自身免疫性疾病（AID）是指机体产生高滴度自身抗体和（或）自身反应性淋巴细胞攻击相应的自身正常细胞和组织，导致组织器官损伤和功能障碍的综合征，是导致复发性流产（RSA）等妊娠并发症的重要原因。临床上常见的较易导致RSA的AID有：系统性红斑狼疮、抗磷脂综合征、干燥综合征、类风湿关节炎、系统性硬化症和未分化结缔组织病等。这些AID导致的RSA的治疗主要为小剂量免疫抑制剂联合抗凝治疗，且疗效肯定。

        复发性流产（recurrent spontaneous abortion， RSA）占妊娠总数的5%，是威胁女性身心健康的疑难病症，由于RSA病因存在复杂性和异质性，加之40%～50%以上的患者流产原因不明，给临床治疗带来极大的困难和盲目性。因此，RSA的规范化诊治是生殖健康领域亟待解决的重大问题［1-2］。浏览更多请关注本刊微信公众号及当期杂志。

To describe the characteristics of thrombophilia in women with idiopathic pregnancy loss.Prospective observational study.Tertiary referral center in a teaching academic hospital.One hundred forty-five patients with repeated pregnancy loss and 145 matched controls.Prospective assessment of thrombophilia in patients and controls.Prevalence of activated protein C (APC) resistance, protein C, protein S, and antithrombin III deficiencies, antiphospholipid antibodies, factor V Leiden, factor II G20210A, and MTHFR C677T mutations.At least one thrombophilic defect was found in 66% of study group patients compared with 28% in control group patients. Combined thrombophilic defects were documented in 21% of women with pregnancy loss compared with 5.5% of control patients. Late pregnancy wastage occurred more frequently in women with thrombophilia compared with women without thrombophilia (160/429 [37%] vs. 39/162 [24%], respectively). APC resistance was documented in 39% of women with pregnancy loss compared with 3% of the control patients. APC resistance without factor V Leiden mutation was documented in 18% of women with pregnancy loss compared with none of the controls. While factor V Leiden mutation was more common in women with pregnancy loss (25% vs. 7.6%), factor II G20210A and homozygosity for MTHFR C677T contributed to pregnancy loss only in the presence of other thrombophilia.Thrombophilia was found in the majority (66%) of women with idiopathic pregnancy loss. APC resistance with or without factor V Leiden mutation is the most common thrombophilic defect, and combined thrombophilia is a frequent finding in women with pregnancy loss. Thrombophilia is associated with increased frequency of late pregnancy wastage.

Recurrent pregnancy loss is a complex health challenge with no universally accepted definition. Inconsistency in definitions involves not only the number of spontaneous abortions (two or three) that are accepted for recurrent pregnancy loss but the types of pregnancy and gestational age at miscarriage. Due to the heterogeneity of definitions and criteria applied by international guidelines for recurrent pregnancy loss, the true incidence of recurrent miscarriage, which is reported to range from 1% to 5%, is difficult to estimate. Moreover, the exact etiology of recurrent pregnancy loss remains questionable; thus, it is considered a polyetiological and multifactorial condition with many modifiable and non-modifiable factors involved. Even after thoroughly evaluating recurrent pregnancy loss etiology and risk factors, up to 75% of cases remain unexplained. This review aimed to summarize and critically analyze accumulated knowledge on the etiology, risk factors, relevant diagnostic options, and management approach to recurrent pregnancy loss. The relevance of various factors and their proposed roles in recurrent pregnancy loss pathogenesis remains a matter of discussion. The diagnostic approach and the management largely depend on the etiology and risk factors taken into consideration by a healthcare professional as a cause of recurrent miscarriage for a particular woman or couple. Underestimation of social and health consequences of recurrent pregnancy loss leads to compromised reproductive health and psychological well-being of women after miscarriage. Studies on etiology and risk factors for recurrent pregnancy loss, especially idiopathic, should be continued. The existing international guidelines require updates to assist clinical practice.

目的 分析复发性自然流产的病因，为临床诊断、治疗提供依据。方法 对2010年1月—2014年10月在上海交通大学医学院附属仁济医院妇科门诊就诊，确诊为复发性自然流产患者1 101例进行病因分析。结果 1 101例患者中，母体因素分析发现：单因素病因者有551例，占50.05%；多因素病因者有148例，占13.44%；另有402例原因不明，占36.51%。结论 复发性自然流产的病因复杂，包括母体因素如夫妻染色体异常、生殖道解剖异常、自身免疫因素、内分泌异常和血栓前状态等，胚胎因素如胚胎染色体异常以及母胎间妊娠免疫耐受失衡等多种因素。对复发性流产患者再次妊娠前进行全面系统而规范的病因筛查，并且针对病因进行个体化综合治疗，对于提高再次妊娠治疗的成功率有非常重要的意义。

Results from epidemological studies are consistent with the hypothesis that disparities in venous thromboembolism (VTE) burden are attributable to differences in genetic structure among populations from different genetic backgrounds. To that end, recent genetic studies have demonstrated not only potential associations between certain alleles and VTE but also clear differences in the distribution of these alleles in patients stratified by ancestry. There are a number of notable clinical and pathophysiological questions that arise from these findings. First at all is defining the precise variant(s) that alter disease susceptibility. The comparatively lower rates of VTE recorded among Asians would imply that risk profile is devoid of many risk factors on comparison to Caucasian or African counterparts or that a putative protective factor is advocated in the former population. Identification of these variants provided specific insight into VTE disease in selected populations and also shed lights on the biology of the disease. The association observed between ancestry and VTE is likely to be multifactorial, possibly reflecting, in addition to genetic variation, also socioeconomic differences. Acknowledgment of this may provide useful information in biomedical contexts and help to identify individual risk factors for VTE.

To critically review the literature regarding inherited thrombophilia and recurrent fetal loss.English-language literature review.Women who experienced repeated pregnancy wastage.Aspirin, glucocorticoids, heparin, and IV immunoglobulin for the prevention of miscarriage.Live birth, miscarriage, preeclampsia, and pregnancy loss.Recurrent fetal loss and other placental vascular pathologies of pregnancy have long been associated with antiphospholipid syndrome, an acquired autoimmune thrombophilic state. The number of known heritable thrombophilic disorders has grown rapidly in recent years with the identification of activated protein C resistance, factor V Leiden mutation, and hyperhomocysteinemia as major causes of thrombosis. Data accumulated over the past 2 years suggest that heritable thrombophilia is associated with an increased risk of fetal loss and preeclampsia. The present review discusses potential pathogenetic mechanisms for this association and evaluates reported therapeutic regimens for the prevention of fetal loss in women with thrombophilia.Placental thrombosis may be the final common pathophysiologic pathway in most women with habitual abortions and repeated pregnancy wastage. Prophylactic antithrombotic therapy is indicated in women with heritable thrombophilia and antiphospholipid syndrome and probably is more effective than the previously used modalities of prednisone, aspirin, and IV immunoglobulin.

There seems to be a clear correlation between antibodies against domain I (anti-DI) of β2Glycoprotein I and severe clinical profiles in antiphospholipid syndrome (APS) patients. We investigated the clinical significance of anti-DI antibodies in a cohort of aPL carriers.One hundred and five carriers persistently positive for IgG anti-β2Glycoprotein 1 antibodies (a-β2GPI) and/or IgG anticardiolipin (aCL) and/or lupus anticoagulants (LAC) were tested for the presence of anti-DI antibodies using the QUANTA Flash® Beta2GPI-Domain I chemiluminescence immunoassay.Anti-DI antibodies were detected in 44 aPL carriers (41.9%) and they were significantly associated to triple aPL positivity (LAC plus IgG a-β2GPI plus IgG aCL antibodies). Isolated LAC and a-β2GPI antibodies were significantly associated to anti-DI negative aPL carriers. During a 82.2 month mean follow-up, ten aPL carriers (9.5%) developed a first thrombotic event so becoming APS patients. Anti-DI antibodies, triple aPL positivity, thromboembolic risk factors and autoimmune disorders significantly prevailed in carriers becoming APS. Logistic regression analysis showed that anti-DI positivity was an independent risk factor for thrombosis.Anti-DI antibody positivity can be considered a new risk factor predictive of the first thrombotic event in aPL carriers, instead, negative anti-DI may be useful to identify low-risk aPL carriers.Copyright © 2018 Elsevier B.V. All rights reserved.

Recurrent pregnancy loss is a distressing pregnancy disorder experienced by ~2.5% of women trying to conceive. Recurrent pregnancy loss is defined as the failure of two or more clinically recognized pregnancies before 20-24 weeks of gestation and includes embryonic and fetal losses. The diagnosis of an early pregnancy loss is relatively straightforward, although progress in predicting and preventing recurrent pregnancy loss has been hampered by a lack of standardized definitions, the uncertainties surrounding the pathogenesis and the highly variable clinical presentation. The prognosis for couples with recurrent pregnancy loss is generally good, although the likelihood of a successful pregnancy depends on maternal age and the number of previous losses. Recurrent pregnancy loss can be caused by chromosomal errors, anatomical uterine defects, autoimmune disorders and endometrial dysfunction. Available treatments target the putative risk factors of pregnancy loss, although the effectiveness of many medical interventions is controversial. Regardless of the underlying aetiology, couples require accurate information on their chances of having a baby and appropriate support should be offered to reduce the psychological burden associated with multiple miscarriages. Future research must investigate the pathogenesis of recurrent pregnancy loss and evaluate novel diagnostic tests and treatments in adequately powered clinical trials.

复发性流产患者需全面筛查病因，对因治疗能取得良好的妊娠结局。低分子肝素主要应用于血栓前状态、抗磷脂综合征和自身免疫性疾病等引起的复发性流产的防治。文章重点讨论低分子肝素在复发性流产患者中的应用与监测相关问题。

自然流产（spontaneous abortion，SA）是妇产科最常见的妊娠并发症之一。育龄期女性发生1次SA的风险为10%左右［1］。复发性流产（recurrent spontaneous abortion，RSA）的发生率为1%～5%［2］，RSA的复发风险随着流产次数的增加而上升。曾有3次以上连续自然流产史的患者再次妊娠后胚胎丢失率为40%～80%［3］。如果不及时干预，不仅会给患者及其家庭带来严重的经济负担，而且还将对患者的身心健康造成极大的影响。浏览更多请关注本刊微信公众号及当期杂志。

Antiphospholipid antibodies (aPL) have been associated with organ damage and certain features in systemic lupus erythematosus(SLE) patients. Our aim was to investigate the differences between SLE patients according to the presence of aPL and/or clinical antiphospholipid syndrome (APS).

The aim of the study was to determine the prevalence and clinical associations of antiphosphatidylserine/prothrombin antibodies (aPS/PT) with thrombosis and pregnancy loss in Chinese patients with antiphospholipid syndrome (APS) and seronegative APS (SNAPS).One hundred and eighty six Chinese patients with APS (67 primary, 119 secondary), 48 with SNAPS, 176 disease controls (79 systemic lupus erythematosus [SLE], 29 Sjogren's syndrome [SS], 30 ankylosing spondylitis [AS], 38 rheumatoid arthritis [RA]) and 90 healthy donors were examined. IgG and IgM aPS/PT, IgG/IgM/IgA anticardiolipin (aCL) and IgG/IgM/IgA anti-β2-glycoprotein I (anti-β2GPI) antibodies were tested by ELISA.One hundred and sixty (86.0%) of APS patients were positive for at least one aPS/PT isotype. One hundred and thirty five (72.6%) were positive for IgG aPS/PT, 124/186 (66.7%) positive for IgM aPS/PT and 99 (53.2%) positive for both. Approximately half of the SNAPS patients were positive for IgG and/or IgM aPS/PT. Highly significant associations between IgG aPS/PT and venous thrombotic events (odds ratio [OR]=6.72) and IgG/IgM aPS/PT and pregnancy loss (OR=9.44) were found. Levels of IgM aPS/PT were significantly different in APS patients with thrombotic manifestations and those with fetal loss (p=0.014). The association between IgG/IgM aPS/PT and lupus anticoagulant (LAC) was highly significant (p<0.001). When both were positive, the OR for APS was 101.6. Notably, 91.95% (80/87) of LAC-positive specimens were positive for IgG and/or IgM aPS/PT, suggesting aPS/PT is an effective option when LAC testing is not available.Anti-PS/PT antibody assays demonstrated high diagnostic performance for Chinese patients with APS, detected some APS patients negative for criteria markers and may serve as potential risk predictors for venous thrombosis and obstetric complications.

Recurrent pregnancy loss (RPL) is one of the most frustrating clinical entities in reproductive medicine requiring not only diagnostic investigation and therapeutic intervention, but also evaluation of the risk for recurrence.The aim of this study was to review and compare the most recently published major guidelines on investigation and management of RPL.A descriptive review of guidelines from the Royal College of Obstetricians and Gynaecologists, the European Society of Human Reproduction and Embryology, the American Society for Reproductive Medicine, the French College of Gynecologists and Obstetricians, and the German, Austrian, and Swiss Society of Gynecology and Obstetrics on RPL was carried out.There is consensus among the reviewed guidelines that the mainstays of RPL investigation are a detailed personal history and screening for antiphospholipid syndrome and anatomical abnormalities of the uterus. In contrast, inherited thrombophilias, vaginal infections, and immunological and male factors of infertility are not recommended as part of a routine RPL investigation. Several differences exist regarding the necessity of the cytogenetic analysis of the products of conception, parental peripheral blood karyotyping, ovarian reserve testing, screening for thyroid disorders, diabetes or hyperhomocysteinemia, measurement of prolactin levels, and performing endometrial biopsy. Regarding the management of RPL, low-dose aspirin plus heparin is indicated for the treatment of antiphospholipid syndrome and levothyroxine for overt hypothyroidism. Genetic counseling is required in case of abnormal parental karyotype. The Royal College of Obstetricians and Gynaecologists, the European Society of Human Reproduction and Embryology, and the French College of Gynecologists and Obstetricians guidelines provide recommendations that are similar on the management of cervical insufficiency based on the previous reproductive history. However, there is no common pathway regarding the management of subclinical hypothyroidism and the surgical repair of congenital and acquired uterine anomalies. Use of heparin for inherited thrombophilias and immunotherapy and anticoagulants for unexplained RPL are not recommended, although progesterone supplementation is suggested by the American Society for Reproductive Medicine and the German, Austrian, and Swiss Society of Gynecology and Obstetrics.Recurrent pregnancy loss is a devastating condition for couples. Thus, it seems of paramount importance to develop consistent international practice protocols for cost-effective investigation and management of this early pregnancy complication, with the aim to improve live birth rates.

复发性流产（RSA）为3次或3次以上妊娠28周之前的胎儿丢失，是临床上常见的妊娠并发症。RSA病因涉及多个方面，包括遗传、解剖、免疫、内分泌、易栓症等因素。易栓症指存在抗凝蛋白、凝血因子、纤溶蛋白等遗传性或获得性缺陷，或者存在获得性危险因素而具有高血栓栓塞倾向，分为遗传性与获得性两种类型。目前研究表明，易栓症与RSA存在相关性，重视RSA患者易栓症的筛查与诊断，并采取相应的措施，可在一定程度上提高患者的妊娠成功率。

This study investigates the thromboelastography (TEG) changes in patients with unexplained recurrent spontaneous abortion (URSA) to identify effective diagnostic markers for URSA.We retrospectively analyzed 160 URSA patients from the Gynecology Department of the First People's Hospital of Lianyungang (June 2017 - June 2020) and compared them with 190 healthy, fertile women without adverse pregnancy histories (control group). TEG parameters were assessed using logistic regression, applying stepwise selection for model optimization. Model performance was evaluated using Receiver Operating Characteristic (ROC) curves, determining sensitivity and specificity. The Youden index identified optimal cut points for predictive probabilities.Significant differences were observed between the URSA and control groups in coagulation reaction time (R), clot formation time (K), clot formation rate (Angle-α), and maximum clot strength (MA) (P<0.05). Multivariable logistic regression identified R, Angle-α, and MA as independent URSA risk factors. The model demonstrated excellent discrimination (AUC: 0.940; 95% CI: 0.918-0.962). The optimal cut point of predictive probability (Youden index) was P=0.355, yielding a sensitivity of 0.925 and specificity of 0.795.URSA patients exhibit a hypercoagulable state even when not pregnant. More research is needed to validate our findings and explore the potential clinical implications of anticoagulants in treating URSA.© 2024 Xu et al.

To develop an evidence‐based guideline on contraception, assisted reproductive technologies (ART), fertility preservation with gonadotoxic therapy, use of menopausal hormone replacement therapy (HRT), pregnancy assessment and management, and medication use in patients with rheumatic and musculoskeletal disease (RMD).

\n Purpose Official guideline of the German Society of Gynecology and Obstetrics (DGGG), the Austrian Society of Gynecology and Obstetrics (ÖGGG) and the Swiss Society of Gynecology and Obstetrics (SGGG). The aim of this guideline was to standardize the diagnosis and treatment of couples with recurrent miscarriage (RM). Recommendations were based on the current literature and the views of the involved committee members.

Sticky platelet syndrome (SPS) is a hereditary disorder. SPS can cause pregnancy complications, such as recurrent miscarriages. However, proper management can prevent the incidence of recurrent miscarriages. Here, we describe a case of a woman who lost her fifth first-trimester pregnancy, and upon assessment, we discovered SPS. The 33-year-old woman underwent consultation with an obstetrician because of her history of five first-semester miscarriages. Gynecology ultrasound, infection parameters, hormonal and metabolic panels, and autoimmune workup were all found to be normal; however, vitamin D deficiency was identified as was SPS from a platelet aggregation test. The patient was then treated with clopidogrel and vitamin D3 supplementation. She became pregnant after five months of treatment. Her pregnancy was normal and she went into delivery at 40 weeks gestation with no maternal or fetal complications.

There are numerous studies reporting a disproportionally high prevalence of thrombophilia in women with a history of recurrent miscarriage (RM), which has led to overdiagnosis and treatment without an improvement in clinical outcomes. The objective of our study was to assess the prevalence of inherited and acquired thrombophilia in a large cohort of women with a history of early RM using internationally agreed diagnostic criteria and inclusion parameters and compare it to the meta-analysis results of existing literature.

Thrombophilias are common disorders that increase the risk of pregnancy-associated venous thromboembolism and pregnancy loss and can also increase the risk of placenta-mediated pregnancy complications (severe pre-eclampsia, small-for-gestational-age infants, and placental abruption). We postulated that antepartum dalteparin would reduce these complications in pregnant women with thrombophilia.In this open-label randomised trial undertaken in 36 tertiary care centres in five countries, we enrolled consenting pregnant women with thrombophilia at increased risk of venous thromboembolism or with previous placenta-mediated pregnancy complications. Eligible participants were randomly allocated in a 1:1 ratio to either antepartum prophylactic dose dalteparin (5000 international units once daily up to 20 weeks' gestation, and twice daily thereafter until at least 37 weeks' gestation) or to no antepartum dalteparin (control group). Randomisation was done by a web-based randomisation system, and was stratified by country and gestational age at randomisation day with a permuted block design (block sizes 4 and 8). At randomisation, site pharmacists (or delegates) received a randomisation number and treatment allocation (by fax and/or e-mail) from the central web randomisation system and then dispensed study drug to the local coordinator. Patients and study personnel were not masked to treatment assignment, but the outcome adjudicators were masked. The primary composite outcome was independently adjudicated severe or early-onset pre-eclampsia, small-for-gestational-age infant (birthweight <10th percentile), pregnancy loss, or venous thromboembolism. We did intention-to-treat and on-treatment analyses. This trial is registered with ClinicalTrials.gov, number NCT00967382, and with Current Controlled Trials, number ISRCTN87441504.Between Feb 28, 2000, and Sept 14, 2012, 292 women consented to participate and were randomly assigned to the two groups. Three women were excluded after randomisation because of ineligibility (two in the antepartum dalteparin group and one in the control group), leaving 146 women assigned to antepartum dalteparin and 143 assigned to no antepartum dalteparin. Some patients crossed over to the other group during treatment, and therefore for on-treatment and safety analysis there were 143 patients in the dalteparin group and 141 in the no dalteparin group. Dalteparin did not reduce the incidence of the primary composite outcome in both intention-to-treat analysis (dalteparin 25/146 [17·1%; 95% CI 11·4-24·2%] vs no dalteparin 27/143 [18·9%; 95% CI 12·8-26·3%]; risk difference -1·8% [95% CI -10·6% to 7·1%)) and on-treatment analysis (dalteparin 28/143 [19·6%] vs no dalteparin 24/141 [17·0%]; risk difference +2·6% [95% CI -6·4 to 11·6%]). In safety analysis, the occurrence of major bleeding did not differ between the two groups. However, minor bleeding was more common in the dalteparin group (28/143 [19·6%]) than in the no dalteparin group (13/141 [9·2%]; risk difference 10·4%, 95% CI 2·3-18·4; p=0·01).Antepartum prophylactic dalteparin does not reduce the occurrence of venous thromboembolism, pregnancy loss, or placenta-mediated pregnancy complications in pregnant women with thrombophilia at high risk of these complications and is associated with an increased risk of minor bleeding.Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and Pharmacia and UpJohn.Copyright © 2014 Elsevier Ltd. All rights reserved.

Autoimmune rheumatic diseases (ARDs) often affect women during their reproductive years, and early studies of pregnancy in these patients reported high rates of adverse outcomes. Continuation or initiation of safe and effective medications in the preconception period is beneficial for maintaining or achieving disease quiescence throughout pregnancy thereby improving both maternal and pregnancy outcomes. The European Alliance of Associations for Rheumatology, the American College of Rheumatology, and the British Society for Rheumatology have published recommendations and guidelines regarding management of ARDs during pregnancy. The American College of Obstetricians and Gynecologists and the American Gastroenterological Association have also provided guidance statements with relevant recommendations. This review provides an overview of available recommendations for medication use in ARD pregnancy, with discussion of safety considerations for maternal and fetal well-being. Medications considered compatible with pregnancy include hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine, tacrolimus, and TNF inhibitors. Methotrexate, mycophenolate, leflunomide, and cyclophosphamide should be avoided before and during pregnancy. Other medications, most of them newer, are largely discouraged for use in pregnancy due to inadequate data or concerns for neonatal immunosuppression, including non-TNF biologics and small molecule therapies. Further investigation is needed regarding effects of non-TNF biologics, biosimilars, and small molecules in pregnancy. Important efforts for the future will include improved methodologies to gather critical safety data, with consideration of inclusion of pregnant women in clinical trials, a complex and controversial issue. Long-term information on outcomes in offspring of treated women is lacking for many of these medications.Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.

Administration of conventional antithrombotic treatment (low-dose aspirin plus low-molecular weight heparin [LDA+LMWH]) for obstetric antiphospholipid syndrome (APS) does not prevent life-threatening placenta insufficiency-associated complications such as preeclampsia (PE) and intrauterine growth restriction (IUGR) in 20% of patients. Statins have been linked to improved pregnancy outcomes in mouse models of PE and APS, possibly due to their protective effects on endothelium. Here, we investigated the use of pravastatin in LDA+LMWH-refractory APS in patients at an increased risk of adverse pregnancy outcomes.We studied 21 pregnant women with APS who developed PE and/or IUGR during treatment with LDA+LMWH. A control group of 10 patients received only LDA+LMWH. Eleven patients received pravastatin (20 mg/d) in addition to LDA+LMWH at the onset of PE and/or IUGR. Uteroplacental blood hemodynamics, progression of PE features (hypertension and proteinuria), and fetal/neonatal outcomes were evaluated.In the control group, all deliveries occurred preterm and only 6 of 11 neonates survived. Of the 6 surviving neonates, 3 showed abnormal development. Patients who received both pravastatin and LDA+LMWH exhibited increased placental blood flow and improvements in PE features. These beneficial effects were observed as early as 10 days after pravastatin treatment onset. Pravastatin treatment combined with LDA+LMWH was also associated with live births that occurred close to full term in all patients.The present study suggests that pravastatin may improve pregnancy outcomes in women with refractory obstetric APS when taken at the onset of PE or IUGR until the end of pregnancy.