission. Kruskal-Wallis and chi-squared tests were performed as appropriate for statistical analysis. Maternal characteristics were comparable between groups, and there was no increase in adverse pregnancy outcomes based on anti-TNF-α treatment. Exposure to anti-TNF-α therapy had no significant effect on the incidence of VUE or other obstetric complications. Within the cohort exposed to anti-TNF-α biologics during pregnancy, the rate of VUE was 9.3%, which is comparable to the reported general population risk. Our data support the safety profile of biologic use in pregnancy.

Cardiovascular risk in rare autoimmune diseases, lessons from a primary antiphospholipid syndrome patients

Abstract Background Antiphospholipid syndrome is a thrombo-inflammatory disease driven by circulating autoantibodies (aPL) that recognize cell surface phospholipids and phospholipid-binding proteins. In the absence of an underlying connective tissue disorder, the persistent presence of these antibodies associated with recurrent fetal losses and arterial or venous thrombosis is defined as a primary antiphospholipid syndrome (PAPS) with a prevalence of 1/2000 people, predominantly female. Purpose Estimation of cardiovascular risk presence based on markers of subclinical cardiovascular impairment. Methods 100 PAPS patients, with an average age of 47.70±13.14y, 93.7% females, were included in the study. Anticardiolipin antibodies (aCL IgG/IgM), anti-ß2 glycoprotein-I (anti-ß2GPI IgG/IgM), and lupus anticoagulant (LAC) were determined. Abnormal cut-off values used for left ventricular diastolic dysfunction (LVDD) were septal E ́<7 cm/sec, lateral E ́ <10 cm/sec, average E/E ́ ratio >14, LA volume index (LAVI) >34 mL/m2, and peak tricuspid regurgitation velocity >2.8 m/sec. LVDD was present if more than half parameters were with abnormal values. Endothelial dysfunction was assessed through ultrasound measurement of brachial artery flow-mediated dilation (FMD) and atherosclerosis progression by ultrasound assessment of intima-media thickness (cIMT) on carotid arteries (common carotid artery, CCA, internal carotid artery, ICA). The results were compared to 90 healthy, age and sex-matched controls. Results LVDD was significantly more prevalent in PAPS patients compared to healthy controls (24.8% vs. 2.2%, p=0.001). FMD was significantly lower in PAPS patients (10.76±5.15% vs. 14.20±6.76%, p=0.0001) and cIMT values were significantly higher (left ICA 0.80±0.29mm vs 0.56±0.20mm, p=0.001). All markers of subclinical atherosclerosis were significantly related to age and standard atherosclerotic risk factors present. Regarding aPL profile, anti-ß2GPI IgG positive PAPS patients had higher levels of cIMT ICA left (p=0.049) and LAC positive higher prevalence of LVDD (p=0.047) CONCLUSIONS: PAPS patients impose significantly higher prevalence of subclinical cardiovascular involvement compare to healthy population. Timely recognition, along with vigorous control of standard atherosclerotic risk factors and a proper therapeutic (antithrombotic and/or anticoagulant) regime, is of great importance.

Comparison of the Nutritional Health Profile of the Pregnant Women and its Association in Developing Anemia: A Progressive Study of the Rich and Poor Pregnant Women of the Ajmer City

Introduction- Anemia in pregnancy is one of the gravest world health crises affecting one fourth of the world population, mainly children and women of the reproductive age. The onset of anemia is attributed to two major classifications being ‘Nutritional’-meaning deficiency of minerals and vitamins, and ‘Non nutritional’ corresponding to infection and hemoglobinopathies. The only micronutrient mandatorily required supplementing to fill the gap between the dietary intake and the demand is iron. Micronutrient’s iron, folate, and vitamins are very vital for the proper growth of the fetus during pregnancy. The diverse consequences of nutritional anemia are recurrent abortion, recurrent fetal loss, congenital abnormalities, preterm labour, reduced birth weight and neonatal and maternal mortalities. Methodology- It’s an empirical, longitudinal, prospective, and comparative study using a structured questionnaire on the target group of the urban population in the city of Ajmer city. Results and Conclusion- Assessing BMI, there were 51.61% of anemic rich pregnant women who were considered malnourished as they belonged to the group with BMI < 18.4 kg/m2 whereas among the poor anemic pregnant women it was 75.87% women under this BMI. Evaluating the poor non-anemic pregnant women, nearly 16.98% of women belonged to BMI < 18.4 kg/m2 category and 8.95% of the rich non-anemic women who had their BMI < 18.4 kg/m2. Among the rich non-anemic pregnant women, there were 37.74% who came under the category of overweight having BMI >23kg/m2 and only 3.77% of poor non-anemic women grouped under over weight. The mean+SD of Hb at third trimester of the rich and poor pregnant women was 10.4+1.02 and 9.0+0.02 respectively.

Association between IgM/IgG Anti-Phospholipids and Miscarriage among Aborted Women in Khartoum State, 2021

Background: Antiphospholipid antibodies (APL) are a heterogeneous group of autoantibodies that are detected in the serum of patients with a variety of conditions, including auto immune diseases, infections, lymphoproliferative disorders, thrombosis, thrombocytopenia and recurrent fetal loss or recurrent miscarriage. Aim: To determined association between IgM/IgG antiphospholipid and miscarriage among aborted women in Khartoum state. Method: A 90 blood samples were collected from 45 aborted women with history of abortion and they sated as case group and 45 healthy women as control. The blood samples were tested for IgM/IgG anti-phospholipid using ELISA technique. Results: The median of IgM anti-Phospholipids was increase significantly (P 0.000) among aborted women (median 26.8) than healthy control (median 7.4), and 80% of aborted women showed positive result and the median of IgG anti-Phospholipids was insignificantly (P 0.923) among aborted women (median 5.9) and healthy control (median 6.2), and 22.2% of aborted women showed positive result. IgM/IgG Anti-phospholipids shows insignificant increase with repeated abortion and age. Conclusion: There was a significant association between IgM antiphospholipid and miscarriage and insignificant of IgG APL.The concentration of IgM/IgG antiphospholipid is insignifiantly increased with age and recurrence of abortion.

Trombosis portal en Síndrome antifosfolipídico: Reporte de caso

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by arterial, venous, or small vessel thrombosis and recurrent early pregnancy loss, fetal loss, or pregnancy morbidity in the context of persistent antiphospholipid antibodies. Characterized by the development of multiple thrombotic manifestations, simultaneously or within a short period of time; being portal vein thrombosis (DVT) a rare and serious clinical manifestation and a predictor of poor prognosis.The case of an elderly patient with abdominal pain and portal vein thrombosis associated with APS with antithrombotic treatment and analgesics of favorable evolution is presented.

Development of venous thromboembolism in an elderly man with plaque psoriasis and antiphospholipid syndrome: A case report

Antiphospholipid syndrome (APS) is a systemic autoimmune disease associated with arterial and venous thromboembolism (VTE) or recurrent fetal loss in individuals carrying antiphospholipid antibodies (aPL). We report a case of a 76-year-old man with plaque psoriasis who presented with VTE and was diagnosed with APS. APS prevalence in patients with psoriasis is currently unknown; our findings suggest that psoriasis patients with VTE may need to be screened for aPL, because the treatment strategy to prevent thrombosis recurrence is different for aPL-positive patients. A 76-year-old Japanese man with a 10-year history of plaque psoriasis presented with the right thigh swelling for 3 days on a routine follow-up. He was overweight (body mass index, 28.3), had a history of hypertension and hepatitis B virus (HBV) infection, and was a current smoker. He spent most of his time in bed since his retirement a year ago. Physical examination showed extensive right thigh swelling and tenderness with purpura (Figure 1A). Laboratory examination revealed a D-dimer level of 13.3 μg/ml (reference range, 0.0–1.0). Therefore, deep venous thrombosis (DVT) was suspected; however, he refused to undergo further testing at that time. A week later, the swelling exacerbated (Figure 1B) and extended to his right toe. He was conscious, afebrile, and reported no shortness of breath. This time, he agreed to undergo imaging studies. Contrast-enhanced computed tomography revealed DVT from the right femoral vein to the inferior vena cava and in the left popliteal vein. Additionally, pulmonary embolism was observed. Thus, the patient was diagnosed with venous thromboembolism (VTE). Serology testing for the underlying clinical conditions of VTE detected lupus anticoagulant (LA, 1.34; reference range, <1.30) and increased anticardiolipin-IgG-antibody (aCL-IgG, 52 U/ml; reference range, <10 U/ml) and anti-β2-glycoprotein I antibody (anti-β2GPI, 14.4 U/ml; reference range, <3.5 U/ml). Consequently, the patient was diagnosed with antiphospholipid syndrome (APS) and was treated with anticoagulants. Repeated testing >12 weeks apart showed LA of 1.87 and increased aCL-IgG (42 U/ml) and anti-β2GPI (20.7 U/ml), meeting the revised Sapporo APS classification criteria.1, 2 His psoriatic lesions were mild (i.e., Psoriasis Area and Severity Index, 5.6) under topical treatments at admission; however, significant recurrence of lesions requiring systemic treatment was noted 9 months after discharge (Figure 1C–D). Because of his advanced age and comorbidities including mild heart failure, HBV infection, and APS, biologics or other oral agents were avoided, and he was treated with apremilast. Four months after the initiation of apremilast, the skin lesions had considerably improved without the recurrence of VTE or other complications (Figure 1E–F). Considering the growing evidence that suggests that patients with psoriasis have an increased risk of VTE, timely recognition, and the management of risk factors for VTE are crucial to prevent thrombotic events. A 1987 study has reported a significant increase of aPL-positive patients with psoriatic arthritis.3 However, a 2008 study has shown that aPL levels were not increased among patients with plaque psoriasis as compared to healthy controls.4 Similar to the case we presented, there is a reported case of a patient with psoriasis and APS developing portal vein thrombosis.5 Additionally, there are several case reports on APS in patients with psoriasis associated with infliximab and adalimumab.6, 7 APS prevalence in patients with psoriasis diagnosed with VTE remains unknown because psoriasis8 and its common comorbidities are well-known risk factors of VTE, which may preclude physicians from screening for aPL. However, when VTE occurs, screening for aPL in these patients is essential because the treatment strategy to prevent the recurrence of thrombosis is different for aPL-positive patients.9 We would like to thank Editage (www.editage.com) for English language editing. The authors declare no conflicts of interest. The patient gave written informed consent to publish his photographs and case details. Approval of research protocol: N/A. Informed Consent: The patient provided written informed consent to publish his photographs and case details. Registry and the Registration No. of the study/trial: N/A. Animal Studies: N/A.

Altered endometrial oestrogen-responsiveness and recurrent reproductive failure.

Graphical abstract Recurrent reproductive failure (RRF) encompasses recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL). These highly prevalent, distressing conditions have many unanswered questions regarding aetiology and management. Oestrogen receptor beta (ERβ) is the predominant oestrogen receptor expressed in the vascular endothelium of the endometrium during the window of implantation (WOI). The establishment of normal endometrial receptivity is integrally associated with progesterone receptor (PR). Therefore, we aimed to investigate whether women with RRF have clinical, type-specific endometrial aberrations of ERβ, PR and Ki-67 expression during the WOI. Thirty-eight endometrial biopsies were collected; 29 RRF (10 RIF, 9 recurrent loss of early pregnancy (RLEP) and 10 recurrent fetal loss (RFL)) and 9 fertile controls (FC). Within RIF, RLEP and RFL groups, the perivascular compartment showed significantly lower levels of ERβ vs FC (P = 0.02, P = 0.03 and P = 0.01, respectively). Vascular endothelium also displayed significantly lower levels of ERβ within RIF and RFL cohorts vs FC (P = 0.03 and P = 0.003). The expression of Ki-67 was significantly lower within vascular endothelium of all RRF; RIF (P = 0.02), RLEP (P = 0.02) and RFL (P <0.01). PR was significantly reduced (P <0.001) in the perivascular area of women with RIF. These findings provide novel insights into biological correlates of clinical subtypes of RRF. The endometrium of women with RRF display significantly altered levels of ERβ, PR and Ki-67 during the WOI, furthering our understanding of the defective endometrial phenotype of women suffering from RRF, with possible impaired glandular function, angiogenesis and decidualisation.Lay summaryRecurrent reproductive failure (RRF) refers to a group of devastating conditions with many unanswered questions regarding their causes and treatment options. The lining of the womb, the endometrium, is primed and suitable for successful embryo implantation for a short time during the menstrual cycle; the window of implantation (WOI). Oestrogen is a key hormone that plays an important role in regulating the endometrium and its effects are exerted via two oestrogen receptor subtypes. Oestrogen receptor beta (ERβ) is the main oestrogen receptor present during the WOI. Progesterone receptor allows the other main hormone, progesterone, to influence the endometrial activity and Ki-67 reflects the proliferative activity of the cells within the endometrium. We investigated the expression of these markers in endometrial samples collected from women with RRF and proven fertility. We found that the endometrium of women with RRF has significantly lower levels of ERβ and Ki-67 during the WOI, possibly leading to unsuccessful pregnancies.

Frequency of Anticardiolipin Antibodies in Women with Recurrent Fetal Loss

Aim: To find out the frequency of Anticardiolipin Antibodies in women with recurrent fetal loss Study design &amp; duration: One year descriptive study Methods: Seventy five females were included in the study with ages ranging from 20-40 years with minimum two miscarriages. Diabetic females and females with history of bacterial or viral diseases were excluded from the study. Results: In this group the mean age was 27.60±3.29 years. Mean number of fetal losses was 2.95±1.45 whereas mean duration of marriage was 5.79±4.11 years. Conclusion: It is suggested that the patient with history of recurrent miscarriages must be screened for Anticardiolipin Antibodies to bring them out of psychological and physical trauma. Keywords: Anticardiolipin Antibodies (aCL), Recurrent fetal loss (RFL), aPTT

Urine Proteomics Differentiate Primary Thrombotic Antiphospholipid Syndrome From Obstetric Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is a multisystem disorder characterized by thrombosis and/or recurrent fetal loss. This clinical phenotype heterogeneity may result in differences in response to treatment and prognosis. In this study, we aimed to identify primary thrombotic APS (TAPS) from primary obstetric APS (OAPS) using urine proteomics as a non-invasive method. Only patients with primary APS were enrolled in this study from 2016 to 2018 at a single clinical center in Shanghai. Urine samples from 15 patients with TAPS, 9 patients with OAPS, and 15 healthy controls (HCs) were collected and analyzed using isobaric tags for relative and absolute quantification (iTRAQ) labeling combined with liquid chromatography-tandem mass spectrometry analysis to identify differentially expressed proteins. Cluster analysis of urine proteomics identified differentiated proteins among the TAPS, OAPS, and HC groups. Urinary proteins were enriched in cytokine and cytokine receptor pathways. Representative secreted cytokines screened out (fold change >1.20, or <0.83, p<0.05) in these differentiated proteins were measured by enzyme-linked immunosorbent assay in a validation cohort. The results showed that the levels of C-X-C motif chemokine ligand 12 (CXCL12) were higher in the urine of patients with TAPS than in those with OAPS (p=0.035), while the levels of platelet-derived growth factor subunit B (PDGFB) were lower in patients with TAPS than in those with OAPS (p=0.041). In addition, correlation analysis showed that CXCL12 levels were positively correlated with immunoglobulin G anti-β2-glycoprotein I antibody (r=0.617, p=0.016). Our results demonstrated that urinary CXCL12 and PDGFB might serve as potential non-invasive markers to differentiate primary TAPS from primary OAPS.

Recurrent Pregnancy Loss and Concealed Long‐QT Syndrome

BackgroundRecurrent pregnancy loss affects 1% to 2% of couples attempting childbirth. A large fraction of all cases remains idiopathic, which warrants research into monogenic causes of this distressing disorder.Methods and ResultsWe investigated a nonconsanguineous Estonian family who had experienced 5 live births, intersected by 3 early pregnancy losses, and 6 fetal deaths, 3 of which occurred during the second trimester. No fetal malformations were described at the autopsies performed in 3 of 6 cases of fetal death. Parental and fetal chromosomal abnormalities (including submicroscopic) and maternal risk factors were excluded. Material for genetic testing was available from 4 miscarried cases (gestational weeks 11, 14, 17, and 18). Exome sequencing in 3 pregnancy losses and the mother identified no rare variants explicitly shared by the miscarried conceptuses. However, the mother and 2 pregnancy losses carried a heterozygous nonsynonymous variant, resulting in p.Val173Asp (rs199472695) in the ion channel gene KCNQ1. It is expressed not only in heart, where mutations cause type 1 long‐QT syndrome, but also in other tissues, including uterus. The p.Val173Asp variant has been previously identified in a patient with type 1 long‐QT syndrome, but not reported in the Genome Aggregation Database. With heterologous expression in CHO cells, our in vitro electrophysiologic studies indicated that the mutant slowly activating voltage‐gated K+ channel (I Ks) is dysfunctional. It showed reduced total activating and deactivating currents (P<0.01), with dramatically positive shift of voltage dependence of activation by ≈10 mV (P<0.05).ConclusionsThe current study uncovered concealed maternal type 1 long‐QT syndrome as a potential novel cause behind recurrent fetal loss.

P–365 Altered endometrial oestrogen-responsiveness and aberrant expression of cell-fate markers may contribute to the aetiology of recurrent pregnancy loss

Abstract Study question Do women with recurrent pregnancy loss (RPL) have an aberrant expression of oestrogen receptor-β(ERβ) and cell-fate markers during the window of implantation (WOI) endometrium? Summary answer Women with RPL are found to have significantly altered levels of ER βand Ki–67 in the WOI endometrium, possibly resulting in anti-proliferative and anti-angiogenic effects. What is known already RPL affects 1% of all women and has been associated with altered endometrial angiogenesis and proliferation when compared with the endometrium of healthy fertile women. RPL can be subcategorised into recurrent loss of anembryonic pregnancy, fetal loss (following evidence of a fetal heartbeat) and recurrent implantation failure (RIF). ERβis the only oestrogen-receptor (ER) known to be expressed in the vascular endothelium of the endometrium and is the dominant ER during the WOI. It has an important role in endometrial regeneration and is proposed to regulate the angiogenic and vascular changes that occur in embryo implantation. Study design, size, duration: This pilot case-control study took place at the Liverpool Women’s Hospital and included 38 women; 29 who suffered RPL and 9 controls with proven fertility (≥2 healthy pregnancies). Of the RPL group, 9 had recurrent loss of anembryonic pregnancy, 10 had recurrent fetal loss and 10 had RIF. Endometrial samples were collected during the WOI (cycle day 22+/–2). Participants/materials, setting, methods To determine whether markers of endometrial cell proliferation and oestrogen-responsiveness are associated with RPL, we assessed the immuno-staining for ER β, progesterone receptor (PR) and cell-fate marker Ki–67 in endometrial biopsies during the WOI using immunohistochemistry. A semi-quantitative immuno-staining score was used to assess the endometrial glands, stroma, luminal epithelium, perivascular and vascular endothelium compartments separately. Statistical differences between groups were calculated by non-parametric tests and significance level set at p &amp;lt; 0.05. Main results and the role of chance During the WOI, the endometrial epithelium of women with RIF and recurrent anembryonic pregnancy loss showed significantly higher levels of ER βwhen compared with fertile controls (p = 0.01 and p = 0.01, respectively). This may indicate an anti-proliferative process occurring at the site of implantation with very early pregnancy losses. In contrast, with women with recurrent fetal loss, a significantly lower level of ERβwas found within the vascular endothelium when compared with the fertile controls (p &amp;lt; 0.01). This supports the theory that increased oxygen levels may compromise trophoblastic invasion, thereby leading to fetal loss. The presence of Ki–67 (a marker of proliferation) was significantly lower within the vascular endothelium of all types of RPL: recurrent anembryonic loss (p = 0.02), RIF (p = 0.02) and recurrent fetal loss (p &amp;lt; 0.01). These findings suggest ineffective endometrial angiogenesis in RPL, resulting in a suboptimal endometrial microenvironment. PR was found to be significantly reduced (p &amp;lt; 0.01) in the perivascular area of women with RIF versus fertile controls. Since decidualisation and preparation of the endometrium for a successful implantation is controlled by critical target genes downstream of PR, this alteration in PR may be an important feature of their defective endometrial phenotype. Limitations, reasons for caution Samples analysed were taken from the functional endometrium and therefore the results do not reflect the basalis. The WOI was identified using history and histological appearance, rather than timing with ovulation. Although we detected statistical significance, generalisation of the results requires further studies with larger sample size. Wider implications of the findings: This data provides novel insight into the biological correlates of clinical types of RPL and suggests that specific alterations in the regulation of endometrial cell fate and oestrogen- responsiveness are associated with different types of RPL. This highlights possible new therapies for RPL, such as selective oestrogen receptor modulators (SERMs). Trial registration number Not applicable

P-365 Pre-selected for an award: Altered endometrial oestrogen-responsiveness and aberrant expression of cell-fate markers may contribute to the aetiology of recurrent pregnancy loss

Abstract Study question Do women with recurrent pregnancy loss (RPL) have an aberrant expression of oestrogen receptor-β (ERβ) and cell-fate markers during the window of implantation (WOI) endometrium? Summary answer Women with RPL are found to have significantly altered levels of ERβ and Ki-67 in the WOI endometrium, possibly resulting in anti-proliferative and anti-angiogenic effects. What is known already RPL affects 1% of all women and has been associated with altered endometrial angiogenesis and proliferation when compared with the endometrium of healthy fertile women. RPL can be subcategorised into recurrent loss of anembryonic pregnancy, fetal loss (following evidence of a fetal heartbeat) and recurrent implantation failure (RIF). ERβ is the only oestrogen-receptor (ER) known to be expressed in the vascular endothelium of the endometrium and is the dominant ER during the WOI. It has an important role in endometrial regeneration and is proposed to regulate the angiogenic and vascular changes that occur in embryo implantation. Study design, size, duration This pilot case-control study took place at the Liverpool Women’s Hospital and included 38 women; 29 who suffered RPL and 9 controls with proven fertility (≥2 healthy pregnancies). Of the RPL group, 9 had recurrent loss of anembryonic pregnancy, 10 had recurrent fetal loss and 10 had RIF. Endometrial samples were collected during the WOI (cycle day 22+/-2). Participants/materials, setting, methods To determine whether markers of endometrial cell proliferation and oestrogen-responsiveness are associated with RPL, we assessed the immuno-staining for ERβ, progesterone receptor (PR) and cell-fate marker Ki-67 in endometrial biopsies during the WOI using immunohistochemistry. A semi-quantitative immuno-staining score was used to assess the endometrial glands, stroma, luminal epithelium, perivascular and vascular endothelium compartments separately. Statistical differences between groups were calculated by non-parametric tests and significance level set at p &amp;lt; 0.05. Main results and the role of chance During the WOI, the endometrial epithelium of women with RIF and recurrent anembryonic pregnancy loss showed significantly higher levels of ERβ when compared with fertile controls (p = 0.01 and p = 0.01, respectively). This may indicate an anti-proliferative process occurring at the site of implantation with very early pregnancy losses. In contrast, with women with recurrent fetal loss, a significantly lower level of ERβ was found within the vascular endothelium when compared with the fertile controls (p &amp;lt; 0.01). This supports the theory that increased oxygen levels may compromise trophoblastic invasion, thereby leading to fetal loss. The presence of Ki-67 (a marker of proliferation) was significantly lower within the vascular endothelium of all types of RPL recurrent anembryonic loss (p = 0.02), RIF (p = 0.02) and recurrent fetal loss (p &amp;lt; 0.01). These findings suggest ineffective endometrial angiogenesis in RPL, resulting in a suboptimal endometrial microenvironment. PR was found to be significantly reduced (p &amp;lt; 0.01) in the perivascular area of women with RIF versus fertile controls. Since decidualisation and preparation of the endometrium for a successful implantation is controlled by critical target genes downstream of PR, this alteration in PR may be an important feature of their defective endometrial phenotype. Limitations, reasons for caution Samples analysed were taken from the functional endometrium and therefore the results do not reflect the basalis. The WOI was identified using history and histological appearance, rather than timing with ovulation. Although we detected statistical significance, generalisation of the results requires further studies with larger sample size. Wider implications of the findings This data provides novel insight into the biological correlates of clinical types of RPL and suggests that specific alterations in the regulation of endometrial cell fate and oestrogen- responsiveness are associated with different types of RPL. This highlights possible new therapies for RPL, such as selective oestrogen receptor modulators (SERMs). Trial registration number Not applicable

Chronic histiocytic intervillositis: manifestation of placental alloantibody-mediated rejection

Chronic histiocytic intervillositis (chronic intervillositis) is defined by a diffuse infiltration of monocytes into the intervillous space, which often leads to poor obstetrical outcomes, including recurrent intrauterine growth restriction, miscarriage, and fetal death. The pathogenesis of chronic intervillositis is still poorly defined, and there is an unmet medical need for improved management. This study aimed to demonstrate the role of anti-human leukocyte antigen alloantibodies in the pathogenesis of chronic intervillositis through the application of criteria used in solid-organ transplantation for the diagnosis of antibody-mediated rejection. A multidisciplinary research study based on thorough immunologic and pathologic investigations was carried out for 2 separate couples who experienced recurrent secondary fetal losses following a first normal pregnancy associated with histologic evidence of chronic intervillositis. Very high levels of complement-fixing, fetus-specific antibodies targeting mismatched human leukocyte antigen alleles, harbored by the 2 paternal haplotypes, were identified in both cases. Polymorphic human leukocyte antigens were expressed on the surface of trophoblastic villi of the inflamed placenta but not in healthy placental tissue. The binding of alloantibodies to paternal human leukocyte antigens induced dramatic activation of the complement classical pathway in trophoblastic villi, leading to C4d deposition and formation of the terminal complex C5b-9. All requirements for the diagnosis of antibody-mediated placental rejection were fulfilled according to the criteria used in the Banff classification of allograft pathology. In silico analysis was performed using a human leukocyte antigen epitope viewer to reconstitute the human leukocyte antigen sensitization history. Reactivity against a single mismatched epitope present in the first-born healthy child accounted for a broad sensitization to human leukocyte antigens, including those harbored by the 2 paternal haplotypes. This finding explained the high rates of chronic intervillositis recurrence during subsequent pregnancies. This study provides novel mechanistic insights into the pathogenesis of chronic intervillositis and provides new avenues for individualized counseling and therapeutic options.

Síndrome antifosfolípido no trombótico: manifestaciones inflamatorias hematológicas y neurológicas

Antiphospholipid syndrome (APS) is an entity defined for the presence of antiphospholipid antibodies and events such as recurrent fetal loss and arterial or venous thrombosis. APS diagnosis is made through classification criteria, including laboratory criteria and clinical manifestations (most of them being thrombotic manifestations). Nonetheless, there is a wide variety of non-thrombotic manifestations of APS, which are not included in classification criteria. These “noncriteria” manifestations are important for decision making, based on their frequency or clinical relevance. Among them, some domains stand out: the hematologic domain, being thrombocytopenia the main manifestation; and the neurological domain with different manifestations such as migraine, epilepsy, dementia and severe manifestations, such as chorea and myelitis. Therefore, in the present article, information concerning two of the most common “non-criteria” domains (neurological and hematological) of APS is reviewed.

Retinal ischemia as the first manifestation of antiphospholipid antibody syndrome

Antiphospholipid antibody syndrome (APS) is characterized by the development of venous and/or arterial thrombosis and by gestational morbidity (recurrent fetal losses) in the presence of antiphospholipid antibodies. We report the case of a 38-year-old woman who was diagnosed with primary APS from thromboembolic abnormalities in the retinal periphery that led to retinal ischemia. The aim of this study is to share with physicians and medical undergraduates an atypical manifestation of the syndrome that is the most common acquired thrombophilia, [...]

Mosaic Double Trisomy Associated with Miscarriage in a Patient with Recurrent Fetal Losses

A 25-year-old pregnant woman with a history of five previous miscarriages was admitted to our clinic. She had undergone abortion in her first pregnancy at 14 weeks gestation due to anhydramnios. Her second pregnancy had ended in a miscarriage at 19 weeks gestation due to premature rupture of membranes. Both of her first two pregnancies showed normal karyotypes. Her third pregnancy was noted to be an ectopic pregnancy leading to abortion at 5 weeks gestation. Afterwards, she experienced two more miscarriages at 7 weeks of gestation due to the lack of fetal cardiac activity which could not been investigated for chromosomal abnormalities.&#x0D; Her current pregnancy was also terminated at 9 weeks of gestation due to the lack of fetal cardiac activity. Cytogenetic analysis of abortion material using GTG banding technique revealed 48,XY,+12,+15[5]/46,XY[25] karyotype (7). Both parents were found to have normal karyotypes and physical examinations showed no obvious abnormalities. Thrombophilia evaluation revealed that she had heterozygous MTHFR C677T polymorphism.

Myeloproliferative neoplasms and pregnancy: Overview and practice recommendations.

Pregnancy in the context of myeloproliferative neoplasms (MPN) poses unique fetal and maternal challenges. Current literature in this regard mostly involves essential thrombocythemia (ET) and less so polycythemia vera (PV) or myelofibrosis. In ET, live birth rate is estimated at 70% with first trimester fetal loss (˜ 30%) as the major complication. Risk of pregnancy-associated complications is higher in PV, thus mandating a more aggressive treatment approach. Herein, we appraise the relevant literature, share our own experience and propose management recommendations. Aspirin therapy may offer protection against fetal loss; however the additive benefit of systemic anticoagulation or cytoreductive therapy, in the absence of high risk disease, is unclear. We recommend cytoreductive therapy in the form of interferon alpha in all high risk and select low-risk ET and PV patients with history of recurrent fetal loss, prominent splenomegaly or suboptimal hematocrit control with phlebotomy. In addition, all women with PV should maintain strict hematocrit control <45% with the aid of phlebotomy. Systemic anticoagulation with low molecular weight heparin is advised in patients with history of venous thrombosis. Further clarification awaits prospective clinical trials that implement risk adapted therapeutic interventions.

Homocysteinemia: Cause of a Rare Case Coexisting DVT and Recurrent Foetal Loss in Pregnancy

Deep vein thrombosis and venous thromboembolism is a major health problem and one of the leading causesof maternal morbidity and mortality Recurrent pregnancy loss either early or late is a serious problem andhas both psychological and physical impact. Thrombophilia are one of the most important causes of DVTas well as Recurrent pregnancy loss as it worsens the physiological hypercoagulable case which exists inpregnancy. Homocysteinemia is rare but an important cause of deep vein thrombosis and recurrent pregnancyloss. Serum homocysteine levels in pregnancy have been linked to preeclampsia,recurrent abortions and lowbirth weight. Diagnosis of this condition is missed on routine basis due to extremely less frequency of theevaluation of serum homocysteine levels on a routine basis. Here we report a case of hyperhomocysteinemiaas underlying cause of bad obstetric history and DVT which are few of the classic presentations of the entityseen in the single patient. the condition was diagnosed by multidisciplinary approach.