Inherited thrombophilias in pregnant patients: detection and treatment paradigm1,2

HIGH-RISK PREGNANCY SERIES: AN EXPERT’S VIEW

We have invited select authorities to present background information on challenging clinical problems and practical information on diagnosis and treatment for use by practitioners.

Inherited Thrombophilias in Pregnant Patients: Detection and Treatment Paradigm Charles J. Lockwood, MD 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 From the Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York. This work was supported in part by a grant from the National Institutes of Health 5 RO1 HL33937-06. We would like to thank the following individuals who, in addition to members of our Editorial Board, will serve as referees for this series: Dwight P. Cruikshank, MD, Ronald S. Gibbs, MD, Gary D. V. Hankins, MD, Philip B. Mead, MD, Kenneth L. Noller, MD, Catherine Y. Spong, MD, and Edward E. Wallach, MD.

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. (Obstet Gynecol 2002;99:333– 41. © 2002 by the American College of Obstetricians and Gynecologists.)

Thromboembolic disease is the leading cause of maternal mortality in the United States.1 Stillbirth, severe (3rd percentile) intrauterine fetal growth restriction (IUGR), abruption, and severe, early-onset, preeclampsia complicate up to 0.2–3% of pregnancies and are leading causes of perinatal morbidity and mortality. Histologic examination of uteroplacental vessels and intervillous architecture from such pathologic pregnancies typically display increased fibrin deposition, thrombosis, and hypoxiaassociated endothelial and trophoblast changes.2 These findings suggest that thrombosis of the uteroplacental circulation underlies these obstetric conditions. The presence of inherited and acquired thrombophilias has recently been linked to most cases of maternal venous thrombotic events as well as these adverse obstetric outcomes.1,3 The most common inherited thrombophilias are heterozygosity for the factor V Leiden, prothrombin G20210A mutation, homozygosity for the 4G/4G mutation in the plasminogen activator inhibitor (PAI-1) gene, and the thermolabile variant of methylenetetrahydrofolate reductase (C677T MTHFR), the most common

VOL. 99, NO. 2, FEBRUARY 2002 © 2002 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.

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Figure 1. The coagulation, anticoagulation, and fibrinolytic pathways (C ⫽ inhibitor; II ⫽ prothrombin; IIa ⫽ thrombin) Lockwood. Inherited Thrombophilias in Pregnant Patients. Obstet Gynecol 2002.

cause of hyperhomocysteinemia. Rarer thrombophilias include autosomal-dominant deficiencies of antithrombin, protein C (PC), and protein S (PS). The principal acquired thrombophilia is antiphospholipid antibody syndrome.3 During pregnancy, the maternal thrombogenic potential of all these disorders is enhanced.3,4 Although collectively present in about 15% of white European populations, these disorders are responsible for more than half of all maternal thromboembolic events and have been linked to a five-fold increased risk of stillbirth, IUGR, abruption, and severe preeclampsia.1,3– 6 However, there are conflicting reports on the association between thrombophilias and recurrent early (less than 10 weeks) spontaneous abortions.1,3,7–12 Although there is consensus on the diagnosis and treatment of antiphospholipid antibody syndrome in pregnancy,3 our approach to the detection and management of inherited thrombophilias in pregnancy remains shrouded in confusion. This review attempts to define a practical approach to screening for, and managing affected patients.

PHYSIOLOGIC INITIATION AND CONTROL OF HEMOSTASIS The primary initiator of coagulation is tissue factor (TF), a cell membrane-bound glycoprotein expressed by perivascular cells throughout the body, but not by cells in contact with the circulation (ie, endothelial cells) (Figure 1). After vascular disruption, perivascular, cell membrane-bound TF complexes with plasma-derived factor VII. The complex of TF and factor VII bound to negatively charged (anionic) phospholipids in the presence of

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ionized calcium initiates clotting. Factor VII is the only zymogenic (ie, precursor) form of a clotting factor to exhibit activity and allows for “on-demand” clotting. Once clotting begins, factor VII is fully activated by thrombin and other activated clotting factors to form factor VIIa, which is 100-fold more active. The TF/VIIa complex directly converts factor X to Xa (extrinsic pathway), or indirectly generates Xa by converting factor IX to IXa, which, in turn, complexes with its cofactor, factor VIIIa, to convert X to Xa (intrinsic pathway). This initial clotting reaction is quickly inhibited by the TF pathway inhibitor, which binds to the TF/VIIa/Xa complex to rapidly stop TF-mediated clotting. However, thrombin and factor XIIa-activated factor XIa sustains the clotting reaction by serving as an alternative activator of factor IX on the surface of newly aggregated platelets. In any case, factor Xa, once generated, complexes with its cofactor, Va, to convert prothrombin (factor II) to thrombin (IIa). Thrombin then cleaves fibrinogen to generate fibrin monomers, which spontaneously polymerize and are cross-linked by thrombin-activated factor XIIIa to form a stable clot (Figure 1). Because the anticoagulant effects of the tissue factor pathway inhibitor can be short-circuited by factor XIa, effective inhibition of the clotting cascade requires inhibition of subsequent factor IXa and Xa activity.1 This is accomplished by the complex of activated PC and PS. Protein C is activated by the complex of thrombomodulin and thrombin residing on the surface of damaged endothelial cells. The activated PC and PS complex inactivates factors VIIIa and Va, the requisite cofactors for factors IXa and Xa, respectively. Both PC and PS are hepatocyte products that depend on vitamin K-dependent enzymes to ␥-carboxylate their glutamine-rich plasma membrane-binding domains.1 Protein C and PS have plasma half-lives of 6 – 8 hours and 42 hours, respectively. Circulating PS exists in both free (40%) and bound (60%) forms. The complement 4b-binding protein serves as a carrier protein for PS. Because only free PS complexes with activated PC, any condition (eg, pregnancy, inflammation, and surgical stress), which increases the complement 4b-binding protein, will reduce PS activity. The most crucial endogenous anticoagulant system involves antithrombin (AT). In addition to its thrombin inhibitory properties, AT can also inactivate factors Xa, IXa, and VIIa.1 The anticoagulant activity of AT is increased 5000 to 40,000-fold by heparin. Finally, fibrinolysis serves to prevent excess clotting by breaking down the fibrin clot. Fibrinolysis is mediated by tissue-type plasminogen activator, which binds to fibrin where it activates plasmin. Plasmin, in turn, degrades fibrin but can be inactivated by ␣-2-antiplasmin

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embedded in the fibrin clot. Fibrinolysis is primarily inhibited by PAI-1, the fast inactivator of tissue-type plasminogen activator. PREGNANCY-ASSOCIATED CHANGES IN HEMOSTASIS AND FIBRINOLYSIS The net effect of pregnancy-associated changes in hemostatic, anticoagulant, and fibrinolytic proteins is to enhance the risk of thromboembolism and, thus, exacerbate the clinical effects of the inherited thrombophilias.1 Pregnancy is associated with a 20 –200% increase in levels of fibrinogen and factors II, VII, VIII, X, and XII, whereas concentrations of factors V and IX are unchanged. In contrast, endogenous anticoagulant levels increase minimally (tissue factor pathway inhibitor), remain constant (AT and PC), or significantly decrease (PS) in pregnancy. Moreover, levels of immunoreactive and functionally active PAI-1 increase up to three-fold in pregnancy. Thus, the net effect of these pregnancyinduced changes is to promote clot formation, extension, and stability. PATHOPHYSIOLOGY OF THE INHERITED THROMBOPHILIAS Factor V Leiden Mutation The factor V Leiden mutation is present in 5–9% of white European populations, but is rare in Asian and African populations.1,13 It arises from a (G 3 A) mutation in nucleotide 1691 of the factor V gene’s 10th exon resulting in a substitution of a glutamine for an arginine at position 506 in the factor V polypeptide (factor V Q506). The resultant amino acid substitution impairs the activated PC and PS complex inactivation of factor Va. This defect is termed the factor V Leiden mutation and is primarily inherited in an autosomal-dominant fashion.1,14 Heterozygosity for the factor V Leiden mutation is present in 20 – 40% of nonpregnant patients with thromboembolic disease.1 Homozygosity for the mutation, although rare, confers a far higher (more than 100-fold) risk of thromboembolism.1 Pregnancy-induced reductions in PS enhance factor V Leiden prothrombotic effects. The proportion of pregnant patients with thromboembolic events attributable to the factor V Leiden mutation has been reported to be around 40% (11–78%).1,4,15 Despite this high occurrence rate, given the low prevalence of thromboembolism in pregnancy, the actual risk of thromboembolism in asymptomatic pregnant patients is only 0.2%.15 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 associ-

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ation between the mutation and late first-, second-, and third-trimester fetal loss, severe IUGR, abruption, and severe preeclampsia.1,6,7,10,16 –18 Prothrombin Gene (G20210A) Mutation Heterozygosity for a mutation in the promoter of the prothrombin gene (G20210A), present in 2–3% of white European populations, leads to increased (150 –200%) circulating levels of prothrombin and an increased risk of thromboembolism.1,15 This mutation accounts for 17% of thromboembolism in pregnancy.15 However, the actual risk of clotting in an asymptomatic pregnant carrier of this mutation is only 0.5%.15 The prothrombin (G20210A) mutation has been associated with an increased risk of fetal loss, abruption, severe preeclampsia, and severe IUGR.1,6,10,19 In one study, seven of 80 recurrent pregnancy loss patients and two of 100 controls were carriers of the prothrombin (G20210A) mutation (P ⫽ .04, odds ratio [OR] 4.6, 95% confidence interval [CI] 0.9, 23.2).9 However, Roque et al found no link between the prothrombin (G20210A) mutation and other inherited thrombophilias and early (less than 10 weeks) pregnancy loss.10 Homozygosity for the prothrombin mutation confers a risk of thrombosis, equivalent to that of factor V Leiden homozygosity.1 4G/4G PAI-1 Mutation The PAI-1 gene’s promoter region contains at least two alleles producing either a 4G or 5G base-pair region. The 5G allele permits the binding of transcription factor inhibitors that suppress gene transcription. In contrast, the 4G allele is too small to permit the binding of gene repressors. Therefore, individuals homozygous for the 4G/4G allele have a three to five-fold higher level of circulating PAI-1 compared with those bearing the 5G/5G or 5G/4G alleles.20 Homozygosity for the 4G/4G allele is relatively common and causes a modestly increased risk of thromboembolism, fetal loss, IUGR, preeclampsia, and preterm delivery.21 AT Deficiency Antithrombin deficiency, also known as ATIII deficiency, is the most thrombogenic of the inherited thrombophilias with a 70 –90% lifetime risk of thromboembolism.1,4 Deficiencies in AT result from numerous point mutations, deletions, and insertions, and are usually inherited in an autosomal-dominant fashion.22 The two classes of AT deficiency are: 1) type I, the most common deficiency, characterized by concomitant reductions in both antigenic protein levels and activity; and 2) type II deficiency, characterized by normal antigenic levels but decreased activity. Type II deficiency is further classified by the site of the mutation (eg, RS ⫽ reactive site,

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HBS ⫽ heparin binding site, and PE ⫽ pleiotropic functional defects).1,22 Because the prevalence of AT deficiency is low, one in 1000 to one in 5000, it is only present in 1% of patients with thromboembolism.4 The risk of thrombosis among affected patients is up to 60% during pregnancy and 33% during the puerperium.1 Preston et al7 reported adjusted OR for miscarriage and stillbirth of 1.7 (95% CI 1.0, 2.8) and 5.2 (95% CI 1.5, 18.1), respectively. However, because of its low prevalence compared with that of fetal loss, severe preeclampsia, IUGR, and abruption, AT deficiency is rarely the cause of these disorders.1,6 PC and PS Deficiencies Deficiencies of PC result from numerous mutations, although two primary types are recognized: 1) type I, in which both immunoreactive and functionally active PC levels are reduced; and 2) type II, where immunoreactive levels are normal, but activity is reduced.1 Protein S deficiency presents with one of three phenotypes: 1) type I, marked by reduced total and free immunoreactive forms; 2) type II, characterized by normal free immunoreactive levels but reduced APC cofactor activity; and 3) type III, in which there are normal total immunoreactive but reduced free immunoreactive levels. Different mutations have highly variable procoagulant sequelae making it extremely difficult to predict which patients with PC or PS deficiencies will develop thromboembolism. The prevalence of PC and PS deficiencies is 0.2– 0.5% and 0.08%, respectively,1 and inheritance is autosomal dominant. The reported pregnancy and puerperal risk of thromboembolism with either PC or PS deficiency appears modest, 5–20%, and may be overstated because of ascertainment biases.1 Preston et al have reported that the risk of stillbirth is modestly increased with both PC and PS deficiencies (adjusted OR 2.3, 95% CI 0.6, 8.3 and OR 3.3, 95% CI 1.0, 11.3, respectively).7 In contrast, the risk of miscarriage does not appear to be increased with either PC and PS deficiency (OR 1.4, 95% CI 0.9, 2.2 and OR 1.2, 95% CI 0.7, 1.9, respectively).7 In addition to fetal loss, the rates of severe preeclampsia, abruption, and IUGR appear increased in affected patients.1,6,17 Patients who are homozygous for PC or PS deficiency present with neonatal purpura fulminans and extensive necrosis are unlikely to be encountered during pregnancy. Hyperhomocysteinemia Homocysteine is generated from the metabolism of the amino acid methionine. It normally circulates in the plasma at concentrations of 5–16 ␮mol/L.1 Inherited hyperhomocysteinemia can be exacerbated by deficien-

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cies in vitamins B6, B12, and folic acid. Hyperhomocysteinemia can be diagnosed by measuring fasting homocysteine levels by gas-chromatography-mass spectrometry or other sensitive biochemical means. The disorder is classified into three categories according to the extent of the fasting homocysteine elevation: 1) severe (more than 100 ␮mol/L), 2) moderate (25–100 ␮mol/L), or 3) mild (16 –24 ␮mol/L). Methionine loading can improve diagnostic sensitivity. The severe form results from an autosomal-recessive homozygous deficiency in either cystathionine ␤-synthase or methylenetetrahydrofolate reductase (MTHFR). The former has a prevalence of one in 200,000 to one in 355,000.1 Severe hyperhomocysteinemia presents with neurologic abnormalities, premature atherosclerosis, and recurrent thromboembolism. The mild and moderate forms of hyperhomocysteinemia generally result from autosomal-dominant (heterozygote) deficiencies in cystathionine ␤-synthase (0.3– 1.4% of population) or, most commonly, from homozygosity for the 667C-T MTHFR thermolabile mutant.1 The latter is present in 11% of white European populations.1 Mild and moderate hyperhomocysteinemia patients are also at risk for atherosclerosis and thromboembolism as well as fetal neural tube defects and recurrent abortion.1 A number of investigators have linked hyperhomocysteinemia with severe preeclampsia, stillbirths, and severe IUGR (less than 5th percentile), respectively.1,6,23 deVries et al observed a 26% prevalence of hyperhomocysteinemia among patients with placental abruption.23 There are conflicting data on the link between hyperhomocysteinemia and recurrent spontaneous abortions.1,9,10,12 A meta-analysis of the association between hyperhomocysteinemia and pregnancy loss before 16 weeks suggested a weak association with an OR of 1.4 (95% CI 1.0, 2.0).24 SUMMARY Taken as a group, inherited thrombophilias clearly increase the risk of maternal thromboembolism and latter adverse pregnancy outcomes. In contrast, there does not appear to be a strong link between the inherited thrombophilias and early (less than 10 weeks) pregnancy loss.10 Our ability to predict which women are at highest risk for thromboembolism or which pregnancies are greatest at risk for fetal loss, abruptions, severe preeclampsia, and IUGR remains extremely poor. Moreover, there are no randomized clinical trials to judge the efficacy of anticoagulation therapy in preventing adverse maternal or fetal outcomes. Therefore, recommendations on the work-up and management of affected patients must rely on expert opinion.

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Table 1. Inheritance, Diagnosis, Prevalence and Relative Pathogenicity of the Inherited Thrombophilias Disorder

Genetics

Assays

Prevalence

Factor V Leiden Prothrombin G20210A Antithrombin Protein C Protein S

AD AD AD AD AD

2–15% 2–3% 0.02% 0.2–0.3% 0.1–2.1%*

Hyperhomocysteinemia

AR

PAI-1

AR

DNA DNA Activity assay Activity assay Activity assay If low, assess total & free antigen Fasting homocysteine level ⫹/⫺ MTHFR mutation screen DNA

Risk of VTE 3 to 8-fold 3-fold 25 to 50-fold 10 to 15-fold 2-fold

11%

2.5-fold (levels ⬎18.5 umol/L and 3 to 4-fold (⬎ 20 umol/L)

high

unknown

From: Guideline: Investigation and management of heritable thrombophilia. Br J Haematol 2001;114:512–28.

Diagnosis: A) Who Should Be Tested? Information on the presence of either inherited or acquired (ie, antiphospholipid antibody syndrome) thrombophilias plays a crucial role in determining the need for anticoagulation therapy in pregnancy. Therefore, all patients with a history of venous thrombotic events who are pregnant or planning to conceive should be tested. Given the strong evidence of an association between thrombophilias and fetal loss, abruption, severe preeclampsia, and severe IUGR, it would appear to be prudent to test women with such a history as well. However, it is unclear whether patients with a history of recurrent early (less than 10 weeks) embryonic losses should be evaluated for inherited thrombophilias. Our most recent data would suggest that such testing is not required.10 Diagnosis: B) How Should Patients Be Tested? The prevalence, inheritance, thrombogenic potential, and diagnostic tests for the major inherited thrombophilias are presented in Table 1. The work-up should begin with the most common disorders (ie, genotyping to rule out heterozygosity for the factor V Leiden or prothrombin (G20210A) mutations. If the patient is not pregnant, the factor V Leiden mutation can be ruled out with a functional assay for actual protein C resistance. Genotyping for the 4G/4G PAI-1 mutation is not yet generally available; however, quantitative assays for plasma PAI-1 protein levels are available in most hospital and commercial labs. In the nonpregnant state, elevations in plasma PAI-1 levels more than three-fold may be viewed as presumptive evidence of homozygosity for the 4G/4G allele. Assays for functionally active AT, PC, and PS should also be obtained. If PS activity levels are

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decreased (eg, we employ cutoff values of less than 60% in the nonpregnant state or less than 35% in pregnancy), both free and total antigenic levels of PS should also be assessed to better define the defect. Fasting plasma homocysteine levels should also be assessed in lieu of, or in addition to, the MTHFR mutation. Although there is no consensus on the proper cutoff value for the diagnosis of hyperhomocysteinemia, we employ more than 12 ␮mol/L to define an elevated homocysteine level in pregnancy and more than or equal to 16 ␮mol/L to define elevations in nonpregnant patients. All coagulation activity testing (eg, AT, PC, and PS) should be performed remote from the thrombotic event and off heparin or other anticoagulant therapy. Heparin induces a decline in AT levels, and coumadin decreases PC and PS concentrations. As noted, pregnancy will reduce the amount of free and total PS such that values between 40 and 60% are not uncommon in unaffected patients.

TREATMENT Regardless of their antecedent history, asymptomatic pregnant patients with AT deficiency or those who are homozygotes or compound heterozygotes for the factor V Leiden or prothrombin (G20210A) mutations are at very high risk for maternal thromboembolic disorders and require therapeutic unfractionated or therapeutic low molecular weight heparin therapy throughout pregnancy.1 The latter regimen has several advantages including less need for monitoring antifactor Xa activity and lower risks of osteopenia, thrombocytopenia, and hemorrhage.1 This therapy should be continued throughout the antepartum period until labor. Because

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Figure 2. The management of patients with a prior venous thromboemolic event. Lockwood. Inherited Thrombophilias in Pregnant Patients. Obstet Gynecol 2002.

low molecular weight heparin has a longer half-life than unfractionated heparin and its use has been associated with epidural hematoma formation, neuroaxial anesthesia should not be used within 18 –24 hours of the last dose of low molecular weight heparin. Alternatively, we replace low molecular weight heparin with unfractionated heparin at 36 –37 weeks to facilitate the use of epidural anesthesia in labor. In any case, 6 –12 hours after delivery, heparin therapy should be resumed and coumadin therapy begun. Heparin should be continued for at least 4 days after the initiation of coumadin and not discontinued until the International Normalized Ratio (INR) has been in the therapeutic range (ie, 2–3) for 2 consecutive days. Premature cessation of heparin may cause a paradoxical thrombosis because coumadin lowers PC and PS levels before that of the vitamin Kdependent clotting factors.1 In AT-deficient patients, antithrombin concentrates can be used during labor and delivery, or when there are obstetric complications in which the risks of bleeding from anticoagulation are increased (eg, placenta previa and abruptions). Coumadin should be continued for at least 6 weeks and longer (3– 6 months) if there have been prior thromboembolic events. Women with or without the other lesser thrombogenic inherited or acquired thrombophilias who develop venous thrombotic disorders during pregnancy require

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full therapeutic heparinization with either unfractionated or low molecular weight heparin for at least 4 months. This can be followed by prophylactic therapy with either the unfractionated or low molecular weight heparin throughout the remainder of the pregnancy. As noted above, low molecular weight heparin can be switched to unfractionated heparin at 36 –37 weeks to permit epidural anesthesia. The heparin should be resumed 6 –12 hours after delivery and coumadin initiated. The heparin should be continued during the postpartum period for at least 4 days and/or for at least 48 hours after the patient has achieved a therapeutic INR on coumadin.1 The latter therapy should be maintained for 6 –18 weeks with the precise duration dependent on the site of the thromboembolism (eg, longer for pulmonary emboli and iliofemoral thromboses, shorter for distal leg thromboses).1 The issue of whether prophylactic heparin therapy should be offered to all pregnant patients with a history of prior venous thrombotic events has recently been examined. Brill-Edwards et al prospectively studied 125 pregnant women with a single previous episode of venous thromboembolism, of whom 95 were tested for laboratory evidence of thrombophilia.25 Antepartum heparin was withheld, but anticoagulant therapy was given for 4 – 6 weeks postpartum. Although three of the 125 women (2.4%) had an antepartum recurrence of

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Figure 3. The management of patients with a lesser thrombogenic thrombophilia. Lockwood. Inherited Thrombophilias in Pregnant Patients. Obstet Gynecol 2002.

venous thromboembolism (95% CI 0.2, 6.9), there were no recurrences among the 44 women without evidence of thrombophilia and whose previous thrombosis was associated with a temporary risk factor (eg, oral contraceptives, fracture-induced immobilization). In contrast, three of 51 (5.9%) women with a thrombophilia or whose prior thrombotic episode was not associated with a temporary thrombotic risk factor had an antepartum recurrence of venous thromboembolism. Thus, it would appear that prophylactic heparin is not required among women without a detectable inherited or acquired thrombophilia in whom a previous venous thrombotic event was associated with a nonrecurring risk factor. However, such therapy should be employed in the postpartum period when the risk of thrombosis is highest (Figure 2). In contrast, antepartum and postpartum prophylaxis appears warranted in patients with previous thromboembolic disease who have an identifiable thrombophilia or whose prior thrombosis occurred in the absence of a nonrecurring risk factor (Figure 2). The management of patients in whom inherited thrombophilias are identified is presented in Figure 3. With the exception of pregnant patients with AT defi-

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ciency or those who are homozygotes or compound heterozygotes for the factor V Leiden or prothrombin (G20210A) mutations, there does not appear to be any justification for antenatal heparin treatment in asymptomatic patients incidentally found to have an inherited thrombophilia but who are without a history of prior venous thrombosis or characteristic adverse pregnancy outcomes. Their risks of thromboembolism and/or adverse pregnancy outcomes are likely less than 1%. However, postpartum prophylaxis appears warranted among such patients if they have an affected first-degree relative or other risk factors for thrombosis (eg, cesarean delivery) (Figure 3). As noted above, patients with a history of thromboembolic events and lesser thrombogenic thrombophilias should receive prophylactic heparin therapy in the antepartum period. Coumadin can be started in the immediate postpartum period with the heparin continued for at least 4 days and/or until the INR has been therapeutic for 48 hours. Coumadin is continued for 4 – 6 weeks (Figure 3). There is no consensus on the need for treatment among asymptomatic women with an inherited throm-

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bophilia of lower thrombogenic potential and only a history of characteristic adverse pregnancy outcomes. However, an argument could be made that the recurrence risk of women with prior fetal loss, abruption, severe IUGR, or severe preeclampsia is high enough (5–30%).10 to justify treatment (Figure 3). Although there are no randomized clinical trials to support such an approach, observational studies of low-dose aspirin, and low molecular weight heparin have reported improvement in birth weight compared with untreated pregnancies.26,27 Such patients should be offered postpartum anticoagulation prophylaxis if they have an affected firstdegree relative or thrombotic risk (eg, cesarean delivery). If hyperhomocysteinemia is the sole coagulation defect, consideration should be given to adding vitamin B6, B12, and folic acid supplementation before and throughout the pregnancy. Although there are no randomized clinical trials to support such an approach, the toxicity of this therapy is minimal, and folic acid has proven value in reducing the occurrence of fetal neural tube defects. Prophylactic heparin should be considered among hyperhomocysteinemic patients with a history of thromboembolism or characteristic adverse pregnancy outcomes, whose elevated homocysteine levels are unresponsive to such vitamin therapy.

1. Lockwood CJ. Inherited thrombophilias in pregnant patients. Prenat Neonat Med 2001;6:3–14. 2. Kingdom JC, Kaufmann P. Oxygen and placental villous development: Origins of fetal hypoxia. Placenta 1997;18: 613–21. 3. Lockwood CJ, Rand J. The immunobiology and obstetrical consequences of antiphospholipid antibodies. Obstet Gynecol Survey 1994;49:432– 41. 4. Girling J, de Swiet M. Inherited thrombophilia and pregnancy. Curr Opin Obstet Gynecol 1998;10:135– 44. 5. Gris J-C, Quere I, Monpeyroux F, Mercier E, RipartNeveu S, Tailland ML, et al. Case-control study of the frequency of thrombophilic disorders in couples with late foetal loss and no thrombotic antecedent. The Nimes Obstetricians and Haematologists Study (NOHA). Thromb Haemost 1999;81:891–9. 6. Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999;340:9 –13. 7. Preston FE, Rosendaal FR, Walker ID, Briet E, Berntorp E, Conard J, et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996;348:913– 6. 8. Ridker PM, Miletich JP, Buring JE, Ariyo AA, Price DT, Manson JE, et al. Factor V Leiden mutation as a risk factor

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weight heparin for the prevention of obstetric complications in women with thrombophilia. Hypertension in Pregnancy 2001. In press. 27. Riyazi N, Leeda M, de Vries JL, Huijgens PC, van Geijn HP, Dekker GA. Low molecular weight heparin combined with aspirin in pregnant women with thrombophilia and a history of preeclampsia or fetal growth restriction: A preliminary study. Eur J Obstet Gynecol Reprod Biol 1998; 80:49 –59. Address reprint requests to: Charles J. Lockwood, MD, The Stanley H. Kaplan, Professor and Chair, Department of Obstetrics and Gynecology, New York University School of Medicine, 550 First Avenue, New York, NY 10016; E-mail: Charles. [email protected]. Received October 9, 2001. Received in revised form December 4, 2001. Accepted December 4, 2001.

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