Inherited thrombophilias in pregnant patients: detection and treatment paradigm

Inherited thrombophilias are the leading cause of maternal thromboembolism and are associated with an increased risk of certain adverse pregnancy outcomes including second- and third-trimester fetal loss, abruptions, severe intrauterine growth restriction, and early-onset, severe preeclampsia. Current information suggests that all patients with a history of prior venous thrombotic events and those with these characteristic adverse pregnancy events should be evaluated for thrombophilias. The most common, clinically significant, inherited thrombophilias are heterozygosity for the factor V Leiden and prothrombin G20210A mutations. The autosomal-dominant deficiencies of protein C and protein S are of comparable thrombogenic potential but are far less common. Homozygosity for the 4G/4G mutation in the type-1 plasminogen activator inhibitor gene and the thermolabile variant of the methylenetetrahydrofolate reductase gene, the leading cause of hyperhomocysteinemia, although relatively common, confer a low risk of thrombosis. In contrast, autosomal-dominant antithrombin deficiency and homozygosity or compound heterozygosity (ie, carriers of one copy of each mutant allele) for the factor V and prothrombin mutations are very rare but highly thrombogenic states. Regardless of their antecedent histories, pregnant patients with these highly thrombogenic conditions are at very high risk for both thromboembolism and characteristic adverse pregnancy outcomes, require full therapeutic heparin therapy throughout pregnancy, and need at least 6 weeks of postpartum oral anticoagulation. There is also compelling evidence that patients with the less thrombogenic thrombophilias and a history of venous thrombotic events or characteristic adverse pregnancy outcomes require prophylactic anticoagulant therapy during pregnancy and, in the case of prior thromboembolism, during the puerperium. Antepartum anticoagulation does not appear warranted among patients with less thrombogenic thrombophilias who are without a history of venous thromboembolism, characteristic adverse pregnancy outcomes, or other high risk factors for venous thrombosis.     

Thrombophilia and adverse pregnancy outcome

PURPOSE OF REVIEW: Recent case-control studies and metaanalyses have attempted to quantify the risks associated with individual thrombophilic defects and adverse clinical events in pregnancy, including fetal loss, preeclampsia, placental abruption and intrauterine growth restriction. This review has examined the evidence. RECENT FINDINGS: The literature is in general agreement that thrombophilia increases the risk of venous thromboembolism and adverse pregnancy outcomes, including pregnancy loss, preeclampsia, placental abruption and intrauterine growth restriction in pregnancy. However, the size of the estimated risks varies between individual studies due to heterogeneity in study design. Low-molecular-weight heparin has been shown to be the superior choice, on the grounds of safety and effectiveness, in preventing venous thromboembolism and improving pregnancy loss. Large-scale, randomized controlled studies are required, however, to confirm these findings. Although selective thrombophilia screening based on prior venous thromboembolism history has been shown to be marginally more cost-effective than universal screening in pregnancy, the overall clinical and economic benefit of universal and selective screening is unsupported. SUMMARY: Despite the growing evidence in the literature, there are still gaps in our knowledge of thrombophilia and pregnancy. In particular, accurate estimates are required of the risks of venous thromboembolism and adverse pregnancy outcomes associated with some thrombophilias and the relative clinical and cost-effectiveness of different anticoagulation therapies in the prevention of venous thromboembolism and pregnancy loss. More large-scale studies are required to better inform clinicians and help determine optimum management and prevention strategies of thrombophilia and associated adverse clinical events in pregnancy.     

Thromboembolism in pregnancy

PURPOSE OF REVIEW: Venous thromboembolism is the leading cause of maternal death in the UK. Thrombophilia underlies many thrombotic disorders in pregnancy. The high prevalence of thrombophilic defects in the population, the association of defects with venous thromboembolism and the special considerations for management make it a widely debated subject. RECENT FINDINGS: A limited number of studies measuring the risk of venous thromboembolism in pregnancy with thrombophilia have been conducted within the last year. Studies confirm that heritable thrombophilias are associated with increased risk of venous thromboembolism in pregnancy. However, estimated risks vary between individual studies. The risk of venous thromboembolism with acquired thrombophilia remains unclear. Guidelines have been published to guide clinicians in preventing and treating venous thromboembolism in pregnancy; however, large-scale, randomized controlled trials need to be conducted to establish the effectiveness of administering antithrombotic agents in pregnancy. Although selective thrombophilia screening based on prior history of venous thromboembolism has been proposed, the overall clinical and economic benefit of universal and selective screening is unsupported. SUMMARY: Due to the lack of studies, gaps still exist in our knowledge of the risk of pregnancy-related venous thromboembolism associated with thrombophilia. In particular, accurate estimates are required for the risks of acquired thrombophilias. Furthermore, the true effectiveness of anticolagulants in pregnancy needs to be established through well-conducted studies and randomized controlled trials. These studies will inform clinicians and help to determine the optimum management and prevention strategies for thrombophilia and venous thromboembolism in pregnancy.     

Anticoagulants

Pregnancy is a period of heightened coagulability and enhanced risk for thrombotic complications. Thromboembolism is the leading cause of maternal mortality. Anticoagulants are very useful during pregnancy for the acute treatment of venous thromboembolism and for the prevention of recurrent venous thromboembolism. They may also be beneficial in patients with thrombophilias, particularly among women who have experienced adverse pregnancy outcomes such as recurrent pregnancy loss. Anticoagulation is essential but problematic in the management of pregnant women with mechanical heart valve prostheses. When utilizing these medications among pregnant women the potential benefits must be balanced against the possibility of maternal haemorrhagic complications, adverse effects on the pregnancy or toxic effects on the fetus. This chapter summarizes current knowledge about the anticoagulant agents, their potential toxicities and their therapeutic role in pregnant women with various indications for anticoagulant therapy.     

Drugs in pregnancy. Anticoagulants.

Pregnancy is a period of heightened coagulability and enhanced risk for thrombotic complications. Thromboembolism is the leading cause of maternal mortality. Anticoagulants are very useful during pregnancy for the acute treatment of venous thromboembolism and for the prevention of recurrent venous thromboembolism. They may also be beneficial in patients with thrombophilias, particularly among women who have experienced adverse pregnancy outcomes such as recurrent pregnancy loss. Anticoagulation is essential but problematic in the management of pregnant women with mechanical heart valve prostheses. When utilizing these medications among pregnant women the potential benefits must be balanced against the possibility of maternal haemorrhagic complications, adverse effects on the pregnancy or toxic effects on the fetus. This chapter summarizes current knowledge about the anticoagulant agents, their potential toxicities and their therapeutic role in pregnant women with various indications for anticoagulant therapy.     

Preconception counseling for women with thrombophilia

Inherited thrombophilias are a heterogeneous group of coagulation disorders that predispose individuals to thromboembolic events. This group of conditions is the major risk factor for thromboembolism during pregnancy and the puerperium. In addition, thrombophilias have been associated with several adverse obstetric events, including pregnancy loss, preeclampsia, placental abruption, and intrauterine growth restriction. An increased risk for these obstetric complications has prompted many authorities to recommend screening and treating pregnant women for thrombophilias. Optimal obstetric management, however, is controversial as thrombophilias are common and many affected individuals are asymptomatic. Indeed, pregnancy outcome in most women with thrombophilias is normal. The most commonly identified inherited thrombophilias are the factor V Leiden and prothrombin G20210A gene mutations. More rare thrombophilias include protein C and S deficiencies, antithrombin III deficiency. Although relatively common, the association between hyperhomocysteinemia and associated mutations (such as the C677 T methylenetetrahydro-folate reductase) and obstetric complications is controversial.     

Thrombophilia screening in pregnancy

Thromboembolism in pregnancy is a major contributor to pregnancy morbidity and mortality with potentially serious adverse effects for both mother and fetus. The purposes of this article are to explore the impact of heritable and acquired thrombophilias on pregnancy and to determine the appropriateness of screening for thrombophilias in pregnancy. In determining the appropriateness of screening, attention was given to the changes that occur in the coagulation and fibrinolytic systems during normal pregnancy. The impact of different heritable and acquired thrombophilias on maternal venous thromboembolism, fetal loss, and its impact on certain obstetric conditions are then explored. Guidelines and conclusions are made as to the appropriateness of screening. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to list the various thrombophilias associate with pregnancy, to describe the impact of thrombophilias on pregnancy, and to outline the appropriate screening guidelines for thrombophilias during pregnancy.     

Two successful pregnancies following eight miscarriages in a patient with antithrombin deficiency

Inherited thrombophilias are associated with an increased risk of maternal thromboembolism and certain adverse pregnancy outcomes, including second- and third-trimester fetal loss, placental abruption, severe intrauterine growth restriction, and early-onset, severe preeclampsia. Pregnant patients with severe thrombophilias, especially antithrombinopathies are at very high risk for both thromboembolism and adverse pregnancy outcomes. A case of a patient with antithrombin deficiency is reported, who had two successful pregnancies after eight miscarriages. Our case shows that a combined treatment with antithrombin substitution and a prophylactic, body-weight-adjusted dose of low-molecular-weight heparin may be successful in preventing pregnancy loss and thromboembolism in antithrombin deficiency during pregnancy, although other complications, such as preeclampsia and intrauterine growth restriction cannot always be prevented.     

Inherited thrombophilia and stillbirth

Thrombophilias are inherited or acquired conditions that predispose individuals to thromboembolism. New inherited thrombophilias are recognized each year. Some, but not all, studies have found an association between inherited thrombophilias and adverse pregnancy outcomes, including fetal loss. The controversy regarding the clinical implications of thrombophilias in pregnancy is clouded by differences in study populations, the number of thrombophilias tested, interactions between thrombophilias, and the retrospective nature of most studies, just to name a few factors. The lack of adequately designed studies also extends to clinical management. Clear evidence to determine when to test, whom to test, which thrombophilias to test for, when to treat, and what to treat with is not available. Further studies to investigate these questions are urgently needed.     

Prothrombin 20210 G-->A, MTHFR C677T mutations in women with venous thromboembolism associated with pregnancy

Over 50 unselected women with maternal venous thromboembolism were screened for the prothrombin 20210 G→A and MTHFR C677T mutations, in addition to screening for other thrombophilias. The prevalence of thrombophilia in these women was compared with its prevalence in the general population in our area. The prothrombin (OR 4.4; 95% CI 1.2-16) and factor V Leiden (OR 4.5; 95% CI 2.1-14.5) mutations were more common in our patients, compared with the general population, whereas women homozygous for the C677T mutation in the methylene tetrahydrofolate reductase gene (OR 0.45; 95% CI 0.13-1.58) were not. It is recommended that women with a personal or strong family history of venous thromboembolism should be screened for the prothrombin mutation either before or early in pregnancy, in addition to screening for other thrombophilias. Screening for the MTHFR mutation does not appear to identify women at increased risk of maternal venous thrombosis.     

Antithrombotic therapy and pregnancy: consensus report and recommendations for prevention and treatment of venous thromboembolism and adverse pregnancy outcomes

Venous thromboembolism and adverse pregnancy outcomes are potential complications of pregnancy. Numerous studies have evaluated both the risk factors for and the prevention and management of these outcomes in pregnant patients. This consensus group was convened to provide concise recommendations, based on the currently available literature, regarding the use of antithrombotic therapy in pregnant patients at risk for venous thromboembolic events and adverse pregnancy outcomes.     

Thromboembolism and thrombophilia in pregnancy

Venous thromboembolism (VTE) is one of the leading causes of maternal mortality worldwide and is also the cause of significant maternal morbidity. This article discusses the risk factors for VTE in pregnancy, the management of the pregnant woman at risk both antenatally and postpartum and the acute management of VTE when it occurs during pregnancy.The thrombophilias, both heritable and acquired are becoming increasingly recognised as a cause of morbidity and mortality both within and outside pregnancy. There has been recent increased interest in the thrombophilias and their link with recurrent miscarriage, pre-eclampsia, abruption and intrauterine growth restriction. The relationship between the thrombophilias and adverse pregnancy outcome is addressed in detail with reference to the current literature available on this evolving subject.     

Thromboembolism and thrombophilia in pregnancy

Venous thromboembolism (VTE) is one of the leading causes of maternal mortality worldwide and is also the cause of significant maternal morbidity. This article discusses the risk factors for VTE in pregnancy, the management of the pregnant woman at risk both antenatally and post-partum, and the acute management of VTE when it occurs during pregnancy.The thrombophilias, both heritable and acquired, are becoming increasingly recognised as a cause of morbidity and mortality both within and outside pregnancy. There has been a recent increased interest in the thrombophilias and their link with recurrent miscarriage, preeclampsia, abruption and intrauterine growth restriction. The relationship between the thrombophilias and adverse pregnancy outcome is addressed in detail, with reference to the current literature available on this evolving subject.     

遗传性易栓症的妊娠期筛查与抗凝治疗评价

汉族人群遗传性易栓症以蛋白C或蛋白S缺乏为主,抗凝血酶缺乏少见,罕见凝血因子ⅤLeiden(FⅤL)突变及PGM突变。遗传性易栓症增加妊娠期血栓栓塞性疾病的风险,是胎盘介导的妊娠并发症的协同性促进因素,而不是主要病因。如果已经明确具有进行治疗的指征,没有必要再行遗传性易栓症的筛查;如果病因不明,而遗传性易栓症筛查的阳性结果可能会影响治疗决策时,筛查或许是有用的。现有证据仅表明,预防性应用低剂量阿司匹林可以减少子痫前期复发。低分子肝素是否能改善胎盘介导的妊娠并发症的再发风险,单中心和多中心研究的结论并不一致。虽然缺乏有力的证据支持,目前仍建议对具有胎盘介导的妊娠并发症病史的遗传性易栓症患者进行选择性、个体化抗凝治疗。     

The relationship of the factor V Leiden mutation and pregnancy outcomes for mother and fetus

OBJECTIVE: We sought to estimate the frequency of pregnancy-related thromboembolic events among carriers of the factor V Leiden (FVL) mutation without a personal history of thromboembolism, and to evaluate the impact of maternal and fetal FVL mutation carriage or other thrombophilias on the risk of adverse outcomes. METHODS: Women with a singleton pregnancy and no history of thromboembolism were recruited at 13 clinical centers before 14 weeks of gestation from April 2000 to August 2001. Each was tested for the FVL mutation, as was the resultant conceptus after delivery or after miscarriage, when available. The incidence of thromboembolism (primary outcome), and of other adverse outcomes, was compared between FVL mutation carriers and noncarriers. We also compared adverse outcomes in a secondary nested carrier-control analysis of FVL mutation and other coagulation abnormalities. In this secondary analysis, we defined carriers as women having one or more of the following traits: carrier for FVL mutation, protein C deficiency, protein S deficiency, antithrombin III deficiency, activated protein C resistance, or lupus anticoagulant-positive, heterozygous for prothrombin G20210A or homozygous for the 5,10 methylenetetrahydrofolate reductase mutations. Carriers of the FVL mutation alone (with or without activated protein C resistance) were compared with those having one or more other coagulation abnormalities and with controls with no coagulation abnormality. RESULTS: One hundred thirty-four FVL mutation carriers were identified among 4,885 gravidas (2.7%), with both FVL mutation status and pregnancy outcomes available. No thromboembolic events occurred among the FVL mutation carriers (0%, 95% confidence interval 0-2.7%). Three pulmonary emboli and one deep venous thrombosis occurred (0.08%, 95% confidence interval 0.02-0.21%), all occurring in FVL mutation noncarriers. In the nested carrier-control analysis (n = 339), no differences in adverse pregnancy outcomes were observed between FVL mutation carriers, carriers of other coagulation disorders, and controls. Maternal FVL mutation carriage was not associated with increased pregnancy loss, preeclampsia, placental abruption, or small for gestational age births. However, fetal FVL mutation carriage was associated with more frequent preeclampsia among African-American (15.0%) and Hispanic (12.5%) women than white women (2.6%, P = .04), adjusted odds ratio 2.4 (95% confidence interval 1.0-5.2, P = .05). CONCLUSION: Among women with no history of thromboembolism, maternal heterozygous carriage of the FVL mutation is associated with a low risk of venous thromboembolism in pregnancy. Neither universal screening for the FVL mutation, nor treatment of low-risk carriers during pregnancy is indicated. LEVEL OF EVIDENCE: II-2.     

Inherited and acquired thrombophilias and poor pregnancy outcome: should we be treating with heparin?

PURPOSE OF REVIEW: The most important acquired thrombophilia related to poor pregnancy outcome is probably antiphospholipid syndrome. Inherited thrombophilias that have been implicated in venous thromboembolism and poor pregnancy outcome and for which standard tests are generally available are antithrombin III deficiency, the factor V Leiden mutation, prothrombin G20210A mutation and the C677T polymorphism in the methylenetetrahydrofolate reductase system implicated in mild hyperhomocysteinaemia. The management of antiphospholipid syndrome with previous fetal losses is well documented and substantiated by small clinical trials. It is the purpose of this review to investigate new contributions to this field since June 2002. RECENT FINDINGS: Only one randomized trial was published during the review period, but a Cochrane review and several excellent review articles appeared detailing management. SUMMARY: There is a dire lack of randomized trials in the literature on the efficacy of heparin or other coagulation modulators on pregnancy outcome in patients with inherited thrombophilias. There is consensus on thrombo-prophylaxis for antiphospholipid syndrome. Protocols for the management of venous thromboembolism and pulmonary emboli related to pregnancy are well established.     

Factor V Leiden mutation in pregnancy

Normal maternal adaptation to pregnancy significantly increases the risk for thrombus formation. Inherited thrombophilias further increase risk for deep venous thrombosis and adverse outcome in pregnancy. Factor V Leiden mutation is the most common inherited thrombophilia, occurring in approximately 5% of the White and 1% of the Black populations. Nurses should be knowledgeable about screening for and diagnosis of factor V Leiden mutation, risk reduction counseling, recommended care of the affected patient, and implications of anticoagulant therapy during the perinatal period.     

Inherited thrombophilias and adverse pregnancy outcome: screening and management

Inherited thrombophilias are a heterogenous group of conditions which have been implicated in a variety of pregnancy complications. Evidence is mounting that implicates these inherited disorders in a range of pregnancy outcomes, including recurrent miscarriage, late fetal loss, preeclampsia, abruptio placentae, and intrauterine growth restriction. The most commonly identified inherited thrombophilias consist of Factor V Leiden and the prothrombin gene mutation G20210A. Rarer inherited thrombophilic conditions include deficiencies of protein S, C and antithrombin. More recently, deficiency of protein Z has been linked to pregnancy complications, including preterm delivery. Clinical manifestations often are associated with the presence of more than one inherited thrombophilia, consistent with their multigenic nature. Some, but not all, studies investigating the use of heparin to prevent adverse pregnancy outcome have demonstrated a benefit. However, an adequate randomized trial is required to definitively determine whether heparin anticoagulation is the best prevention option in patients who harbor one or more inherited thrombophilias and are at risk for adverse pregnancy outcome. This review will summarize the association of thrombophilic conditions and obstetrical complications.     

The role of inherited thrombophilia in venous thromboembolism associated with pregnancy.

Venous thromboembolism is an important cause of maternal morbidity and mortality. The puerperium should be regarded as the period of greatest risk. However, fatalities in early pregnancy emphasise the need to assess thrombotic risk at all stages of pregnancy. In many cases those at increased risk are potentially identifiable on clinical grounds alone such as those with a personal or family history of venous thromboembolism, obesity, or surgery. Identification of women with multiple clinical risks for thrombosis during pregnancy remains the key to reducing the incidence of this condition. In women who present with a personal or family history of proven venous thromboembolism, thrombophilia screening should be performed in early pregnancy, since the results may influence subsequent management during pregnancy. The investigation and management of patients considered at increased risk of venous thrombosis during pregnancy requires close liaison between obstetricians and haematologists familiar with this rapidly expanding and complex field of thrombophilia.     

Thromboembolic disease in pregnancy

Venous thromboembolic disease is a major cause of maternal morbidity and mortality. Virchow's triad of hypercoagulability, venous stasis, and vascular damage all occur during pregnancy. The risk of venous thromboembolism is five to six times higher during pregnancy and the puerperium. Risk factors include age greater than 35, antiphospholipid antibodies, inherited thrombophilias, operative delivery, increased parity, obesity, mechanical heart valves,and family history. Prophylactic and therapeutic anticoagulation is recommended for women at risk. Low molecular weight heparins are safe and effective in most cases.