子痫前期抗凝治疗的研究进展

子痫前期是一种严重影响母儿预后及远期生存质量的妊娠期特发性疾病,病理性高凝状态及胎盘血管重铸障碍为其发病基础,合理的抗凝治疗可能改善子痫前期的妊娠结局。低分子肝素(LMWH)和小剂量阿司匹林已经在多个研究中证实了在妊娠期间使用的安全性,是目前妊娠期间常用的抗凝药物。LMWH对子痫前期的预防和治疗尚存在争议,但研究提示早发型或有严重并发症的子痫前期可能有较好的治疗效果。小剂量阿司匹林用于子痫前期高危孕妇的预防及治疗已经得到了各个指南的共同推荐。LMWH和阿司匹林联合治疗子痫前期目前仍存在争议,各个实验之间异质性较大,需要较大样本量的有严格纳入标准的临床研究进一步证明。重组人可溶性血栓调节蛋白(r-TM)是一种新型的抗凝药物,目前动物实验已经证实可能有逆转子痫前期的潜力,有望为子痫前期的治疗提供新的方向。     

阿司匹林预防子痫前期的局限性和临床应用选择

孕期口服小剂量阿司匹林是广泛使用的预防子痫前期的方法.在临床工作中,存在扩大阿司匹林使用适应证、高估预防效果的情况.文章将结合循证医学证据,介绍目前阿司匹林预防子痫前期的局限性、精准选择适应人群的意义,避免孕期模式化使用小剂量阿司匹林.     

阿司匹林预防子痫前期的相关问题

子痫前期是严重威胁母胎安全的常见产科疾病,降低其发病率具有重要意义。近年研究表明,阿司匹林作用于血小板环氧化酶1(cyclooxygenase 1,COX1)等多个子痫前期发病的关键靶点,从而在预防疾病发生中发挥重要作用。掌握阿司匹林预防子痫前期的应用指征及时机,排除应用禁忌证后合理用药,可有效降低子痫前期的发病率,或减缓其病情严重程度。     

小剂量阿司匹林预防子痫前期的循证医学意义

循证医学证据表明,小剂量阿司匹林能够预防高危孕妇发生子痫前期,减少其不良妊娠结局。推测小剂量阿司匹林通过抗血栓作用,改善胎盘微循环及妊娠结局。现有的研究证据也表明,未发现孕期使用小剂量阿司匹林有明确的危害,特别是针对高危孕妇,获益大于潜在的风险。然而,使用阿司匹林预防子痫前期的最佳剂量和时机、高危人群的有效覆盖尚无法断定。     

妊娠期高血压疾病的热点问题讨论

主要讨论内容:1．妊娠高血压疾病的分类;2．早发型子痫前期的处理;3．子痫前期一子痫的解痉治疗;4．小剂量阿司匹林能否预防子痫前期;5．子痫前期患者心衰的处理。     

小剂量阿司匹林在子痫前期高危患者中的应用价值研究

目的 观察在子痫前期高危患者中实施小剂量阿司匹林治疗的临床价值。方法 选取160例子痫前期高危患者,将其根据治疗方法不同分为对照组与研究组,每组80例。对照组患者给予安慰剂进行常规干预,研究组患者给予小剂量阿司匹林进行治疗。比较两组患者临床效果。结果 研究组子痫早期发生率13.75%低于对照组的28.75%(P<0.05)。研究组早产率、产后出血率、新生儿窒息率及胎盘早剥率与对照组比较,差异无统计学意义（P>0.05）。结论 子痫前期高危患者给予小剂量阿司匹林干预,能够有效预防子痫前期的发生,值得临床推广。     

睡前口服小剂量阿司匹林预防高危孕妇子痫前期的发生

目的:探讨小剂量阿司匹林对高危孕妇子痫前期及妊娠诱发的高血压综合征的预防作用。方法:将242例存在子痫前期高危因素暴露的孕13~16周的妇女随机分成阿司匹林处理组(n=120,睡前口服75 mg阿司匹林至分娩)和对照组(n=122,安慰剂替代阿司匹林),随访至妊娠结束后2周,记录子痫及妊娠高血压综合征的发生率。结果:本研究中共失访5例,其中阿司匹林组2例,对照组3例。子痫前期的发生率,阿司匹林组低于对照组(18.6%vs 52.9%),其中轻度子痫前期、早发子痫前期、严重子痫前期的发生率阿司匹林组(11.0%、3.4%、4.2%)均低于对照组(26.9%、12.6%、13.4%)。妊娠诱发高血压的发生率(4.2%vs 16.0%)、宫内发育迟缓发生率(13.6%vs 30.3%)、出生孕周<34周的孕妇比例(4.2%vs 13.4%)、37周前分娩的孕妇比例(18.6%vs 40.3%)、流产比例(2.5%vs 10.1%),阿司匹林组均低于对照组。平均出生体质量(2 890±340 g vs 2 611±479 g)、平均出生孕周(36.8±2.0 vs 35.0±3.1),阿司匹林组大于对照组(P<0.05)。阿司匹林组与对照组在新生儿围产期内死亡率(0.8%vs 1.7%)、胎盘早剥率(6.8%vs 5.0%)、阴道分娩率(43.2%vs 40.3%)之间均无统计学差异(P>0.05)。结论:睡前口服小剂量阿司匹林能使子痫前期高危孕妇受益。     

子痫前期凝血状态评估及抗凝治疗

<正>正常妊娠时,孕妇血液处于凝血和抗凝系统平衡的血栓前状态(PTS)。重度子痫前期患者,特别是早发型重度子痫前期患者,凝血和抗凝系统失衡,凝血系统处于病理性高凝状态。失衡的PTS,为抗凝治疗提供了依据。近年对小剂量阿司匹林和低分子肝素(LMWH)在子痫前期的应用进行了大量的临床研究,表明有子痫前期高危因素的患者使用小剂量阿司匹林和LMWH,可预防子痫前期的发生,改善妊娠结局和新生儿预后。     

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.     

高血压患者孕前和孕期风险评估及处理

高血压患者妊娠易发生重度子痫前期及多脏器损害,导致母儿严重并发症。高血压患者孕前应综合评估妊娠风险,孕前应将血压控制在正常范围,选择合适妊娠时间。孕期加强监护,应用阿司匹林预防子痫前期。终止妊娠时机及方式应根据病情严重程度及母儿情况综合决定。分娩过程中注意监测血压,产后加强随访。     

Preeclampsia prevention: lessons from the low-dose aspirin therapy trials

The ability of low-dose aspirin therapy to prevent preeclampsia is controversial. The 19 randomized, placebo-controlled trials of low-dose aspirin therapy reported in the literature were categorized according to the risk factors of the women studied-nulliparity, underlying medical illness, poor obstetric history, and multiple gestation. Low-dose aspirin therapy reduced the incidences of preeclampsia among women with poor obstetric histories and among high-risk nulliparous women but was ineffective among women with underlying medical illness. It was marginally effective among low-risk nulliparous women, and benefits for women with multiple gestations are unclear. More research is needed to better identify high-risk nulliparous women who might benefit from the use of low-dose aspirin therapy and to define potential benefits for women with multiple gestations. The differential effects of low-dose aspirin therapy in the various risk groups are probably a result of varying roles in the groups of abnormal arachidonic acid metabolism in mediating preeclampsia. It is premature to abandon the use of low-dose aspirin therapy for preeclampsia prevention.     

Aspirin and Prevention of Preeclampsia

Summary: 1. A heterogeneous group of randomized trials have been conducted using low-dose aspirin to prevent preeclampsia. The results do not support widespread use of low-dose aspirin to prevent preeclampsia.
2. On the basis of existing literature, it is reasonable to use prophylactic low-dose aspirin from early pregnancy in the following groups:
(i) Women with prior fetal loss after the first trimester, with placental insufficiency (ii) Women with severe fetal growth retardation in a preceding pregnancy either
due to preeclampsia or unexplained
(iii) Women with severe early-onset preeclampsia in a previous pregnancy
necessitating delivery at or before 32 weeks' gestation.
3. On the basis of existing literature, it is recommended that aspirin not be used in the following groups:
(i) Healthy nulliparous women
(ii) Women with mild chronic hypertension
(iii) Women with established preeclampsia.
4. The data are sufficient to support further trials in more homogeneous select subgroups of women considered at risk of developing preeclampsia.     

An aspirin a day to prevent prematurity.

Intrauterine fetal growth retardation and preeclampsia remain a substantial cause of preterm birth world wide. There is evidence to suggest that a functional imbalance between vascular prostacyclin and platelet-derived thromboxane A2 production plays a central role in the pathogenesis of these disorders. Low-dose aspirin appears to reverse the above functional balance resulting in increased prostacyclin to thromboxane ratio. The efficacy and safety of low-dose aspirin in preventing preeclampsia and fetal growth retardation were tested in several randomized and uncontrolled trials. The data in the literature suggest that low-dose aspirin is effective in reducing preterm birth due to the above complications in selected high-risk pregnant women.     

Decreased Pathological Placental Findings in Aspirin-Treated Pregnant Women at Risk of Hypertensive Complications

Objective: The small controlled trials reporting large reductions in the incidence of preeclampsia and intrauterine growth restriction (IUGR) in highrisk pregnant women treated with low-dose aspirin have recently been followed by large clinical trials suggesting less beneficial results. The effect of low-dose aspirin on placental lesions associated with preeclampsia and IUGR has not yet been studied.

Methods: We participated in the large multicenter randomized collaborative low-dose aspirin study in pregnancy (CLASP) trial of low-dose aspirin for the prevention and treatment of preeclampsia and intrauterine growth restriction. As part of this study, we evaluated placentae submitted from 25 women treated with aspirin and 28 with placebo.

Results: More of the pathological findings classically described in preeclampsia and IUGR were demonstrated in the placentae from the placebo group than from the aspirin group (54% vs. 16%, P = 0.02). The placental findings did not correlate with clinical pregnancy outcome or Doppler flow parameters of the fetal umbilical artery in either group.

Conclusions: Our results support the assumption that aspirin may have some inhibitory effect on the uteroplacental circulatory ischemic changes typically occurring in preeclampsia and IUGR.     

Favorable Maternal and Fetal Effects of Danshensu in an Experimental Mice Model of Preeclampsia

Background. Preeclampsia is a serious pregnancy-specific complication that results in high maternal and neonatal mortality and morbidity worldwide. Till date, there is no satisfactory pharmacotherapeutic treatment, except for aspirin and heparin, to stop the preeclampsia progression. Although the mechanism of preeclampsia is poorly understood, it has proved to be associated with coagulation activation. Researches on prophylactic and remedial application of anticoagulants maybe benefit the clinical aspects of preeclampsia individuals. Methods. Sixty-six preeclampsia-like pregnant mice, induced by phosphatidyleserine/phosphatidylcholine (PS/PC) microvesicle administration, were randomly divided into six groups as follows: control group (group C), preeclampsia model group (group PE), group treated with heparin (group H), group treated with aspirin (group A), group treated with low-dose danshensu (group LD), and group treated with high-dose danshensu (group HD). Systolic blood pressure (SBP), proteinuria, mean platelet counts, plasma antithrombin III activity (AT III), D-dimmer levels, thrombin time (TT), fibrin deposition with phosphotungstic acid hematoxylin (PTAH) staining, and thrombomodulin (TM) expression with immunohistochemistry staining in placentas were examined as indices for maternal syndrome. Meanwhile, the number of potentially viable fetuses, weight of fetuses and placentas, weight of fetal brains, nose-breech length, ponderal index (PI), and neurons with hematoxylin-eosin (H/E) and toluidine blue-eosin (Nissl's) staining were all evaluated as indices for fetal syndrome. Results. Heparin presents significant effects on maternal syndrome of preeclampsia such as hypertension and proteinuria, and different dose danshensu also presents the certain effects. High-dose danshensu and aspirin all process better effects than low-dose danshensu on decreasing blood pressure to normal level, whereas high-dose danshensu process better effects than aspirin and low-dose danshensu on decreasing proteinuria to normal level. As to danshensu's effects on hemostatic function, high- and low-dose danshensu's marked effects on increasing the plasma AT III activity are same as that of aspirin and inferior to heparin. High-dose danshensu's better effect on elevating the platelet counts is superior to low-dose danshensu and aspirin. Low-dose danshensu's obvious effect on decreasing D-dimmer levels is close to heparin and superior to high-dose danshensu and aspirin. High- and low-dose danshensu's significant effects on reduced TT level are same to that of heparin. Different anticoagulants all have the improvement roles on placental fibrin depositions, but heparin and high-dose danshensu's roles on lowering thrombomodulin expression in placentas are superior to low-dose danshensu and aspirin. But anticoagulant function of high-dose danshensu is still inferior to heparin. Furthermore, we found the following changes: increasing fetal body weight and length in every group, obvious overall improvement in group H, greater amelioration equaling to that in heparin group on maternal body weight, fetal nose-breech length and fetal brain weight in group HD, better changes on survival fetal number in group LD than in other groups, and more corrected brain development in group HD than in group A. We found long-term use of heparin and aspirin, in spite of low-dose administration, can raise the risk of bleeding such as placental abruption and intestinal hemorrhage. But no side effect was observed in mice treated with different dose of danshensu in our study. Conclusions. Danshensu has proven effective in ameliorating the prognosis of maternal syndrome and fetal syndrome in the PE mouse model. We suggest long-term provision of low-dose danshensu in pregnancy, leading to an improvement of preeclampsia syndrome with considerable maternal safety.     

Preventing preeclampsia and its fetal complications with low-dose aspirin in East Asians and non-East Asians:A systematic review and meta-analysis

Background: Low-dose aspirin can reduce the incidence of preeclampsia and intrauterine growth restriction (IUGR). However, the effects of ethnicity upon low-dose aspirin’s efficacy has not been analyzed. Here, we comparatively evaluated the efficacy of low-dose aspirin in preventing preeclampsia and related fetal complications in East Asian and non-East Asian pregnant women at risk for preeclampsia. Methods: Several databases were searched for randomized controlled trials (RCTs) comparing low-dose aspirin with either placebo or no treatment in pregnant women at risk for preeclampsia. Odds ratios (ORs) and associated 95% confidence intervals (CIs) for preeclampsia and related fetal outcomes were tabulated. Results: Low-dose aspirin significantly reduced preeclampsia risk in both East Asians (OR = 0.20, 95% CI: 0.11–0.35) and non-East Asians (OR = 0.84, 95% CI: 0.77–0.92). Low-dose aspirin significantly reduced IUGR risk in East Asians (OR = 0.36, 95% CI: 0.20–0.67) but not in non-East Asians (OR = 0.85, 95% CI: 0.41–1.77). Low-dose aspirin did not significantly reduce the risk of cesarean section in either East Asians (OR = 0.67, 95% CI: 0.14–3.22) or non-East Asians (OR = 1.01, 95% CI: 0.86–1.19). Conclusions: Low-dose aspirin is effective in reducing preeclampsia risk in both East Asians and non-East Asians and has differential effects in East Asians and non-East Asians with respect to IUGR.     

Low-dose aspirin: treatment for the imbalance of increased thromboxane and decreased prostacyclin in preeclampsia

The discovery of the imbalance of increased thromboxane and decreased prostacyclin production in preeclamptic women has explained the cause of the major clinical symptoms of this disorder and has formed the basis and rationale for clinical studies with low-dose aspirin to treat preeclampsia. Low doses of aspirin (60 to 81 mg/day) have a remarkable ability to inhibit thromboxane production selectively without significantly inhibiting prostacyclin production. Therefore the actions of thromboxane to increase vasoconstriction, stimulate platelet aggregation, increase uterine contractility, and decrease uteroplacental blood flow are attenuated, and the ratio of thromboxane to prostacyclin is altered in favor of prostacyclin. Prostacyclin promotes vasodilation, inhibits platelet aggregation, decreases uterine contractility, and increases uteroplacental blood flow. The initial clinical studies with low doses of aspirin are very encouraging with respect to the treatment and prevention of preeclampsia. Substantial evidence already indicates that low-dose aspirin therapy decreases the incidence of preeclampsia; it decreases the maternal systemic arterial pressor response to angiotensin II; and it does not seem to be harmful to the fetus. Treatment of preeclampsia with prostacyclin appears to be contraindicated because prostacyclin is a potent systemic vasodilator and the clinical outcome of preeclamptic women infused with prostacyclin has been poor. The mechanism whereby low-dose aspirin preferentially inhibits thromboxane synthesis is not known.(ABSTRACT TRUNCATED AT 250 WORDS)     

What we have learned about preeclampsia

Preeclampsia is a multisystem disorder that complicates 6% to 8% of pregnancies, with higher rates in women with preexisting hypertension, diabetes mellitus, or previous history of preeclampsia. Recent large randomized trials, including two large trials conducted by members of the Maternal-Fetal Medicine Network, have not shown a benefit in reducing the rate of preeclampsia or perinatal outcome from the use of low-dose aspirin. Secondary analysis from these trials revealed that the onset of mild gestational hypertension or mild preeclampsia at or near term was associated with minimal to low neonatal and maternal morbidities. During review of the medical records we found considerable differences among the various centers regarding the definitions of both mild and severe preeclampsia. These differences were more prevalent in those women with pre-existing hypertension or diabetes mellitus. The majority of adverse pregnancy outcomes occurred in women who developed severe gestational hypertension-preeclampsia prior to 35 weeks' gestation and in those women with previous preeclampsia and/or pre-existing vascular disease. We also found that epidural anesthesia is safe in parturients receiving low-dose aspirin in pregnancy and in women with severe preeclampsia.