子痫前期高危孕妇阿司匹林抵抗与基因多态性相关性

子痫前期是妊娠期特有的高血压疾病,近年尤其是早发型子痫前期,是孕产妇和新生儿发病和死亡的重要原因。低剂量的阿司匹林在国外已明确用于子痫前期的预防,可以减少子痫前期的发展,并降低早产和胎儿生长受限的发生率。但部分患者不能达到预期效果,存在阿司匹林抵抗。在阿司匹林预防血栓相关研究中同样存在阿司匹林抵抗现象。目前基因多态性与阿司匹林抵抗的相关性已成为研究热点。研究较多的有ABC转运蛋白家族基因、环氧合酶(COX)基因(COX-1和COX-2)、TXA2R基因、ADP受体基因、GP受体等基因多态性及其相互作用。由于其在孕妇中鲜有研究而在心脑血管疾病中研究较多,现重点从基因多态性角度阐述在心脑血管疾病中阿司匹林抵抗的可能机制,以指导阿司匹林在孕妇这类特殊人群的用药,改善妊娠结局。     

子痫前期患者内皮素受体A基因G-231A多态性的研究

目的:探讨内皮素受体A(EDNRA)G-231A基因多态性与子痫前期有无关联。方法:用聚合酶链反应-限制性片段长度多态性分析法(PCR-RFLP),对成都地区220例子痫前期患者(其中轻度71例,重度149例)和270例健康对照组孕妇EDNRA基因G-231A多态性进行检测。结果:子痫前期组和正常孕妇组EDNRA基因G-231A位点A等位基因频率分别为35.9%、31.3%,两组之间等位基因频率分布无显著差异(P>0.05);重度子痫前期组与轻度子痫前期组比较,A等位基因频率分别为36.3%、35.2%,二者无显著差异(P>0.05)。此外,子痫前期组和正常孕妇组不同基因携带者收缩压和舒张压水平无统计学差异(P>0.05)。结论:本研究未发现EDNRA基因G-231A多态性与子痫前期发病有关联。     

子痫前期高危人群GPIba和COX-1基因多态性与阿司匹林抵抗的相关性研究

目的 探讨GPIba和COX-1基因多态性与子痫前期（preeclampsia,PE）高危人群发生阿司匹林抵抗的相关性。方法 将2022年3月至2023年3月在乌鲁木齐市妇幼保健院进行孕检符合入组标准的77例孕12～20周孕妇作为研究对象,连续口服阿司匹林肠溶片100mg,连续7～14 d,空腹抽取2管静脉血各4mL,利用血栓弹力图分析仪检测血小板功能,计算花生四烯酸（AA）的抑制率。根据抑制率分为阿司匹林抵抗组（AR组）和敏感组（AS组）。实时荧光定量PCR法检测GPIba(GP1BA,rs6065)和COX-1(PTGS1,rs10306114)基因表达,利用PCR扩增和直接测序法对2种基因多态性进行分析,并收集相关临床检验指标。结果 两组孕妇基线资料及PE发生率比较,差异无统计学意义。与AS比较,AR组中GP1BA和PTGS1表达均明显上调（P<0.01）,但rs10306114仅有花生四烯酸（AA）1种基因型,rs6065有3种基因型,且rs6065位点的基因型在两组中的分布差异无统计学意义;AA抑制率较敏感组均明显降低,血小板AA含量较敏感组明显增加,差异有统计学意义（...     

小剂量阿司匹林对子痫前期早期干预和预防作用

子痫前期是母儿围产期死亡及医源性早产的重要原因,近年来越来越多研究表明妊娠期应用小剂量阿司匹林可改善子痫前期发病过程中前列环素(PGI2)/ 血栓素A2(TXA2)比例失衡所致的血液高凝状态,从而预防子痫前期的发生。建议有高危因素的孕妇,在妊娠早期结束后尽快开始口服小剂量阿司匹林,在有效预防子痫前期发病的同时并不增加胎儿及产妇的出血风险,从而获得良好的母儿结局。     

COX-1,COX-2在子痫前期患者胎盘和脐带组织的表达

目的:研究环氧合酶-1(COX-1),环氧合酶-2(COX-2)在子痫前期患者胎盘和脐带组织的表达,探讨它们在子痫前期发病机制中的作用。方法:用免疫组化SP法检测50例子痫前期患者(轻度30例,重度20例)胎盘和脐带组织中COX-1,COX-2表达,20例正常孕妇为对照组。结果:(1)COX-1、COX-2在轻、重度子痫前期组的表达水平均明显高于对照组,两两比较,差异有统计学意义(P<0.05)。COX-1在重度子痫前期组和轻度子痫前期组中表达均无统计学差异(P>0.05),而COX-2重度子痫前期组与轻度子痫前期组的差异有统计学意义(P<0.05)。结论:COX-1,COX-2参与了子痫前期胎盘螺旋小动脉和脐带血管动脉粥样硬化的发展过程。     

LMP基因多态性及其在母胎间共享与子痫前期相关性研究

目的:探讨孕妇及胎儿巨大多功能蛋白酶体(LMP)基因多态性及母胎LMP共享与重度子痫前期的关系。方法:利用聚合酶链反应-限制性内切酶片段长度多态性(PCR-RFLP)方法对2006年7月至2010年8月于我院住院治疗的77例重度子痫前期母胎和200例正常妊娠母胎的LMP2、LMP7基因进行多态性对应分析。结果:(1)LMP2-R/R、LMP7-B/B在重度子痫前期组孕妇分布频率明显低于对照组,LMP2-R/H在重度子痫前期组孕妇分布频率明显高于对照组,OR值分别为0.211,0.238,4.594;(2)LMP2及LMP7共12种等位基因型在重度子痫前期组和对照组胎儿间分布的差异无统计学意义;(3)母胎间共享一个基因重度子痫前期组明显低于对照组,共享四个基因型者重度子痫前期组明显高于对照组,OR值分别为0.051和5.360。结论:LMP2-R/H可能是重度子痫前期的易感基因,LMP2-R/R、LMP7-B/B可能是重度子痫前期的保护基因。母胎LMP基因共享率高对重度子痫前期的发生可能是独立因素。     

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。     

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。     

ACE基因I/D多态性与子痫前期高血压和肾脏损害关系的研究

目的探讨血管紧张素转换酶（ACE）基因插入／缺失（I／D）多态性与子痫前期患者高血压和肾脏损害程度的相关性。方法选择子痫前期患者82例，正常孕妇45例，利用多聚酶链反应（PCR）分析其外周血白细胞中ACE基因多态性，计数两组孕妇ACE基因型和等位基因分布频率，比较不同基因型子痫前期患者高血压程度和肾功能。结果根据插入／缺失片段的有无，将ACE基因分为DD、ID、II三种基因型，子痫前期患者和正常孕妇ACE基因型和等位基因频率无统计学差异。子痫前期患者中携带D等位基因孕妇的收缩压和舒张压呈升高趋势，血清尿酸含量显著增加，但肌酐、尿素氮水平无统计学差异。结论ACE基因与子痫前期肾脏损害密切相关，携带D等位基因的子痫前期患者肾脏损害严重，血压也有升高趋势，提示D等位基因可能是子痫前期患者病情加重的不利因素。     

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。     

Placental tissue cyclo-oxygenase 1 and 2 in pre-eclamptic and normal pregnancy.

OBJECTIVE: To investigate the activities of the 2 isoforms of prostaglandin synthetic enzyme cyclo-oxygenase (COX), COX-1 and COX-2, in the placental tissue of women with pre-eclampsia and healthy pregnant women. The relationship between placental lipid peroxidation and the activities of COX-1 and COX-2 was also investigated. METHODS: Tissue specimens were obtained from pre-eclamptic women (20 had severe pre-eclampsia and 38 had mild pre-eclampsia) and 27 healthy pregnant women who underwent cesarean section before the onset of labor. Malondialdehyde (MDA) levels and COX-1 and COX-2 activities were measured in placental tissue homogenates. RESULTS: Mean activities for COX-1 and COX-2 were significantly lower in women with severe pre-eclampsia than in healthy controls (P<0.05 and P<0.01, respectively). COX-1 and COX-2 activities were also lower in women with mild pre-eclampsia than in healthy controls, but the difference was of borderline significance (P=0.049 and P=0.059, respectively). The mean placental MDA level was significantly higher in pregnant women with severe and mild pre-eclampsia than in healthy pregnant women (P<0.01 for both). The correlation analysis showed significant negative correlations between MDA and COX-1 (r=-0.44, P<0.001) and MDA and COX-2 (r=-0.45, P<0.001) in the placental tissue of women with pre-eclampsia. CONCLUSION: These results suggest that COX-1 and COX-2 activities are decreased in the placental tissue of women with pre-eclampsia, probably by oxidative stress.     

Prediction and prevention of pregnancy-induced hypertensive disorders.

Because hypertensive disorders complicating pregnancy are common and constitute a leading cause of maternal, fetal and neonatal morbidity and mortality, prevention attempts appear to be justified. Primary prevention is only possible by avoiding pregnancy. Secondary prevention requires identification of patients at risk. A large number of predictive methods have been published and the majority appear to be of no or limited value. At present only the determination of inactive urinary kallikrein and uteroplacental colour-pulsed Doppler velocimetry show promise and require further assessment. Analysis of the many interventions advocated for prevention of pre-eclampsia reveals that only dietary calcium supplementation and prophylactic low-dose aspirin have shown promise of efficacy in small controlled clinical trials, but the results of large, multicentre trials are disappointing. The disappointing results obtained in large, multicentre trials may be explained, at least in part, by the lack of strict eligibility criteria and end-points and by low patient compliance. Prophylactic low-dose aspirin is recommended in women at high risk because it is associated with a moderate reduction in risk, may reduce the severity of pre-eclampsia if it develops and appears to be safe for mother and infant. The present data do not support any prophylactic intervention in pregnant women at low or medium risk.     

Synergistic effect of renin-angiotensin system and nitric oxide synthase genes polymorphisms in pre-eclampsia

BACKGROUND: Components of the renin-angiotensin system and endothelial nitric oxide synthase may co-operate in spiral artery remodelling during placentation, and thus reduce the uteroplacental resistance typical of normal pregnancy. Since lack of such remodelling and abnormal placentation are specific features of pre-eclampsia, it has been suggested that abnormal function of both components of the renin-angiotensin system and endothelial nitric oxide synthase may be involved in its pathogenesis. However, previous studies of the association between pre-eclampsia and polymorphisms of single genes encoding renin-angiotensin system components and endothelial nitric oxide synthase have yielded conflicting results. The aim of this study was to assess if interactions among different polymorphisms of the renin-angiotensin system and nitric oxide synthase are involved in the pathogenesis of pre-eclampsia. METHODS: Some 359 pregnant women were enrolled: 103 normotensive, 50 with chronic hypertension, 86 with gestational hypertension, and 120 with pre-eclampsia. DNA analysis was performed to evaluate angiotensin-converting enzyme I/D, angiotensin-II receptor 1 1166A/C, angiotensinogen M235T and endothelial constitutive nitric oxide synthase 4b/a polymorphisms. Odds ratios (OR) with 95% confidence interval (CI) and chi2 tests were calculated. RESULTS: The frequency of single gene polymorphisms was similar in each group. The frequency of pairs including the DD genotype of the angiotensin-converting enzyme I/D polymorphism plus other homozygous genotypes was significantly higher in pre-eclamptic patients than in controls (OR=3.04, 95% CI=1.16-7.93). CONCLUSIONS: Synergism of angiotensin-converting enzyme I/D and other polymorphisms of renin-angiotensin system components and nitric oxide synthase may be a risk factor for pre-eclampsia.     

杀伤细胞免疫球蛋白样受体基因多态性与子痫前期发病的相关性

目的 探讨杀伤细胞免疫球蛋白样受体(KIR)基因多态性(SNP)与子痫前期发病的相关性.方法 序列特异性引物PCR(PCR-SSP)技术检测子痫前期患者71例(子痫前期组)和正常孕妇100例(对照组)的外周血KIR基因型;实时荧光定量PCR技术检测两组各5例孕妇胎盘组织中KIR2DL4 mRNA的表达情况;DNA直接测序技术检测子痫前期组40例和对照组38例孕妇外周血KIR2DL4基因外显子区及其和内含子交界区的SNP.结果 (1)基因型:对照组共发现50种KIR基因型,子痫前期组共发现40种KIR基因型,两组有16种基因型重合;子痫前期组以基因型42的表达频率最高(15.5%),其次是基因型51(9.9%)和基因型47(7.0%);对照组以基因型47的表达频率最高(22.O%),其次是基因型48(11.O%).两组16种重合的KIR基因型的分布比较,差异有统计学意义(P=0.01).(2)胎盘组织KIR2DL4 mRNA的表达:子痫前期组患者胎盘组织KIR2DL4 mRNA的表达最为14.05±0.25,对照组为12.19±0.85,两组比较,差异有统计学意义(P=0.02).(3)KIR2DL4基因测序:KIR2DL4基因测序发现18个SNP位点,其中有7个为新发现的SNP位点,检测到的所有SNP位点的等位基因、基因型在两组的分布比较,差异无统计学意义(P>0.05).结论 KIR基因型可能与子痫前期的发病相关;KIR2DL4 mRNA表达量下降可能参与子痫前期的病理生理过程.     

Anticoagulant therapy and pregnancy

Low dose aspirin therapy is one of the anticoagulant treatments used during pregnancy. Anticoagulant agents may be useful for several disorders, such as recurrent miscarriage, pre-eclampsia, fetal growth restriction and infertility. However, it is unclear whether anticoagulant therapy can increase the live birth rate in all of these cases. Recent data suggest that a low-dose aspirin and heparin combination therapy is effective in the prevention of recurrent pregnancy loss in women with antiphospholipid syndrome. Thrombogenic diseases, for example, protein C deficiency, protein S deficiency, factor XII deficiency and hyperhomocysteinemia, may cause pregnancy loss. The etiology of recurrent miscarriage is often unclear and may be multifactorial, with much controversy regarding diagnosis and treatment. Although 70% of recurrent pregnancy losses are unexplained, anticoagulant therapy is effective in maintaining pregnancy without antiphospholipid antibody syndrome. We conclude that a low-dose aspirin and heparin combination therapy can be useful for unexplained cases of recurrent pregnancy loss without antiphospholipid antibody syndrome. (Reprod Med Biol 2008; 7 : 1–10)     

Anwendungsbeschränkung von Aspirin während der Schwangerschaft

The case of a high-risk pregnant woman is reported (morbid obesity, gestation-related hypertension, and diabetes mellitus) who died of hemorrhagic shock a few hours after giving birth by Cesarian section followed by intra-abdominal bleeding and emergency hysterectomy. The patient had been taking acetylsalicylic acid (aspirin, 100 mg per day) until the day before delivery due to her history of a brainstem infarction. Indications for low-dose, administration of aspirin during pregnancy include (1) secondary prophylaxis for myocardial or cerebral infarction, (2) prevention of placental insufficiency with intrauterine growth restriction, (3) prevention of pre-eclampsia, and (4) treatment of antiphospholipid syndrome. Aspirin inhibits platelet thromboxane A2 formation, even at very low doses (e.g. 40–60 mg per day). Since this pharmacological effect persists for the lifespan of the entire circulating platelet population (7–10 days), even after a single dose the drug must be discontinued at least 5 days prior to any scheduled operation. During pregnancy, aspirin (including low-dose administration) must be stopped in all cases after the 37th week of gestation and, if possible, should not be administered during the last 3 months of gestation. For individual patients, an alternative antithrombotic treatment with a low-molecular-weight heparin may be considered.     

Barbados Low Dose Aspirin Study in Pregnancy (BLASP): a randomised trial for the prevention of pre-eclampsia and its complications

Objective To determine whether prophylactic, low dose controlled-release aspirin improves outcome for pregnant women and their babies in Barbados.
Design Randomised placebo-controlled trial.
Setting The Queen Elizabeth Hospital, Barbados.
Population All women attending antenatal clinics between 12 and 32 weeks of gestation were eligible, if without specific contraindications to aspirin and unlikely to deliver immediately.
Methods Randomisation was computer-generated in the antenatal clinic; 1822 women were allocated to receive 75 mg controlled-release aspirin and 1825 matching placebo.
Main outcome measures Proteinuric pre-eclampsia, other pregnancy-induced hypertension, pregnancy duration, birthweight, stillbirths and neonatal deaths, major neonatal events.
Results All but three women from each group were followed up successfully. Forty-four percent were primigravid, and 8% had previous obstetric complications. There were no significant differences between the allocated treatment groups in the incidence of proteinuric pre-eclampsia (40 [2.2%] of those allocated aspirin, compared with 46 [2.5%] allocated placebo), of preterm delivery (255 [14.0%] vs 270 [14.8%]), of birthweight < 1500 g (32 [1.7%] vs 33 [1.8%]) or of stillbirth and neonatal death (44 [2.4%] vs 38 [2.1%]). Aspirin was not associated with excess risk of maternal orfetal bleeding.
Conclusions The results of this study in Barbados do not support the routine use of low dose aspirin for prevention of pre-eclampsia or its complications, confirming results of previous large trials in other settings.     

A comparison of the inactive urinary kallikrein:creatinine ratio and the angiotensin sensitivity test for the prediction of pre-eclampsia

Objective To determine the relation between the inactive urinary kallikreimcreatinine ratio (IUK:Cr) and the angiotensin sensitivity test (AST) at 28 weeks of gestation and to assess each as a screening test for pre-eclampsia.
Design Prospective interventional study.
Subjects Four hundred and fifty-nine normotensive nulliparous women recruited from hospital antenatal clinics.
Setting John Radcliffe Maternity Hospital, Oxford, and Queen Charlotte's and Chelsea Hospital, London.
Interventions A urine sample for IUK:Cr measurement was provided before performing the AST at 28 weeks of gestation. Those women who demonstrated increased sensitivity to angiotensin II were entered into a randomised placebo controlled trial of low dose aspirin for the prevention of pre-eclampsia (CLASP).
Main outcome measures The development of pre-eclampsia.
Results The IUK:Cr ratio was significantly lower in those women who showed increased sensitivity to angiotensin II (   P < 0.0001  Student's t test). The sensitivity and specificity for detecting pre-eclampsia were, respectively, 22% and 85% for the AST and 67% and 75% for the IUK:Cr. Low-dose aspirin (60 mg) had no effect on the pregnancy outcome.
Conclusion There appears to be some relation between the IUK:Cr and AST tests in pregnancy. However, in this population, the IUK:Cr ratio was a better screening test for pre-eclampsia than the AST, but overall neither test was a powerful predictor for the syndrome.