血栓前状态与复发性流产及抗凝治疗

摘要：复发性流产是一种常见的妊娠相关疾病,发生率大约1%～3%。目前,妊娠期血栓前状态是复发性流产领域的研究热点。遗传性血栓前状态及获得性血栓前状态都是自然流产的高危因素。抗凝治疗是针对血栓前状态有效的治疗措施,仍需更完善的循证医学证据来证实其对于复发性流产患者的有效性。     

地屈孕酮联合阿司匹林与低分子肝素治疗不明原因复发性流产的效果观察

目的 观察地屈孕酮联合阿司匹林与低分子肝素治疗不明原因复发性流产的效果。方法 选取200例不明原因复发性流产患者为研究对象,按照随机数字表法分成对照组与研究组,各100例。对照组采用地屈孕酮+小剂量阿司匹林治疗,研究组采用地屈孕酮+小剂量阿司匹林+低分子肝素治疗。比较两组患者的妊娠结局、不良反应发生情况、临床症状改善时间、治疗前后免疫功能及凝血功能指标。结果 对照组足月产80例(80.00%)、早产17例(17.00%)、流产3例(3.00%);研究组足月产60例(60.00%)、早产25例(25.00%)、流产15例(15.00%)。研究组妊娠结局优于对照组(χ²=9.524,P=0.002)。研究组免疫功能及凝血功能指标优于对照组,临床症状改善时间短于对照组(P<0.05)。两组不良反应发生率比较,差异无统计学意义(χ²=0.307,P=0.594)。结论 地屈孕酮联合小剂量阿司匹林与低分子肝素治疗不明原因复发性流产,可改善妊娠结局,值得推广。     

低分子肝素联合丹参治疗复发性流产的疗效分析

目的:探讨低分子肝素(LMWH)联合丹参治疗血栓前状态(PTS)和(或)自身免疫因素所致的复发性流产(RSA)患者的临床结局,分析治疗效果。方法:选择2016年10月至2018年10月就诊于贵州医科大学附属医院生殖中心的PTS和(或)自身免疫因素所致的185例RSA患者,根据治疗意愿,124例采用LMWH联合丹参治疗的患者纳入联合组,61例采用LMWH治疗的患者纳入单药组。比较两组妊娠结局、凝血指标和LMWH使用量、胎盘血流指数水平、妊娠期并发症及药物不良反应情况。结果:联合组孕期保胎成功率、抱婴率、分娩孕周及新生儿出生体质量均明显高于单药组,差异均有统计学意义(P 0. 05);联合组孕早期D-二聚体、纤维蛋白原(FIB)、孕期LMWH总使用量、孕中期胎盘脐血流指数[收缩期/舒张压(S/D)、搏动指数(PI)、阻力指数(RI)]、羊水过少、胎儿生长受限(FGR)及胎盘早剥的发生率均明显低于单药组,差异有统计学意义(P 0. 05)。联合组患者用药过程中过敏和总不良反应的发生率低于单药组,差异有统计学意义(P 0. 05);联合组孕期PLT水平、早产、前置胎盘、妊娠期高血压疾病(HDP)、产后出血、新生儿窒息及死亡的发生率均低于单药组,但差异无统计学意义(P 0. 05)。结论:LMWH联合丹参治疗RSA患者,可改善高凝状态及胎儿脐血流指标,降低胎盘相关疾病的发生率,提高保胎成功率,不良反应少,安全性高。     

子痫前期抗凝治疗安全性和有效性的循证评价

妊娠期凝血功能的改变是子痫前期发病机制中重要环节,采用抗凝治疗可以有效预防妊娠期高血压疾病及其并发症的发生.低分子肝素和小剂量阿司匹林是目前应用较多的抗凝药物,作者从循证医学的角度评价这两种药物在子痫前期抗凝治疗中的安全性和有效性.     

低分子肝素对妊娠早期复发性流产患者子宫动脉血流影响的自身对照前瞻性研究

目的:研究低分子肝素(LMWH)对复发性流产(RSA)患者妊娠早期子宫动脉血流的影响,以及PI值、RI值和S/D比值对LMWH的敏感性。方法:选取2016年1月至2017年12月在中国医科大学附属盛京医院门诊就诊的妊娠早期子宫动脉血流异常、皮下注射LMWH 8000IU/d的RSA患者255例。根据用药时长分为A组(2周)、B组(3周)、C组(4周)和D组(6周)。比较分析用药前后子宫动脉血流PI值、RI值、S/D比值和切迹的变化情况,通过绘制ROC曲线对各指标进行敏感度分析。结果:A组治疗前后的子宫动脉血流PI值、RI值、S/D比值无明显差异(P0.05),B、C、D组治疗前后有显著差异(P0.05)。治疗前,4组的子宫动脉血流PI值、RI值、S/D比值比较,差异无统计学意义(P0.05),随着治疗时间的增加,各项指标数值逐渐降低,PI值在3～4周稳定,RI值在4周左右稳定,S/D比值在4周时达到最低值,而到6周时又升高到3周水平。治疗后4组子宫动脉舒张期血流切迹均有部分转阴,治疗4周前后有明显差异(P0.05)。子宫动脉血流S/D比值对LMWH治疗的敏感度明显高于PI值和RI值,两侧数值之和的敏感度高于右侧和左侧。结论:对于早期妊娠的RSA患者,LMWH皮下注射8000IU/d,持续4周以上,可有效改善异常子宫动脉血流,子宫动脉血流双侧S/D比值之和对LMWH的敏感度更高。     

重视妊娠期抗凝药物的合理应用

<正>妊娠期的孕妇处于高凝状态,有些妊娠期的生理变化和危险因素会引起和凝血相关的并发症的风险明显增加。这些危险因素包括,但不仅仅局限于:孕妇的凝血因子增加,蛋白S水平下降,纤溶功能受影响,胎盘会产生纤溶抑制剂,静脉淤滞,妊娠晚期下腔静脉受增大子宫的压迫,剖宫产,雌孕激素水平的上升,卵巢过度刺激综合征,多胎,易栓症,感染,肥胖,吸烟等。虽然中华妇产科学会产科学组于2016年发布了"复发性流产诊治的专家共识",但仅仅是针对     

低分子肝素在复发性流产中的应用及监测

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。     

低分子肝素在复发性流产中的应用及监测

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。     

复发性流产的诊断与治疗

复发性流产的病因及相关因素 张建平教授 复发性自然流产（recurrent spontaneous abortion，RSA）是指与同一性伴侣连续遭受2次或2次以上在妊娠20周前的胎儿（体重≤500g）丢失者，是育龄妇女的常见病。从不同地区、不同阶层及不同年龄统计，自然流产的发生率约为15％～40％。2次或2次以上的流产患者约占生育期妇女的5％，而3次或3次以上者约占1％～2％。国内仍把3次或3次以上在妊娠28周之前的胎儿丢失称习惯性流产。     

复发性流产与自身免疫性疾病

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。     

复发性流产病因学研究进展

复发性流产（recurrent spontaneous abortion, RSA）一般指与同一配偶发生连续３次或３次以上的自然流产。近年来许多学者提出将连续发生2次的自然流产者纳入RSA的范畴,原因是连续发生2次自然流产后,再次妊娠的流产率可高达50%以上,要引起足够的重视。RSA的病因复杂,目前已知的病因有染色体异常、生殖道解剖异常、内分泌失调、感染性疾病因素、血栓前状态、自身免疫因素等。除此之外,临床上仍有至少40%以上的患者病因不明。由于RSA的病因复杂,造成了RSA的难治性,是目前基础与临床研究的难点与热点。     

妊娠合并自身免疫性疾病的抗凝治疗

妊娠合并自身免疫性疾病患者因病理生理性的血栓形成倾向大大增加,常导致严重的母胎并发症。低分子肝素和阿司匹林等抗凝药物作为妊娠期安全用药,在改善此类患者的母胎结局中发挥着重要作用。因此,规范抗凝治疗有助于改善母胎不良结局。     

复发性流产的内分泌因素

复发性流产是一种常见妊娠并发症,病因复杂多样,其中内分泌因素占8%～12%,文章主要就甲状腺功能异常、高催乳素血症、多囊卵巢综合征及代谢异常、糖尿病、黄体功能不全等内分泌因素进行综述,旨在为复发性流产的预防及治疗方面带来新的思考。     

KDR gene polymorphisms and idiopathic recurrent spontaneous abortion

Objective: Process of angiogenesis is essential for successful gestation. Disruption in this pathway leads to various undesirable consequences in pregnancy such as recurrent spontaneous abortion (RSA). One of the most important genes involved in angiogenesis is kinase-insert domain-containing receptor (KDR). This study aimed to investigate the associations between two single-nucleotide polymorphisms (SNPs) of KDR gene, 1719A?>?T and 1192G?>?A, with idiopathic RSA in south-east Iran.

Methods: A total of 230 women, including 110 women with a history of at least two consecutive spontaneous miscarriages and 120 healthy women were recruited in this study. Genomic DNA was extracted from peripheral blood samples of participants using the Salting out method. The KDR 1719A?>?T and 1192G?>?A polymorphisms were genotyped by the standard amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) technique.

Results: For the case group, frequencies of 2.73%, 30% and 67.27% were observed for AA, AT and TT genotypes in1719A?>?T SNP, respectively, and the genotype frequencies for controls were equal to AA?=?3.33%, AT?=?32.5% and TT?=?64.17%. Distribution of genotypes in 1192G?>?A SNP in the case group was 79.1%, 19.1% and 1.8% for GG, AG and AA, respectively, whereas the corresponding values for the controls were GG = 80%, AG = 20% and AA = 0. No significant difference was found between the case and control groups based on the frequency of KDR gene polymorphisms with the susceptibility to RSA.

Conclusions: There is no association between these two SNPs of KDR gene and the susceptibility to RSA in women from south-east Iran.     

复发性自然流产抗心磷脂抗体阳性血清对滋养细胞发育能力的影响

目的评价抗心磷脂抗体阳性的复发性流产患者血清对滋养细胞发育能力的影响及阿司匹林对滋养细胞发育的调节。方法选取2007年1月至9月在山东省立医院产科门诊就诊的自身抗体阳性复发性流产妇女8例(研究组),同期有足月分娩史的健康妇女8名(对照组)。将BeWo细胞分为4组,分别与含或不含阿司匹林的研究组血清或正常对照组血清进行孵育,四甲基偶氮唑蓝比色法(MTT)检测细胞成活力,流式细胞仪检测调亡相关抗体M30表达,酶联免疫吸附法(ELISA)检测加入腺苷酸环化酶激活剂(forskolin)后融合成的合体滋养细胞β-人绒毛膜促性腺激素(β-HCG)的分泌情况,评价各组BeWo细胞的发育能力。结果研究组较对照组490nmOD值(0.2061±0.0191对0.2414±0.0320)和β-HCG浓度[(19.4488±1.8132)U/L对(22.9900±2.2568)U/L]明显减少,M30平均表达[(4.7868±0.5170)%对(0.7900±0.1786)%]明显增多(均P<0.05)。对照组加入阿司匹林后,490nmOD值为0.2411±0.0327,β-HCG浓度为(23.2288±2.0581)U/L,M30表达为(0.6325±0.1701)%,与加入前相比P>0.05。研究组加入阿司匹林后490nmOD值、β-HCG浓度、M30平均表达、分别为0.2369±0.0311,(21.5675±1.3338)U/L,(2.7037±0.8920)%,与加入前相比P<0.05。结论抗心磷脂抗体可以导致滋养细胞的成活力及融合分泌能力减低,调亡增多;阿司匹林在一定程度上能够逆转这一不良影响,改善滋养细胞成活力及融合分泌能力,减少滋养细胞凋亡。     

Aspirin or heparin or both in the treatment of recurrent spontaneous abortion in women with antiphospholipid antibody syndrome: a meta-analysis of randomized controlled trials

Objective: This study was designed to evaluate the efficacy of aspirin or heparin or both in the treatment for recurrent spontaneous abortion (RSA) in women with antiphospholipid antibody syndrome (APS).

Methods: Systematic searches for randomized clinical trials (RCTs) evaluating on live birth and preterm delivery, preeclampsia, intrauterine growth restriction, gestational diabetes, bleeding of RSA with APS patients receiving aspirin, and heparin therapy were carried out, from PubMed, EMBASE, ScienceDirect, and CNKI. Related data were extracted from eligible studies and then subjected to Reviewer Manage 5.3 for analysis. Relative risk (RR) and its 95% confidence interval were calculated.

Results: Nineteen publications with randomized controlled trials were selected for this study, which included a total of 1251 pregnant patients with diagnosis of RSA with APS. With respect to live birth, it was remarkably improved in aspirin plus heparin or heparin alone group [RR?=1.23, 95% CI (1.12–1.36), p?p?=?.02]; aspirin alone group, however, there was no statistically significant difference compare to placebo [RR?=?0.97, 95% CI (0.80–1.16), p?=?.71]. Meanwhile, aspirin plus heparin therapy did not significantly reduce the risk of recurrent placenta-mediated pregnancy complications including preterm birth, intrauterine growth retardation (IUGR), gestational diabetes, and minor bleeding. A beneficial therapeutic effect of heparin alone therapy was found on preventing preterm birth and low-dose aspirin plus heparin therapy was significant reduce the risk of preeclampsia.

Conclusion: An improvement of pregnancy outcomes in women with RSA and APS can be achieved by treatment strategies combining low-dose aspirin plus heparin or heparin alone. Aspirin alone, by contrast, seemed inferior to other treatments in achieving more live birth.     

T regulatory markers expression in unexplained recurrent spontaneous abortion

Objective: To evaluate expression of glucocorticoid-induced tumor necrosis factor receptor (GITR), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and IL-10 in peripheral blood mononuclear cells (PBMCs) of 20 women with unexplained recurrent spontaneous abortion (URSA) compared to 20 normal non-pregnant women (NNP) during luteal phase in the window of implantation.

Methods: Quantitative real-time PCR (qRT-PCR) was performed using the Taqman method for expression of GITR and SYBR Green method for expression of CTLA-4 and IL-10.

Results: Expression of CTLA-4 in the NNPs (median; interquartile range; 3; 1.8–10) was significantly higher than the URSAs (0.72; 0.26–3.81, p?=?0.015). Expression of GITR in the NNPs (53; 10–139) was significantly higher than the URSAs (6; 3–27, p?=?0.005). However, IL-10 expression in the URSAs was significantly higher than the NNPs, did not meet a significant value. A significant correlation was found between CTLA-4 and GITR expression in the study population (p?=?0.0001).

Conclusions: Expression of CTLA-4 and GITR were significantly down-regulated in the URSAs compared to NNPs at the window of implantation, which shows the essential role of Treg cells in creating an immunological privileged site for fetus as an allograft at the maternal–fetal interface by high expression levels of CTLA-4 and GITR during a normal pregnancy.     

原因不明复发性流产的诊治

复发性流产严重威胁人类的生殖健康,约50%患者病因不明,基于循证医学的诊断和治疗策略相对匮乏,是生殖医学中最困难的领域之一。文章重点阐述原因不明复发性流产的病因学和治疗研究现状及进展。