Meta-analysis of aspirin-heparin therapy for un-explained recurrent miscarriage

Objective This study was designed to evaluate the efficacy and safety of aspirin-heparin treatment for un-explained recurrent spontaneous abortion(URSA). Methods Literatures reporting the studies on the aspirin-heparin treatment of un-explained recurrent miscarriage with randomized controlled trials(RCTs) were collected from the major publication databases. The live birth rate was used as primary indicator, preterm delivery, preeclampsia, intrauterine growth restriction, and adverse reactions(thrombocytopenia) were used as the secondary indicators. The quality of the included studies was evaluated using RCT bias risk assessment tool in the Cochrane Handbook(v5.1.0). Meta-analysis was conducted using RevM an(v5.3) software. Subgroup analyses were conducted with an appropriately combined model according to the type of the treatments if heterogeneity among the selected studies was detected. Results Six publications of RCTs were included in this study. There were a total of 907 pregnant women with diagnosis of URSA, 367 of them were pooled in the study group with aspirin-heparin therapy and 540 women in the control group with placebo, aspirin or progesterone therapy. Meta-analysis showed that the live birth rate in the study group was significantly different from that in the control group [RR = 1.18, 95% CI(1.00-1.39), P=0.04]. Considering the clinical heterogeneity among the six studies, subgroup analysis were performed. Live birth rates in the aspirin-heparin treated groups and placebo groups were compared and no significant difference was found. There were no significant differences found between the two groups in the incidence of preterm delivery [RR=1.22, 95% CI(0.54-2.76), P=0.64], preeclampsia [RR=0.52, 95% CI(0.25-1.07), P=0.08], intrauterine growth restriction [RR=1.19, 95% CI(0.56-2.52), P=0.45] and thrombocytopenia [RR=1.17, 95% CI(0.09-14.42), P=0.90]. Conclusion This meta-analysis did not provide evidence that aspirin-heparin therapy had beneficial effect on un-explained recurrent miscarriage in terms of live birth rate, but it was relatively safe for it did not increase incidence of adverse pregnancy and adverse events. More well-designed and stratified double-blind RCT, individual-based meta-analysis regarding aspirin-heparin therapy are needed in future.

Relationship between expression of COX-2,TNF-α,IL-6 and autoimmune-type recurrent miscarriage

Objective:To investigate the roles of COX-2,TNF-α,IL-6 in the pathogenesis of autoimmunetype recurrent spontaneous abortion(RSA).Methods:RT-PCR was used to detect the mRNA of COX-2,TNF-α.IL-6 in the trophoblast cells of murine RSA and normal pregnant models.The COX-2,TNF-α.IL-6 protein expressions were determined by using immunohistochemisry staining method.The COX-2,TNF-α,IL-6 protein expressions were determined by ELISA.Results:The embryo loss rates in experiment group was significantly higher than that in normal pregnancy control group,the expression of COX-2,TNF-α,IL-6 in the trophoblast cells of murine RSA and normal pregnant models.The expression of COX-2 in autoimmunetype recurrent spontaneous abortion was significantly lesser than in normal pregnant models.The expression of TNF-α,IL-6 in autoimmune-type recurrent spontaneous abortion was significantly higher than in normal pregnant models.There was a positively correlation between TNF-αand IL-6.There was no relationship between COX-2,TNF-αand IL-6.Conclusions:The abnormal expression of COX-2,TNF-αand IL-6 may result in RSA.

Intravenous Immunoglobulin Treatment of Recurrent Miscarriage:an Update of Placebo-controlled Trials

Background Immunological disturbances which may be treated with intravenous immunoglobulin (IvIg) play a significant role in the majority of patients with recurrent miscarriage (RM). The present study aimed to review the current knowledge about IvIg treatment in RM primarily based on results from published placebo controlled trials. Seven placebo controlled trials were identified comprising a total of 343 patients. The background variables, the treatment protocols and the results were extremely different between the trials. Among the patients with secondary RM, a meta analysis showed that the pooled odds ratio for live birth among IvIg treated women compared with women infused with placebo was 1.69 (95 % CI = 0.72～3.96, not significant). IvIg also seemed to be efficacious in patients with repeated second trimester intrauterine fetal deaths. A new big placebo controlled trial should be conducted which focus on RM patients with secondary RM or recurrent second trimester fetal deaths. Sufficient IvIg doses should be given with optimal time intervals.

Coagulation Factor XII Congenital Deficiency in Women with Recurrent Miscarriage

Factor XII (Hageman factor) is an important protease that plays a major role in the initiation of the intrinsic pathway of blood coagulation and fibrinolysis and kinin formation. It is still unclear whether factor XII deficiency causes any disorders during pregnancy. Because the main clinical feature in patients with factor XII deficiency is thrombosis rather than bleeding, low dose aspirin would be expected to prevent first trimester miscarriage and a decrease in factor XII level itself was found to be an independent risk factor in recurrent miscarriage. The woman in a 31-year-old patient, with personal and family antecedents without interest and preceding obstetrics of two spontaneous abortions in the first quarter of the pregnancy without apparent cause. In the study of infertility practiced emphasizes a partition of not more than one centimetre of length in the uterine found by hysteroscopy exploration and in the study of hipercoagulability a light deficiency of the factor XII. Himself guideline processing with low dose of aspirin (125 mgr/day) and preconception folic acid (5 mgr/day), remains expectant mother and in the week 12 of her third pregnancy itself guideline antitrombotic prophylaxis with heparin of low molecular weight by subcutaneous way. The pregnancy reaches the week 39 without incidents of interest and the expectant mother give birth of spontaneous form to health boy. Repeated abortions may be associated with reduced level of factor XII activity of unknown origin and low-dose aspirin may prevent miscarriage caused for decreased factor XII levels in patients with a history of recurrent first trimester miscarriage.

A successful birth of severe secondary recurrent miscarriage case after a decline of phosphatidylserine-dependent anti-prothrombin antibody by intravenous immunoglobulin administration

A 33 years old woman was referred to our hospital since her sixth pregnancy had been revealed. In fact, at 19 years of age she had diagnosed as having systemic lupus erythematosus without organ failure. In addition, she had a past history of uncontrollable severe pregnancy-induced hypertension occurred during the second pregnancy, resulting in extremely premature delivery and following postpartum HELLP syndrome. It was so severe that we employed administration of dexamethasone and plasma exchange to ameliorate a life-threatening situation. In the course of her recovery it was revealed that she had been complicated with antiphospholipid antibodies, and at the same time we observed that phosphatidylserine-dependent anti-prothrombin antibody IgG levels were declining as her condition was getting better. There-after, she became pregnant three times, but all pregnancies ended in miscarriage despite administration of prednisolone and anticoagulant therapy. Therefore, we realized that her recurrent miscarriages could not be prevented with generally acceptable therapies, so we tried intravenous immunoglobulin shortly after fetal heart beats were detected. In fact, her sixth pregnancy was going well, but we had to terminate it at the 35th week of gestation due to the onset of HELLP syndrome-like condition. However, she could achieve an almost intact pregnancy outcome without neonatal complications or persistently worsening postpartum HELLP syndrome-like condition. Considering the etiologic relation overlapping between systemic lupus erythematosus, antiphospholipid syndrome and recurrent miscarriage, intravenous immunoglobulin can be one of the treatment options for severe secondary recurrent miscarriage, although the evidence of the treatment is always certain. In addition, a decline of phosphatidylserine-dependent anti-prothrombin antibody IgG levels we observed in this case may represent its therapeutic immunomodulatory effects.

Recurrent Miscarriage: Hysteroscopy-Assisted Management

Objective: To apply office hysteroscopy in assessment/management of patients with recurrent miscarriage, thus to/or not to recommend office hysteroscopy as a routine procedure in such cases. Study design: Retrospective analysis. Setting: University hospital’s outpatient abortion clinic. Subjects & Methodology: Patients’ records during the period between March 2015 and January 2017 for subjects with at least 2 previous miscarriages, who had undergone office hysteroscopy were reviewed. Results: Cases with 2 previous miscarriages (n = 95) were assessed and compared with those with 3 or more miscarriages (n = 105). Abnormal uterine findings were diagnosed in 24.1% of the former, and 43.8% of the latter group. The prevalence of uterine lesions among cases with 2 recurrent miscarriages was 42.1%;meanwhile, for subjects with 3 or more consecutive miscarriages, it was 43.8%. Conclusion: In addition to safety profile, simplicity and outpatient basis of use, outpatient hysteroscopy in recurrent miscarriages would be an added-value to practitioners as a diagnostic and therapeutic tool.

Overview of genetic causes of recurrent miscarriage and the diagnostic approach

Recurring miscarriage(RM)is a frustrating reproductive complication with variable etiology.Numerous genetic defects have been known to play a crucial role in the etiology of RM.Chromosomal abnormalities are frequently detected,while other genetic defects cannot be diagnosed through routine research,such as cryptic chromosomal anomalies,single nucleotide polymorphism,single-gene defect,and gene copy number variation.Diagnostic laboratories have recently used variable advanced techniques to detect potential genetic abnormalities in couples with RM and/or in products of conception.Here we aim to summarize the known genetic causes of RM,with a focus on the new diagnostic techniques.Knowledge of the genetic profile of miscarriages is important for prognosis and potential counseling planning,as well as the prenatal diagnostic strategy in subsequent pregnancies.

History of recurrent miscarriage in traditional Chinese medicine literature

Recurrent miscarriage （RM） as a gynecological disorder was recognized by traditional Chinese medicine （TCM）practitioners long before the age of modern medicine. TCM physicians reported and recorded RM in the canonical TCMliterature, which dates back more than 1500 years. The first cases of RM as a fertility abnormality were reported inChanjing, which was written during the Nanbei Dynasty of China （420 A.D. – 589 A.D.）. Some prescriptions for thetreatment of RM are still actively used by modern TCM practitioners. In addition, many recent pharmacological andclinical studies have focused on the TCM therapy for RM. To identify the new therapeutic targets for RM and furtherpromote the interest in treating RM with TCM, we reviewed the etiology, pathogenesis, treatment, and prevention of RMdiscussed both in the TCM literature and in contemporary pharmacological and clinical studies.

Expression of E2A in Mid-secretory Endometrium of Women Suffering from Recurrent Miscarriage

E2A is involved in promoting forkhead box P3（FOXP3） and retinoid-related orphan receptor gamma t（RORγt） gene transcription, which are pivotal transcription factors of T regulatory cells and Th17 cells, respectively. Little is known about the involvement of E2 A in pregnancy process. This study aimed to investigate the expression of E2 A, cytotoxic T-lymphocyte-associated protein 4（CTLA-4）, and Foxp3 in luteal phase endometrium of women suffering recurrent miscarriage（RM）（n=21） and control group（n=11） by immunohistochemistry, with the Vectra？ automated quantitative pathology imaging system for analysis. The percentage of E2 A＋ cells and CTLA-4＋ cells was significantly higher in the endometrium of women with RM than in the controls. There was positive correlation between E2 A and CTLA-4（r=0.523, P=0.002）, E2 A and FOXP3（r=0.380, P=0.032）, and FOXP3 and CTLA-4（r=0.625, P=0.000） in the mid-secretory phase of endometrium for all subjects. It was concluded that the abnormal expression of endometrial E2 A existed in mid-secretory endometrium of women with RM, and there was a positive correlation between E2 A and FOXP3, and E2 A and CTLA-4, suggesting the possible regulation role of E2 A involved in regulating endometrium receptivity.

Observational study:efficacy of aspirin and low-molecular-weight heparin in the management of recurrent miscarriage

In the present study,we aimed to assess the comparative efficacy of low-molecular-weight heparin(LMWH)in combination with low-dose aspirin for the management of recurrent miscarriage and scrutinize alterations in coagulation function following such treatment.A retrospective analysis was conducted on clinical data obtained from 97 patients with recurrent miscarriage treated at our institution from January 2019 to June 2020.Patients were categorized into either the study or control groups based on the administration of LMWH.The control group comprised 48 patients treated solely with aspirin,while the study group included 49 patients treated with both LMWH and aspirin.Comparative evaluations between the two groups encompassed pregnancy outcomes,coagulation function,adverse reactions,and blood loss during delivery.Results revealed a higher term birth rate in the study group(83.67%)compared to the control group(50%).Post-treatment,the study group exhibited lower prothrombin time,plasminogen activator inhibitor,and D-dimer levels than the control group.Moreover,the study group experienced fewer adverse reactions and reduced blood loss during delivery in comparison to the control group,demonstrating statistical significance(P<0.05).The combination of LMWH and low-dose aspirin exhibited noteworthy application in the management of recurrent miscarriage.This therapeutic approach not only fostered the enhancement of coagulation function conducive to pregnancy but also diminished the incidence of adverse reactions observed with aspirin alone.

基于超声子宫内膜容受性参数和淋巴细胞免疫表型对复发性流产再孕早期流产的影响因素分析

目的基于超声子宫内膜容受性参数和淋巴细胞免疫表型探究不明原因复发性流产患者再妊娠后妊娠结局的影响因素。方法选择2022年4-8月南通市妇幼保健院收治的不明原因复发性自然流产再次妊娠患者166例。根据妊娠结局分为成功分娩组和再次流产组,检测子宫内膜容受性参数及外周血T淋巴细胞,筛查不明原因复发性流产患者再次妊娠流产的影响因素。结果166例患者中成功分娩102例(61.45%),再次流产64例(38.55%)。成功分娩组患者的子宫内膜厚度、内膜容积、血管化血流指数(VFI)均高于再次流产组(P<0.05)。成功分娩组患者的CD4^(+)、CD4^(+)/CD8^(+)低于再次流产组(P<0.05)。CD4^(+)、CD4^(+)/CD8^(+)是妊娠失败的危险因素(P<0.05),子宫内膜厚度、内膜容积、VFI是妊娠失败的保护因素(P<0.05)。结论不明原因复发性流产患者再妊娠的妊娠结局与子宫内膜厚度、内膜容积、VFI、CD4^(+)、CD4^(+)/CD8^(+)有关。

寿胎丸加减治疗复发性流产的疗效及对患者凝血功能、Th17细胞相关因子的影响

目的:探究寿胎丸加减治疗复发性流产的疗效及其对患者凝血功能、辅助T淋巴细胞17(Th17)细胞相关因子的影响。方法:对2021年3月—2022年3月石家庄市第六医院收治的120例复发性流产患者相关资料予以回顾性分析,按治疗方式将患者分为对照组与研究组,对照组57例接受黄体酮治疗,研究组63例在对照组基础上加用寿胎丸加减治疗。比较两组临床疗效,治疗前后中医证候积分、凝血功能、Th17与调节性T细胞(Treg)水平、Th17/Treg细胞相关因子,以及不良反应发生率。结果:研究组患者临床总有效率90.48%高于对照组75.44%(P<0.05);两组患者治疗后中医证候积分、凝血功能、Th17与Treg水平、Th17/Treg细胞相关因子均明显改善(P<0.01),研究组患者治疗后中医证候积分均明显低于对照组(P<0.01),研究组患者治疗后中医证候积分、凝血功能、Th17与Treg水平、Th17/Treg细胞相关因子等改善均优于对照组(P<0.01);研究组患者治疗期间不良反应发生率7.94%低于对照组12.28%,但差异无统计学意义(P>0.05)。结论:应用寿胎丸加减治疗复发性流产疗效显著,有助于减轻患者凝血功能障碍,纠正患者Th17细胞相关因子水平异常,临床应用效果良好。

Sperm DNA fragmentation, recurrent implantation failure and recurrent miscarriage

Evidence is increasing that the integrity of sperm DNA may also be related to implantation failure and recurrent miscarriage （RM）. To investigate this, the sperm DNA fragmentation in partners of 35 women with recurrent implantation failure （RIF） following in vitro fertilization, 16 women diagnosed with RM and seven recent fathers （control） were examined. Sperm were examined pre- and post-density centrifugation by the sperm chromatin dispersion （SCD） test and the terminal deoxynucleotidyl transferase dUTP nick end labeling （TUNEL） assay. There were no significant differences in the age of either partner or sperm concentration, motility or morphology between three groups. Moreover, there were no obvious differences in sperm DNA fragmentation measured by either test. However, whilst on average sperm DNA fragmentation in all groups was statistically lower in prepared sperm when measured by the SCD test, this was not seen with the results from the TUNEL assay. These results do not support the hypothesis that sperm DNA fragmentation is an important cause of RIF or RM, or that sperm DNA integrity testing has value in such patients. It also highlights significant differences between test methodologies and sperm preparation methods in interpreting the data from sperm DNA fragmentation tests.

温阳化浊法治疗不明原因复发性流产经验

不明原因复发性流产(unexplained recurrent spontaneous abortion,URSA)因其发病机制尚不明确,缺乏可靠、有效的临床治疗方法。夏天教授根据临床实践经验将URSA的根本病机总结为脾肾阳虚、湿浊内蕴,提出温阳化浊为治疗大法,自拟温阳化浊方,以温肾健脾、化湿蠲浊为主要治则,并注重孕前调理,预培其损,改善URSA患者的妊娠结局,临床疗效显著。简要论述温阳化浊法治疗URSA的理论和诊治思路,并举验案一则。

泰山磐石散对复发性流产小鼠母胎界面TGF-β、VEGF、PIGF影响

目的 观察泰山磐石散对复发性流产(RSA)小鼠母胎界面血管生成相关调控因子[转化生长因子-β(TGF-β)、血管内皮生长因子(VEGF)、胎盘生长因子(PIGF)]、胎盘蜕膜组织病理学形态的影响,并探讨其降低流产率的作用机制。方法 构建RSA小鼠模型32只,将造模成功的小鼠随机分为4组:模型组及泰山磐石散高、中、低剂量组,每组各8只;构建正常妊娠小鼠模型8只,作为空白组。自妊娠第1天,分别予相应药物干预,14 d后处死孕鼠,收集样本并计算小鼠流产率;采用苏木精-伊红(HE)染色对小鼠胎盘蜕膜组织病理形态变化进行观察;采用ELISA法检测小鼠血清中TGF-β、VEGF、PIGF含量。结果 模型组胎盘及蜕膜组织细胞形态不规则,排列紊乱,血管壁不完整且血管数量明显减少;经泰山磐石散方药干预后,各中药组小鼠胎盘及蜕膜组织病理形态均得到明显改善。与空白组相比,模型组小鼠流产率明显增加(P<0.05),血清中TGF-β、VEGF、PIGF含量显著降低(P<0.05);与模型组比较,泰山磐石散高、中剂量组均可有效降低小鼠流产率(P<0.05),且显著升高血清中TGF-β、VEGF、PIGF含量(P<0.05),其中泰山磐石散高剂量组降低流产率、升高血管生成相关调控因子情况尤为显著。结论 泰山磐石散通过上调TGF-β、VEGF、PIGF含量,参与复发性流产小鼠母胎界面的血管重塑过程,改善血管壁通透性,维持血流供应,从而改善胎盘蜕膜组织病理形态,发挥防治流产作用,提高RSA小鼠胚胎存活率。

原因不明复发性流产诊治及临床研究进展

复发性流产(recurrent spontaneous abortion,RSA)是目前常见的一种早期妊娠并发症,在近50%的病例中,RSA的病因仍然不明,这类病例通常被称为原因不明的复发性流产(unexplained recurrent spontaneous abortion,URSA)或特发性复发性流产。通过在PubMed上检索近十年来的相关研究,总结URSA疾病妇女发生流产事件的影响因素和机制,此外,还总结了现有临床实验诊断技术和治疗方法,探讨不同治疗之间的差异性与局限性,以及在未来临床研究过程中须待解决的问题和重要的优先事项。

反复妊娠丢失中同种免疫功能异常机制的研究进展

反复妊娠丢失(RPL)在育龄妇女中发病率达2%~5%,是一种多病因导致的严重危害患者身心健康的生殖疾病。越来越多的研究表明,同种免疫功能紊乱通过影响母胎界面的免疫平衡耐受、子宫内膜蜕膜化、滋养层细胞的凋亡、胎盘血管生成参与了RPL的发生。包括自然杀伤细胞、巨噬细胞和树突状细胞的数量及活性异常在内的固有免疫异常,和包括CD4+辅助性T细胞(Th1、Th2和Th17)、CD4+CD25+Foxp3+调节性T细胞、CD8+T细胞、γδ-T细胞、CD19+调节性B细胞和细胞因子数量及活性异常在内的适应性免疫异常,共同构成了同种免疫性RPL的免疫紊乱模式,但具体机制需要进一步研究和探讨。本文就目前RPL的同种免疫源性的病因机制研究及进展进行综述。

泰山磐石散对不明原因复发性流产模型Treg/Th17免疫平衡的影响

目的 观察泰山磐石散对不明原因复发性流产模型小鼠胚胎丢失率、子宫净重、蜕膜组织白细胞介素17A(IL-17A)、转化生长因子β(TGF-β)表达水平的影响,探讨其治疗机制。方法 将CBA/J雌鼠与DBA/2雄鼠建立复发性流产模型,按受孕时间随机分为4组,即盐水组和中药低、中、高剂量组,CBA/J雌鼠与BALB/C雄鼠建立正常组模型。确认妊娠后盐水组与正常组妊娠14 d内予0.9%氯化钠溶液,中药各组予低、中、高剂量中药灌胃。计算胚胎丢失率,称重胚胎;苏木精伊红染色观察蜕膜组织结构;酶联免疫吸附测定(ELISA)法检测各组孕鼠组织匀浆上清液IL-17A和TGF-β吸光度;计算TGF-β/IL-17A比值。结果 与正常组比较,盐水组形态紊乱,胚胎丢失率升高(P=0.001),子宫净重降低(P<0.05),TGF-β表达水平下降(P<0.05),IL-17A表达增加(P<0.05),TGF-β/IL-17A比值向IL-17A偏倚(P<0.05)。与盐水组比较,中药高剂量组结构规整;中药高、中剂量组胚胎丢失率降低(P<0.05);中药高剂量组的子宫净重增加(P<0.05),TGF-β表达增加(P<0.05),IL-17A表达下降(P>0.05);中药各组TGF-β/IL-17A比值均向TGF-β偏倚(P<0.05),但每个中药组间的差异不具有统计学意义(P>0.05)。结论 泰山磐石散可以降低胚胎丢失率,提高子宫净重,增加TGF-β表达,降低IL-17A表达,改变孕鼠蜕膜组织TGF-β/IL-17A表达平衡,可能通过调节孕鼠调节性T细胞(Treg)与辅助性T细胞Th17的偏倚改善母胎界面免疫平衡,最终改善妊娠结局。

赵宏利治疗复发性流产经验介绍

介绍赵宏利主任中医师治疗复发性流产的临床经验。赵宏利主任中医师诊治复发性流产从脾肾两亏、带脉不利、阴阳未济、胞宫瘀阻着手,治疗上重视孕前、孕后分阶段治疗。孕前重视大补脾肾、以培其本,通利带脉、以固胎元,燮理阴阳、调周助孕;孕后重视脾肾为本、化瘀止血,养血活血、理气安胎。

尤昭玲教授治疗轻中度宫腔粘连所致复发性流产经验

宫腔粘连是现代社会导致女性复发性流产的重要因素。尤昭玲教授从中西结合的角度出发,运用阴道三维超声对子宫内膜容受性的评估建立宫腔粘连的评分标准,通过判断宫腔粘连的不同程度决定治疗复发性流产的中西诊疗方案。对于轻中度宫腔粘连患者,提出带粘速孕,顺应月经的生理周期,从肾-天癸-冲任-胞宫轴学说论治宫腔粘连所致复发性流产,提出既需孕前调理助孕(月经期活血行气、清热化瘀;卵泡期补肾健脾、滋阴养血;排卵期温阳行气),同时也要注重孕后保胎,从而提高妊娠成功率。