低分子肝素在产科常见疾病中的应用

低分子肝素（LMWH）在达到有效的抗凝血作用的同时,可以减少肝素所致的出血等不良反应,在临床上具有一定的应用价值。目前LMWH广泛应用于产科临床,其不仅能预防妊娠期和产褥期深静脉血栓形成（DVT）,还能预防、治疗易栓症引起的子痫前期（PE）、胎儿生长受限（FGR）等产科常见并发症。对妊娠期及产褥期DVT的危险因素进行评估后,可考虑使用LMWH。研究发现,LMWH也能改善非易栓症孕妇的不良妊娠结局,降低高危人群（有胎盘早剥、早发型PE病史的孕妇）患早发型PE、重度PE、FGR及晚期流产的风险,延长妊娠时间,提高新生儿存活率和出生体质量。现综述近年来LMWH应用于产科DVT、PE和FGR的相关研究进展。     

低分子肝素在产科应用中的研究进展

低分子肝素(LMWH)是由标准肝素经裂解产生的分子量较小的肝素片段产物。LMWH与肝素相比,具有皮下注射吸收率高、半衰期长、生物利用度高、出血少及副作用小等优势,近年已逐渐取代肝素,在临床上得到广泛应用。血栓前状态是指多种因素引起的凝血、抗凝和纤溶系统功能失调或障碍的一种病理状态,可导致早发型重度子痫前期、胎儿宫内生长受限、妊娠期肝内胆汁淤积症及复发性流产等并发症。LMWH能有效改善机体血栓前状态,从而改善不良妊娠结局。     

阿司匹林及低分子肝素在子痫前期中应用的研究进展

子痫前期是妊娠中晚期常见的一种特发疾病,其病情变化快,发生HELLP综合征、胎盘早剥、子痫、早产、胎儿窘迫等严重并发症的概率高,是导致发展中国家孕妇不良妊娠结局的主要原因之一,目前缺乏有效的防治措施。子痫前期的基本病理改变为全身小动脉痉挛,致滋养细胞受损、侵蚀不良,胎盘浅着床,合体滋养细胞缺血、缺氧,炎性因子、促凝物质释放,使血压升高、凝血与纤溶系统失衡,血液早期处于高凝状态。低分子肝素（low molecular weight heparin,LMWH）和阿司匹林是产科常用的两种具有抗凝作用的药物,由于子痫前期患者与正常孕妇的凝血状态存在差异,这两种药物在子痫前期中的应用引起了国内外学者的关注。现就其在子痫前期防治过程中的有效性及安全性的研究进展进行综述。     

子宫螺旋动脉重铸与病理妊娠

子宫螺旋动脉重铸是妊娠正常进行的关键环节,绒毛外滋养细胞的增殖和侵袭是血管重铸过程的必要条件。滋养细胞生物学功能的完整和调控机制的协调起着至关重要的作用。滋养细胞浸润不足,栓塞螺旋动脉不彻底,母-胎循环的发生提前,使绒毛受到直接的机械损伤,氧化应激作用间接地造成细胞机能障碍和损伤,出现胎盘退化变性;人肿瘤蛋白p53(TP53)介导细胞通路对细胞周期蛋白依赖性激酶抑制剂1A(CDKN1A)和Bax基因的异常表达,微小RNA-520(miR-520)过度调控滋养细胞的凋亡导致母体出现复发性流产。由滋养细胞分泌产生的基质金属蛋白酶9(MMP-9)的异常表达和大量炎性因子的释放造成了胎盘缺血缺氧,表现出子痫前期的相关症状。胎盘绒毛的血管密度、绒毛间隙体积的降低、滋养细胞分化程度下降、微环境缺氧以及突触缺陷因子1(SYDE1)呈低水平表达,可能是造成胎儿生长受限的重要原因。因此研究螺旋动脉重铸过程对病理妊娠的早期诊治有着重要意义。     

低分子肝素治疗抗心磷脂抗体阳性引起流产的疗效观察

肝素临床上多用于抗凝治疗，同时肝素具有免疫抑制和免疫调节的双重作用。1997年3月开始，我们用低分子肝素静脉滴注治疗抗心磷脂抗体阳性引起的流产．井与传统的治疗方法进行了前瞻性对照研究。     

低分子肝素治疗重度子痫前期合并胎儿生长受限疗效观察

目的探讨小剂量低分子肝素对重度子痫前期合并胎儿生长受限（FGR）患者的疗效和安全性。方法将44例重度子痫前期合并FGR患者按随机数字表随机分为研究组和对照组,对照组给予硫酸镁基础治疗,研究组给予基础治疗外加用小剂量低分子肝素,分别于治疗前及治疗后1周彩超监测胎儿生长情况及脐血流指标;治疗前及治疗后1周检测血常规、凝血四项、血细胞比容（HCT）及D-二聚体;记录新生儿Apgar评分、体质量和胎盘质量。结果研究组治疗后胎儿每周头围[（1．0±0．5）mm]、双顶径[（2．3±0．7）mm]、腹围[（1．2±0．6）mm及股骨长[（2．2±0．6）mm]增长明显,治疗后脐血流PI（0．7±0．2）、RI（0．5±0．4）和S／D（2．5±0．3）均降低,HCT[（35．8±1．1）％]和D-二聚体[（2．0±0．4）mg／L]均明显改善,新生儿胎龄[（34．3±1．5）周]、出生体质量[（2150±210）g]及胎盘质量[（317±32）g]均明显增加,与对照组比较,差异均有统计学意义（P〈0．05）。两组均无并发症发生。结论小剂量低分子肝素治疗重度子痫前期合并FGR安全有效。     

低分子肝素在产科应用的研究进展

正一、病例摘要患者,女,31岁,孕0产0。体检发现CA125升高于2019年1月29日入院。2016年底体检发现CA125升高(具体数值不详)。2017年1月因便血于外院行肠镜示距肛缘8 cm肿物,病理为低分化腺癌,盆腔核磁考虑直肠癌(T3N2)。2017年1-2月于外院行奥沙利铂+氟尿嘧啶(FOLFOX方案)化疗2个周期。2017年3月于外院开腹探查,术中见肿瘤位于腹膜反折处,与子宫关系密切,右侧髂总血管下方及髂血管分叉处4 cm质硬结节。行髂血管区淋巴结活检,病理结果为淋巴组织增生,偶见脉管内可疑癌栓。     

表观遗传学在产科领域的研究进展

表观遗传学是研究表观遗传变异的遗传学分支学科.近年来,随着研究的深入,表观遗传学已在人类生长发育中的某段时期以及妊娠特发性疾病的发生及其防治方面显示其不可估量的作用和广阔的前景.在哺乳动物的生殖细胞发育时期和植入前胚胎期,其基因组范围内的甲基化模式通过大规模的去甲基化和接下来的再甲基化过程发生重编程,从而产生具有发育潜...     

表观遗传学在产科领域的研究进展

表观遗传学是研究表观遗传变异的遗传学分支学科。近年来,随着研究的深入,表观遗传学已在人类生长发育中的某段时期以及妊娠特发性疾病的发生及其防治方面显示其不可估量的作用和广阔的前景。在哺乳动物的生殖细胞发育时期和植入前胚胎期,其基因组范围内的甲基化模式通过大规模的去甲基化和接下来的再甲基化过程发生重编程,从而产生具有发育潜能的细胞。妊娠期间的环境因素包括接触有毒有害物质、内分泌干扰物以及食物、药品等均可改变表观遗传模式,导致妊娠妇女及其后代发生各种疾病。     

低分子肝素对胎儿生长受限的治疗作用

胎儿生长受限是围生期主要并发症之一,严重危害胎儿生存质量,其病因包括胎儿、胎盘、母体3方面。目前临床上常用补充营养物质等治疗,虽在一定程度上维持了胎盘功能,取得了一定效果,但部分患者治疗后并无改善。近年来用低分子肝素与一般营养支持等改善微循环的对照研究发现,低分子肝素能改善胎盘血供,促进胎儿生长发育,改善围生儿预后,对胎儿生长受限有较可靠的效果,且对母儿安全。     

Assessment of the effectiveness of using low molecular weight heparin in the prophylaxis of venous thrombo-embolic diseases in obstetrics

OBJECTIVES: Assessment of the effectiveness of using low molecular weight heparin in the prophylaxis of venous thrombo-embolic diseases in pregnant women, parturients and puerperants. MATERIAL AND METHODS: 14,106 female patients were retrospectively analysed in the period between 1990-1999. The patients were divided into 4 groups: I--142 pregnant patients with crural varices, II--10 pregnant patients who had suffered from deep venous thrombosis, III--5 patients with implanted artificial cardiac valves, IV--13,949 patients without any risk factors. In the patients in groups I-III low molecular weight heparin was used prophylactically. RESULTS: In the studied groups no cases of pulmonary embolism were observed. Superficial venous thrombosis occurred in 10 women (3 in group I and 7 in group IV). Deep venous thrombosis occurred in 5 patients (2 in group I and 3 in group IV). In patients who received low molecular weight heparin over a long period of time, no excessive bleeding during delivery was observed. Other complications in the form of osteoporosis and thrombocytopenia were also not observed. CONCLUSIONS: 1. Administering of low molecular weight heparin during pregnancy, labour and puerperium has no influence on the increase of maternal et fetal complications. 2. Administering of low molecular weight heparin in pregnant women, in labour and in puerperium with increase risk of thrombo-embolic disease allows to avoid pulmonary arteries embolism. 3. Pregnant women and women in puerperium with increased risk of venous thrombo-embolic disease should be under control of experienced obstetrician in cooperation with vascular surgeon and hematologist.     

Venous thromboembolic complications in obstetrics and gynecology with a focus on the role of low molecular weight heparin

Venous thromboembolism is a major cause of morbidity, mortality, and economic expense in the field of obstetrics and gynecology. Without prophylaxis, as many as 30% of at-risk patients will suffer deep vein thrombosis, and nearly 1% of these patients will succumb to a fatal pulmonary embolism. Both deep venous thrombosis and pulmonary embolism manifest few specific symptoms, and the presentation of these entities is often clinically silent. Therefore, a prophylactic approach is preferred. We review the pathophysiology, risk factors, prophylactic choices, and treatment of venous thromboembolic complications for the general obstetric and gynecology population. We focus on the role of low molecular weight heparin because of its convenient dosing and favorable risk/benefit profile.     

Pharmacokinetics of low molecular weight heparin and unfractionated heparin in pregnancy

OBJECTIVE: Little pharmacokinetic data are available for either low molecular weight heparins (LMWHs) or unfractionated heparins (UFHs) in pregnancy. The objectives of this study were to determine whether differences exist in the pharmacokinetics of dalteparin and UFH before and during the first, second, and third trimesters of pregnancy in women with the antiphospholipid antibody syndrome (APS). Adjustments in our dosing protocol would be made if differences existed. METHODS: Women with APS who were contemplating pregnancy were randomized to dalteparin 2500 U, 2500 U, 5000 U, and 7500 U daily, or UFH 5000 U, 5000 U, 7500 U, and 10,000 U every 12 hours, prior to pregnancy and the first, second, and third trimesters, respectively. Serial plasma concentrations of heparin were measured during 4 blood sampling days by determining anti-factor Xa activity. RESULTS: Fifteen (n = 9 receiving dalteparin and n = 6 receiving UFH) completed all four sampling periods. For dalteparin, significant differences (P <.05) were detected, using area under the curve (AUC), between pre-pregnancy versus third trimester, first versus second trimester, first versus third trimester, and second versus third trimester. No significant differences were detected in the UFH group. CONCLUSION: In APS, our original dosing protocol of dalteparin yielded significant differences (P <.05) in drug exposure throughout pregnancy. Based on these results, we recommend a prophylactic dalteparin dosing regimen of 2500 U every 24 hours pre-pregnancy (and for 6 weeks postpartum), and 5000 U every 24 hours during the first, second, and third trimesters. Due to lack of significant differences in AUC throughout pregnancy for UFH, we recommend continuing with our original dosing protocol.     

Comparison of low molecular weight heparin vs. unfractionated heparin in gynecological surgery. II: Reduced dose of low molecular weight heparin.

In a double blind, randomized trial the hemorrhagic complications of a reduced dose of low molecular weight heparin (LMWH) (Fragmin, KabiPharmacia) were compared to those of the conventional dose of unfractionated heparin (UH). 2500 anti-XaU of LMWH was given once daily and UH in a dose of 5000 anti-XaU twice daily. During a one year period 141 patients undergoing gynecological surgery were included in this study. The patients were examined clinically for hematomas and for deep venous thrombosis (DVT) on the third and fifth day. Venography was performed when DVT was suspected. No patients developed clinical DVT. One woman in the LMWH group had pulmonary embolism 3 days after the prophylaxis was stopped. Two women in the LMWH group died, one from a stroke on day 2, one from cancer on day 39. There was no significant difference in serious bleeding complications between the two regimens, 20% in the LMWH group and 14% in the UH group. Even with the reduced dose of LMWH the mean plasma concentration of heparin in the LMWH group was higher (mean 0.14 anti-XaU/ml) than in the UH group (0.029 anti-XaU/ml) 3 hours after injection on the 2nd postoperative day. A reduced dose of LMWH (2500 anti XaU once daily) does not cause more bleeding complications than the conventional heparin regimen to prevent thrombosis, as was the case in our previous study with 5000 anti XaU of LMWH once daily.     

Thromboprophylaxis with low molecular weight heparin in thrombophilia-complicated pregnancy

We treated three thrombophilia-complicated pregnant women (two antiphospholipid antibody syndrome, one protein C deficiency) with low molecular weight heparin (dalteparin). All three pregnancies including one twin pregnancy ended in live births without a decrease in bone mineral density. This treatment modality was effective and safe preventing thrombosis during their pregnancies.     

The use of unfractionated heparin and low molecular weight heparins in pregnancy

Currently unfractionated heparin (UH) and low molecular weight heparins (LMWH) are the agents of choice for anticoagulation in pregnancy. LMWH have been used safely without monitoring in nonpregnant patients; however, because of documented changes in the pharmacokinetics of these agents in pregnancy, monitoring with anti-Xa levels is necessary in pregnancy to maintain target therapeutic ranges. Patients requiring only prophylaxis during pregnancy with either UH or LMWH might benefit from occasional assessment of anti-Xa levels to confirm that target prophylactic ranges are being achieved. Although LMWH may cause less osteoporosis than UH at therapeutic doses, the incidence of heparin-induced osteoporosis seems to be low when only prophylactic dosing is used and therefore LMWH do not seem to offer this advantage at low doses. Experience with newer agents such as pentasaccharide inhibitors and direct thrombin inhibitors are limited in pregnancy and it remains to be seen what role these agents will play in women who require anticoagulation in pregnancy.     

The safety of low molecular weight heparin therapy during labor.

OBJECTIVE: Current recommendations are to discontinue low molecular weight heparin (LMWH) at least 24 hours prior to labor induction or administering epidural anesthesia. We assessed the safety of discontinuing LMWH 12-24 hours before delivery. METHODS: We evaluated the prevalence of hemorrhagic complications during labor, cesarean or epidural catheter placement in 284 women treated with enoxaparin during pregnancy as compared with 16132 untreated women. Treated participants were divided into subgroups by the various intervals between last LMWH dose hemorrhage-prone events (vaginal delivery,epidural, cesarean etc.). The rate of hemorrhagic complications and hemoglobin values were compared between the study and control groups. RESULTS: Postpartum hemorrhage was uncommon and occurred in 2.1% and 1.9% in study and control groups, respectively (p=0.13). Antenatal as well as postnatal hemoglobin values were very similar for treated and untreated women. No differences were noted between women who discontinued enoxaprin 12-24 hours before labor and those who discontinued treatment later with regard to maternal hemorrhagic complications. No spinal hematomas were report among 12792 treated and un-treated women who had epidural or spinal block. No hemorrhagic neonatal complications were encountered. CONCLUSION: Discontinuing LMWH more than 12 hours before delivery is safe in relation to maternal hemorrhagic complications.     

Comparison of low molecular weight heparin vs. unfractionated heparin in gynecological surgery

In a double-blind, randomized trial, the antithrombotic effect and haemorrhagic complications of low molecular weight heparin (LMWH) (Heparin fragment 2165, KabiVitrum) and unfractionated heparin (UH) were compared. LMWH (5000 anti-XaU) was injected every 24 h, UH (5000 IU) every 12 h; both drugs by subcutaneous injection. During 1984-85, 215 patients were examined clinically and by plethysmography. Venography was performed whenever DVT was suspected. None of the patients proved to have DVT. Bleeding complications were found in 54% of the cases. The LMWH group had a statistically significant predominance of bleeding complications as reflected by wound haematomas (p = 0.02) and the number of blood transfusions (p = 0.02). The heparin concentration was higher in the LMWH group (mean 0.13 IU/ml) than in the UH group (mean 0.13 IU/ml) measured 2 h after the injection. In the doses administered, LMWH and UH seem effective in the prevention of thrombosis. The increased bleeding tendency in the LMWH group probably was a consequence of the to high dosage.