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.     

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.     

Inherited thrombophilias

Many inherited thrombophilias have been detected and the pathophysiologic insight has increased tremendously during the last decades. Despite, however, the overwhelming observational evidence on the association between inherited thrombophilia and several women's health issues, including VTE, thus far the implications for clinical practice are uncertain. Although there is firm epidemiologic evidence that is helpful in counseling women who have inherited thrombophilia to prevent a first or recurrent VTE, the uncertainty is particularly present for women who have other pregnancy complications, such as recurrent pregnancy loss and pre-eclampsia. For this group, well-designed placebo-controlled trials to assess the harm-benefit ratio are urgently needed.     

Rezidivierende Spontanaborte (RSA) bei hereditärer Thrombophilie

Haemorheological disorders in pregnancy represent a specific risk for the mother and the unborn child. Successful pregnancies require fine tuning of fibrinolytic activities to secure fibrin polymerization and stabilization of the placental basal plate as well as to prevent excess fibrin deposition in placental vessels and intervillous spaces. Among inherited thrombophilias, the factor V Leiden mutation and factor II 20210 dimorphism appear to play a significant role in recurrent pregnancy loss and other pregnancy-related disorders. Testing for these mutations might be prudent in light of potential therapeutic options. In patients with recurrent miscarriages and established inherited thrombophilias the use of low molecular weight heparin seems to significantly improve live birth rates.     

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.     

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。     

Testing for inherited thrombophilia in recurrent miscarriage

Approximately 1-5% of women trying to conceive experience recurrent miscarriage, and in 50% of these women, the cause of the preceding miscarriages is unknown. Inherited thrombophilias such as factor V Leiden mutation, prothrombin gene mutation (PT 20210A), and deficiencies of natural anticoagulants protein C, protein S, and antithrombin are associated with recurrent miscarriage. Knowledge of the association between inherited thrombophilia and recurrent miscarriage and of potential treatment options for improving chances of a live birth could tempt physicians to test for inherited thrombophilia in women with recurrent miscarriage. However, the strength of the association between inherited thrombophilia and recurrent miscarriage is not very strong, and more importantly, no evidence indicates that the use of anticoagulants improves the chance of live birth in these women. With the current state of evidence, testing for inherited thrombophilia should not lead to altered clinical management and therefore, should not be performed routinely in women with recurrent miscarriage but only in the context of scientific studies.     

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.     

How strong is the association between maternal thrombophilia and adverse pregnancy outcome? A systematic review.

OBJECTIVE: To determine whether inherited and acquired thrombophilias are associated with adverse obstetric complications. STUDY DESIGN: A systematic review; studies where women with adverse obstetric complications were tested for one or more acquired and inherited thrombophilias were included. MAIN OUTCOME MEASURES: Prevalence of thrombophilia in women with severe pre-eclampsia/eclampsia, severe placental abruption, intrauterine growth restriction or unexplained stillbirth. RESULTS: Compared with controls, placental abruption was more often associated with homozygous and heterozygous factor V Leiden mutation, heterozygous G20210A prothrombin gene mutation, homocysteinaemia, activated protein C resistance or anticardiolipin IgG antibodies. Women with pre-eclampsia/eclampsia were more likely to have heterozygous factor V Leiden mutation, heterozygous G20210A prothrombin gene mutation, homozygous MTHFR C677T mutation, protein C deficiency, protein S deficiency or activated protein C resistance compared with controls. Unexplained stillbirth, when compared with controls, was more often associated with heterozygous factor V Leiden mutation, protein S deficiency, activated protein C resistance, anticardiolipin IgG antibodies or lupus anticoagulant. Women with intrauterine growth restriction had a higher prevalence of heterozygous G20210A prothrombin gene mutation, homozygous MTHFR C677T gene mutation, protein S deficiency or anticardiolipin IgG antibodies than controls. There was wide heterogeneity in the prevalence of thrombophilia between the studies. CONCLUSIONS: Women with adverse pregnancy outcome are more likely to have a positive thrombophilia screen but studies published so far are too small to adequately assess the true size of this association. Screening for thrombophilia should not become standard practice until clear evidence emerges that thromboprophylaxis during pregnancy improves perinatal outcome. Further research into the link between the observed association, causality and heterogeneity is required.     

Recurrent miscarriage: pathophysiology and outcome

PURPOSE OF REVIEW: This article reviews new concepts in the aetiology of recurrent miscarriage, presents new outcome data and evaluates new modalities of treatment for unexplained recurrent miscarriage. RECENT FINDINGS: Preimplantation genetic diagnosis has been considered an option for couples who have structural chromosomal abnormalities or unexplained recurrent miscarriage. The association between thrombophilias and adverse pregnancy outcome is further reviewed. In relation to this, there is increasing support for the use of thromboprophylaxis in improving pregnancy outcome in women with inherited thrombophilias. Nonrandomized studies have shown that the reduction in insulin levels with metformin in insulin-resistant individuals may reduce miscarriage risk by restoring normal haemostasis and improving the endometrial milieu. With respect to immunological concepts there is now evidence to suggest that, in addition to a suppression of maternal cell-mediated immunity, some elements of the innate immune system are activated in successful pregnancies. SUMMARY: With the exception of aspirin and heparin for the prevention of recurrent miscarriage in women with the antiphospholipid syndrome, no other suggested therapies for this heterogeneous group of patients have been evaluated in randomized controlled trials. These include thromboprophylaxis for inherited thrombophilias and use of insulin sensitizers in women with insulin resistance and/or polycystic ovarian syndrome. The role of the innate immune system in pregnancy was recently highlighted, and use of nonspecific therapies to suppress the maternal immune response to pregnancy should be reassessed.     

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.     

Evidence-based care of recurrent miscarriage

Between 0.5 and 1.0% of couples experience recurrent pregnancy loss (RPL), which is defined as three or more consecutive miscarriages. Losses are classified as pre-embryonic (<5 weeks), embryonic (5-10 weeks) or fetal (>10 weeks). Genetic abnormalities are responsible for RPL in 2-4% of these couples. Inadequate progesterone production has been proposed a cause of RPL and progesterone is given to prevent miscarriage, despite a lack of supportive evidence. The factor V Leiden and prothrombin G20210A mutations are common inherited thrombophilias also associated with RPL. Antenatal thromboprophylaxis is sometimes recommended although no data exist regarding efficacy. Antiphospholipid syndrome is known to cause RPL and antenatal thromboprophylaxis reduces the risk of miscarriage. Uterine abnormalities might also result in RPL. About 50% of cases of RPL have no identifiable cause. Alloimmune incompatibility has been proposed as a cause for RPL in these women. The concept of alloimmune-related RPL has not been scientifically validated.     

Thrombophilia and the risk for venous thromboembolism during pregnancy, delivery, and puerperium

The main inherited thrombophilias (antithrombin deficiency, protein C and S deficiency, FVL, the prothrombin gene variant, and MTHFR C677T homozygotes) have a combined prevalence in Western European populations of 15% to 20%. One or more of these inherited thrombophilias is usually found in approximately 50% of women who have a personal history of VTE. Obstetricians must therefore be aware of the interaction between thrombophilias and the procoagulant state of pregnancy and should have an understanding of additional risk factors that may act synergistically with thrombophilias to induce VTE. Such knowledge combined with the appropriate use of thromboprophylaxis and treatment in women who have objectively confirmed VTE continue to improve maternal and perinatal outcomes.     

High frequency of thrombophilic disorders in women with recurrent fetal miscarriage

OBJECTIVES: Our purpose was to examine whether genetic thrombophilias are etiological factors for recurrent fetal miscarriage or not. STUDY DESIGN: We compared the rate of thrombophilic anomalies in women with unexplained recurrent fetal miscarriages to the rate of age-matched women with successful pregnancies as a case-control study. RESULTS: A total of 101 consecutive patients with 102 age-matched controls were included in the study. The rate of Factor V (FV) Leiden mutation, Factor (F) II mutation, protein S, protein C, antithrombin III deficiencies and overall thrombophilia in patients with recurrent fetal loss was significantly higher than the frequencies in control patients. CONCLUSION: Women with recurrent fetal miscarriages have an increased incidence of thrombophilia. Genetic thrombophilias may be one of the major etiological factors for recurrent abortion and fetal demise.     

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.     

Inherited thrombophilia and pregnancy with fetal loss

Maternal thrombophilia (inherited and acquired) has recently been identified as a major cause of thrombembolism (TE), but it may also contribute to adverse pregnancy outcomes and recurrent pregnancy loss. If the acquired thrombophilia is a well-established factor in etiology of fetal loss, the contribution of specific inherited thrombophilic genes is still controversial. The most common inherited traits are deficiency of antithrombin, protein C or protein S; Factor V Leiden; prothrombin G20210A; MTHFR C677T This review focuses on association of recurrent fetal loss with specific gene thrombophilic defects. Overall 52% of women with obstetric complication other than TE carry thrombophilic gene defects. The role of specific genes is different in etiology of early and late pregnancy loss. Inherited thrombophilia is now view as multicausal model; clinical manifestation can be heterogeneous result of gene-gene and gene-environment interactions. Therefore the criteria for genetic screening affected women with history of fetal loss should not be very stringent. The implication of screening for thrombophilic mutations allow to find women at risk of thrombosis and vascular gestational abnormalities in which antithrombotic drugs may have potential therapeutic benefit.     

Thromboembolic disease in pregnancy

Recent publications have produced some new estimates of the incidence of pregnancy-related venous thromboembolic disease, and have found increasing evidence of an association between inherited thrombophilias and pregnancy complications and fetal loss. The balance of benefit and risk of thromboprophylaxis remains to be evaluated, and studies are needed to provide a sound basis for clinical practice.