Placental pathology in fetal thrombophilia

The aim of this study was to test the hypothesis that placental vascular lesions of the fetal circulation are caused by fetal thrombophilic mutations. The study included 64 newborns of women with one or more of the following pregnancy complications: preeclampsia, placental abruption, and intrauterine growth restriction. The most prevalent inherited thrombophilias--factor V Leiden, factor II (prothrombin) G20210A, and homozygosity for methyltetrahydrofolate reductase C677T--were examined in maternal blood and fetal umbilical cord blood. One pathologist reviewed all of the slides for fetal vascular lesions. Associations between fetal thrombotic vasculopathy and fetal thrombophilia were tested for using Fisher's exact test; Z scores and gestational age were compared using the Student t-test. Fetal thrombophilic mutations were diagnosed in 19 of 64 newborns, 15 of whom had coexistent maternal thrombophilia. There was no statistical difference in the prevalence of thrombotic lesions of the fetal circulation between newborns with and without thrombophilia. The combination of maternal and fetal thrombophilia was also not associated with increased fetal vascular lesions. The results indicate that fetal thrombophilia alone, even in the context of maternal underperfusion, is not associated with fetal vascular lesions of the placenta, although it may represent an underlying risk factor for lesions triggered by other process(es).     

Thrombophilia and adverse pregnancy outcome

Congenital and acquired thrombophilias are the most common predisposing factors for thromboembolism, but they may also contribute to pathophysiological processes involved in recurrent pregnancy loss, fetal death, intrauterine growth restriction, placental abruption, placental infarction, and pre-eclampsia. The most common thrombophilias are deficiencies of antithrombin III, protein C, and protein S, acquired protein C resistance, genetic mutation encoding for factor V Leiden, prothrombin gene, and inherited hyperhomocysteinemia, and antiphospholipid syndrome. Although adverse pregnancy outcomes are more common in women with thrombophilia, the current evidence does not support routine thrombophilia screening of all pregnant women. Selective thrombophilia screening may be justified in certain group of women, particularly those with a history of thromboembolism. More research is required to confirm or refute the causal link between thrombophilia and abnormal placentation, and assess effectiveness and safety of thromboprophylaxis in pregnant women.     

Do placental lesions reflect thrombophilia state in women with adverse pregnancy outcome?

We examined the relationship between placental histology and thrombophilia status in women who were admitted with severe pre-eclampsia/eclampsia, placental abruption, intrauterine growth restriction or unexplained stillbirth. All women had thrombophilia screen at least 10 weeks after delivery (antithrombin III, protein C, protein S, activated protein C resistance, anticardiolipin antibodies, lupus anticoagulant, fasting plasma homocysteine and specific mutations to methylenetetrahydrofolate reductase C677T, G20210A prothrombin gene and factor V Leiden. Placental histology reports were examined to identify the frequency of thrombotic lesions in the placenta including fetal stem vessel thrombosis, fetal thrombotic vasculopathy, placental infarction, perivillous fibrin deposition, intervillous thrombosis and placental floor infarction. During a 17 month period, a cohort of 79 women met the study criteria. Thirty (70%) out of 43 women with abnormal thrombophilia screen had abnormal placental histology. Twenty-eight (78%) out of 36 women with negative thrombophilia screen had abnormal placentae. No specific histological pattern could be identified when thrombophilia positive and thrombophilia negative groups were compared. We propose that there is a poor correlation between thrombophilia status and pathological changes of the placenta in women with severe pregnancy complications.     

妊娠合并妊娠期高血压疾病晚期妊娠258例临床分析

目的探讨妊娠期高血压疾病对晚期妊娠的影响。方法选取我院3年来孕28w以上住院分娩病例,以妊娠合并妊娠期高血压疾病258例作观察组,随机抽取正常妊娠孕妇480例作对照组,对比分析胎盘早剥、早产、胎儿窘迫、胎儿宫内发育迟缓、死产、产后出血发生率、新生儿窒息率、剖宫产率和对孕妇的影响。结果观察组的胎盘早剥、早产、胎儿窘迫、胎儿宫内发育迟缓、死胎、新生儿窒息率、产后出血发生率、剖宫产率等母婴并发症均明显高于对照组（P〈0．05）。结论妊娠期高血压疾病对晚期妊娠的母婴结局有许多不良影响。     

The thrombophilic fetus

Thrombophilia is the increased tendency to thrombosis. Inherited and acquired factors may determine thrombophilia. Some physiologic conditions, such as pregnancy are themselves "thrombophilic". In pregnancy, in fact, there is a decrease of all natural anticoagulant systems, such as antithrombin, protein C and protein S that are partially compensated by an increased fibrinolysis. It has been well established that women with thrombophilic disorders are at greater risk of venous thromboembolism in pregnancy and puerperium. It has also been observed that those women have higher prevalence of those obstetric complications in which microplacental thrombosis may play a pathogenetic role, such as placental abruption, preeclampsia, intrauterine growth restriction, intrauterine fetal death, repeated spontaneous miscarriage. Given that those complications are not always associated with maternal thrombophilia, controversy still exists on the exact impact of the disorders with the adverse pregnancy outcomes. While we are convinced that thrombophilias are extensively implicated in pregnancy complications, we feel that there has not been completely elucidated the role of the different factors, the gestational age at which those factors may intervene, nor has been given enough relevance to the weight of fetal thrombophilias in the origin of some specific form of those obstetric complications. We should bear in mind that some thrombophilias may be inherited from the mother, the father or both. Our hypothesis is that maternal thrombophilias may be responsible for venous thromboembolism, preeclampsia HELLP and eclampsia, whereas fetal thrombophilia, may account for IUGR or stillbirth. This last would also explain some stillbirth or repeated late (>10 gestational weeks) miscarriage observed in non-thrombophilic mothers. The two sides of thrombophilia may, of course, concur, resulting in the more severe clinical presentations.     

妊娠高血压疾病并发胎盘早剥25例病例分析

目的探讨妊娠高血压疾病并发胎盘早剥早期诊断、早期治疗及预后情况。方法对我院1997年7月-2009年8月20日25例妊娠高血压疾病并发胎盘早剥患者的临床资料进行回顾性分析。结果 (1)25例妊娠高血压疾病并发胎盘早剥患者中妊娠期高血压2例(8%),子痫前期17例(68%)其中重度子痫前期15例(60%),轻度子痫前期2例(8%),慢性高血压并发子痫前期1例(4%),子痫5例(20%)。(2)25例妊娠高血压疾病并发胎盘早剥患者行剖宫产18例(72%),自然分娩7例(28%),其中产钳助产1例(4%)。(3)25例妊娠高血压疾病并发胎盘早剥患者胎死宫内8例(32%)其中6例B超提示死胎,2例自感胎动消失,新生儿窒息8例(32%),新生儿死亡0例,孕产妇死亡0例,子宫切除2例(8%),产后出血3例(12%),DIC1例(4%)。结论胎盘早剥是威胁孕产妇及胎儿生命的妊娠晚期并发症,尤其是并发妊娠高血压疾病的胎盘早剥,更应早期诊断、早期治疗,以提高母婴预后。     

The impact of the factor V Leiden mutation on pregnancy

A resistance to the anticoagulant activity of activated protein C (APC), most frequently due to a point mutation in the Factor V gene (the Leiden mutation), represents the most common genetic cause of thrombophilia. The Leiden mutation has been significantly related to pregnancy complications associated with hypercoagulation, e.g. deep vein thrombosis during pregnancy (8-fold increased risk), pre-eclampsia (prevalence of the mutation up to 26%), placental infarction extending to > 10% of the placenta (10-fold increased risk), abruptio placentae (prevalence of the mutation up to 29.6%), and second- and third-trimester pregnancy failure (prevalence of the mutation up to 31.3%). An association of the maternal mutation with recurrent first-trimester miscarriage does not emerge from the literature, although fetal mutation (frequency higher than twice compared with that of the general population) has been related to early spontaneous miscarriage. Although some evidence suggests an association between APC resistance and intrauterine growth retardation, no significant relationship emerges currently from the literature. Screening for the Leiden mutation would seem advisable in women with previous pregnancy complications amongst those associated with APC resistance. Carriers of the mutation should be given appropriate counselling. The screening of asymptomatic women is not recommended at present.     

Thrombophilia and pregnancy complications

Thrombophilic risk factors are common and can be found in 15% to 25% of Caucasian populations. Since pregnancy is an acquired hypercoagulable state, women harboring thrombophilia may present with clinical symptoms of vascular complications for the first time during gestation or at the postpartum period(1).Women with thrombophilia may have an increased risk of placental vascular complications, including pregnancy loss, preeclampsia, intrauterine growth restriction,and placental abruption. Accumulating data suggest that maternal antithrombotic prophylaxis may result in improved gestational outcome. Randomized trials are under way and hopefully will optimize maternal and neonatal outcome.     

Prevalence of factor V Leiden, hyperhomocysteinemia, prothrombin G20210A, and methylene tetrahydrofolate reductase C677T mutations in obstetrical complications]

The etiology and pathogenesis of intrauterine fetal death, preeclampsia or fetal growth retardation remain still unknown in many cases. However, placental thrombosis and/or infarction might lead to inadequate maternal-fetal circulation. So, the relevance of an additional thrombotic risk factor that enhances the physiological hypercoagulable state of gestation has been suggested in the development of these adverse outcomes of pregnancy. Several genetic mutations are newly recognized associated with an increased frequency of venous thrombosis: mutation of adenine to guanine at nucleotide 506 in the factor V gene, mutation of cytosine at nucleotide 677 in the methylenetetrahydrofolate gene and mutation of guanine to adenine at nucleotide 20210 in the prothrombin gene. In this issue, a review of literature has allowed us to evaluate the prevalence of these genetic predisposing thrombotic factors with the development of obstetrical complications. Furthermore, therapeutic approach is considered.     

Obstetric complications in patients with hereditary thrombophilia identified using the LCx microparticle enzyme immunoassay: a controlled study of 5,000 patients

Factor V Leiden (FVL) and prothrombin (PT) G20210A mutations are associated with increased risk of deep venous thrombosis, pulmonary embolism, and obstetric complications. The development of inexpensive and reliable screening methods will assist in defining subpopulations of patients at risk who should undergo testing. We used a method, developed by Abbott Laboratories (Abbott Park, IL), to study 5,000 pregnant women and evaluated the association of obstetric complications with the presence of the FVL and PT G20210A mutations. We found a statistically significant association between FVL and stillbirth. There were also trends toward an association between FVL and placental abruption and between PT G20210A and intrauterine growth retardation. In addition, an association may exist between PT G20210A and preterm delivery for white women. All other parameters studied, including miscarriage and preeclampsia, did not show a statistically significant association with FVL or PT G20210A. These results confirm the association between genetic thrombophilia and selected obstetric complications.     

妊娠期高血压疾病的孕期干预与妊娠结局的关系

目的:探讨妊娠期高血压疾病的孕期干预与妊娠结局的关系。方法:回顾性分析1093例孕产妇临床资料,包括妊娠期高血压疾病患者规律产检组(干预组)389例,不规律产检组(对照组)204例,同期分娩的正常妊娠孕产妇(正常组)500例,观察孕期干预对妊娠期高血压疾病孕产妇并发症如胎盘早剥、早产、产后出血、眼底出血、中重度贫血、HELLP综合征等的发生率,以及新生儿窒息、胎儿宫内生长受限(FGR)、胎儿窘迫等围产儿不良结局的发生率。结果:正常组孕产妇并发症、围产儿不良结局及剖宫产率均低于两妊娠期高血压疾病组,差异有统计学意义(P均<0.05);干预组孕产妇并发症发生率(27.25%)和围产儿不良结局发生率(42.42%)均低于对照组,差异有统计学意义(P均<0.05)。结论:妊娠期高血压疾病的孕期监测及保健治疗干预可以降低孕产妇及围产儿不良事件的发生率,改善母婴预后。     

Clinical cure of severe, early onset preeclampsia with low molecular weight heparin therapy in primigravida with hyperreactio luteinalis and thrombophilia

Inherited thrombophilias, suggested to be risk factors for ovarian hyperstimulation syndrome and known to be associated with venous thromboembolism during pregnancy, may also increase the risk for preeclampsia (PE). We describe the case of a 29-year-old woman with primary infertility with no history of thrombosis, hypertension or renal disorders. In her first pregnancy, achieved by frozen embryo transfer, she developed severe early-onset (23rd gestational week) PE with heavy proteinuria, and at the same time was found to have enlarged ovaries with hyperreactio luteinalis. After admission we found that she was a heterozygotic carrier of the factor V Leiden mutation. After administering low molecular weight heparin (LMWH) therapy, her blood pressure normalized, proteinuria diminished and her d-dimer values returned to that of a normal pregnant level. The fetus grew normally. Her ovaries normalized during the pregnancy, as determined by ultrasound examinations. At term she delivered spontaneously a normal weight, healthy girl. Previously, only prophylactic LMWH, in subsequent pregnancy, have been administered in patients with thrombophilia and a history of severe PE. We describe a case of spontaneous hyperreactio luteinalis, where the clinical characteristics of PE improved after beginning LMWH therapy in severe, very early onset PE. Inherited thrombophilia, spontaneous hyperreactio luteinalis and PE may be associated phenomena.     

Factor V Leiden: association with venous thromboembolism in pregnancy and screening issues

Disturbances of the natural balance between procoagulant and anticoagulant mechanisms can result in bleeding or thrombotic tendencies. Factor V, on activation by thrombin to factor Va, forms an essential component of the prothrombinase complex, in which it demonstrates its cofactor activity for factor Xa. Down-regulation of factor Va by activated protein C (APC) occurs through cleavage of specific peptide bonds in the heavy chain of the molecule. Factor V Leiden (FV Leiden) is a mutation of factor V that renders factor Va resistant to APC, due to loss of one of these cleavage sites. This mutation predisposes the patient to thrombosis. Prevalence of FV Leiden varies; however, heterozygosity for the FV Leiden mutation is recognised as the most common heritable thrombophilic defect in Caucasian populations. The association this inherited thrombophilia has with venous thromboembolism (VTE) is well established. Pregnancy is notably an acquired hypercoagulable state, due in part to physiological changes that occur in the coagulation system. This seems to have potential for interaction with FV Leiden to cause adverse experiences. A role has been suggested for FV Leiden in VTE events during pregnancy. At present only selected women are screened for FV Leiden. Pregnant women with a history of VTE or with a family history of the mutation are investigated. Whether or not the introduction of a routine screening plan for this mutation is justified remains a matter for debate.     

Thrombophilias as risk factors for disorders of pregnancy and fetal damage

Inherited thrombophilias have been suggested as a possible condition of increased susceptibility to adverse pregnancy outcomes. Although there is no consensus on the association between the factor V Leiden mutation and early (less than 10 weeks) pregnancy loss, the evidence suggests an association between the mutation and second-, and third-trimester fetal loss and severe preeclampsia. At present the relationship between the prothrombin G20210A mutation and inherited thrombophilias and adverse pregnancy outcomes remains controversial. Due to the low prevalence, AT and PC deficiencies have been rarely found as the cause of complicated pregnancy, whereas increased risk for preeclampsia and fetal losses has been found in relation to PS deficiency. Concerning the association between pathological pregnancies and PAI-1 4G/5G deletion/insertion polymorphism, only few controversial data are available. A meta-analysis of ten case-control studies suggested an association between hyperhomocysteinemia, MTHFR C677T mutation and repeated pregnancy losses before 16 weeks. Recently a role for Angiotensin Converting Enzyme I/D polymorphism in obstetrical complications has been suggested.     

The possible role of AhR in the protective effects of cigarette smoke on preeclampsia

Although smoking during pregnancy may lead to many adverse effects, such as fetal growth restriction, placental abruption, stillbirth, and preterm labor, smoking is the only environmental exposure known to consistently reduce the risk of preeclampsia and gestational hypertension. The exact mechanisms through which cigarette smoke reduces the risk of preeclampsia are not yet understood. Aryl hydrocarbon receptor (AhR), as the most abundant expression protein in the placenta, was widely studied in the human reproduction. We propose that cigarette smoke decreases the risk of developing preeclampsia via direct activation of AhR system in placenta. In this review we will address, and provide evidence for, our specific hypotheses that: cigarette significantly enhance trophoblast invasion and decrease placental oxidative damage through activation of AhR. This mechanism of suppression must be further investigated as they may provide valuable clues to novel therapeutic design in the realm of preeclampsia research.     

高龄产妇并发妊娠期高血压疾病对围生期结局的影响

目的探讨孕高龄产妇并发妊娠期高血压疾病对围生期结局的影响。方法对43例35岁或以上的妊娠期高血压疾病孕妇（观察组）进行了回顾性分析并与同期分娩的35岁以下的妊娠期高血压疾病孕妇238例（对照组）作对照分析。结果观察组子痫前期、子痫的发生率与对照组比较差异有非常显著性（P〈0.01）;观察组胎盘早剥、HELLP综合征、妊娠高血压心脏病等严重并发症的发生率与对照组比较无显著性差异（P〉0.05）;观察组早产、胎儿生长受限、围产儿死亡的发生率比对照组高,差异有显著性（P〈0.05）;新生儿窒息、胎儿窘迫的发生率两组比较,差异无显著性（P〉0.05）,观察组剖宫产率较对照组明显增加,两组间差异有显著性（P〈0.05）。结论高龄产妇并发妊娠期高血压疾病病情重,对母儿危害大,恰当的围产期管理并适时终止妊娠是治疗成功的关键。     

Oxidative Stress: Placenta Function and Dysfunction

During pregnancy, the placenta is a site of active oxygen metabolism that continuously generates oxidative stress (OS). Overproduction of reactive oxygen species and reactive nitrogen species can destroy normal placental functions. Therefore, the feto‐placental unit generates abundant antioxidants to keep OS under control. Properly controlled oxidative species have been proven to serve as indispensable cellular signal messengers by regulating gene expression and downstream cellular activities. OS also plays an important immunoregulatory role during pregnancy. Oxidative disorder and immune disturbances are associated with adverse pregnancy outcomes such as spontaneous abortion, preeclampsia and intrauterine growth restriction. In this review, we introduce recent studies revealing basal functions and regulatory roles of placental OS in metabolism and immunity. The relationships between OS‐ and pregnancy‐related disorders are also discussed.     

The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation.

BACKGROUND: Point mutations in the factor V gene (factor V Leiden) and the prothrombin gene (the substitution of A for G at position 20210) are the most common causes of inherited thrombophilia. Whether or not factor V Leiden increases the risk of recurrent deep venous thrombosis is controversial, and there is no information on the risk of recurrence among carriers of both mutations. METHODS: We studied a retrospective cohort of 624 patients who were referred for a first episode of deep venous thrombosis. After excluding 212 patients with other inherited or acquired causes of thrombophilia, we compared 112 patients who were heterozygous carriers of factor V Leiden with 17 patients who were heterozygous for both factor V Leiden and the prothrombin mutation and 283 patients who had neither mutation. The relative risk of recurrent deep venous thrombosis was calculated with use of a proportional-hazards model. RESULTS: Patients who were heterozygous for factor V Leiden alone had a risk of recurrent deep venous thrombosis that was similar to that among patients who had neither mutation (relative risk, 1.1; 95 percent confidence interval, 0.7 to 1.6; P=0.76). In contrast, patients who were heterozygous for both factor V Leiden and the prothrombin mutation had a higher risk of recurrent thrombosis than did carriers of factor V Leiden alone (relative risk, 2.6; 95 percent confidence interval, 1.3 to 5.1; P=0.002). When the analysis was restricted to patients with spontaneous recurrences (i.e., ones that occurred in the absence of transient risk factors for venous thrombosis), the risk among carriers of both mutations, as compared with carriers of factor V Leiden alone, remained high (relative risk, 3.7; 95 percent confidence interval, 1.7 to 7.7; P<0.001), particularly if the first event had also been spontaneous (relative risk, 5.4; 95 percent confidence interval, 2.0 to 14.1; P<0.001). In contrast, the risk of recurrence in the presence of transient risk factors was similar among carriers of both mutations and carriers of factor V Leiden alone. CONCLUSIONS: The risk of recurrent deep venous thrombosis is similar among carriers of factor V Leiden and patients without this mutation. Carriers of both factor V Leiden and the G20210A prothrombin mutation have an increased risk of recurrent deep venous thrombosis after a first episode and are candidates for lifelong anticoagulation.     

自然流产患者血栓前状态的多因子发病趋势分析

目的 通过对自然流产患者血栓前状态的相关血栓标志物进行筛查,评估其发病规律及高危因子,提供有效的预防及治疗方案.方法 将1300例自然流产患者按流产次数分为1次、2次、3次及以上,分别进行血栓标志物的检测,探讨其与流产次数的关系.结果 抗凝血酶Ⅲ、纤溶酶原活性、交联纤维蛋白降解产物、纤维蛋白降解产物、纤溶酶原活化物抑制因子、组织型纤溶酶原激活物等对不良妊娠结局的影响差异具有统计学意义（P＜0.01）,随着流产次数的增加差异具有统计学（P＜0.01）.蛋白C活性、蛋白S活性对不良妊娠结局的影响具有显著统计学差异（P＜0.01）,随着流产次数的增加2次与3次及以上经两两比较不具备统计学差异（P＞0.05）.结论 蛋白C活性、蛋白S活性可能是自然流产血栓前状态诊断与治疗的特征性指标或者无相关性.抗凝血酶Ⅲ、纤溶酶原活性、交联纤维蛋白降解产物、纤维蛋白降解产物、纤溶酶原活化物抑制因子、组织型纤溶酶原激活物是自然流产的影响因素,随着流产次数的增加特征性明显.     

Discordancy for maternal floor infarction in dizygotic twin placentas

Maternal floor infarction (also known as massive perivillous fibrin/fibrinoid deposition) is a rare and devastating pregnancy disorder associated with prematurity, fetal growth restriction, spontaneous abortion, and long-term neurologic impairment. Recurrence in multiple pregnancies is common. Little is known regarding either the pathophysiology or the management and treatment of patients at risk for recurrence in subsequent pregnancies. Most authors have emphasized maternal risk factors believed to act in a dominant fashion irrespective of fetal genotype. We report on dizygotic twins discordant for the development of placental maternal floor infarction and fetal growth restriction. The mother was a poorly controlled class C diabetic, and the onset of disease was coincident with the clinical onset of preeclampsia. This case demonstrates that fetal genotype, or some other factor specific to an individual fetoplacental unit, can lead to the differential expression of maternal floor infarction in dizygotic twins gestating in the same intrauterine environment.