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  Andra H. James Venous Thromboembolism in Pregnancy Print ISSN: 1079-5642. Online ISSN: 1524-4636 Copyright © 2009 American Heart Association, Inc. All rights reserved.Greenville Avenue, Dallas, TX 75231is published by the American Heart Association, 7272  Arteriosclerosis, Thrombosis, and Vascular Biology doi: 10.1161/ATVBAHA.109.1841272009;29:326-331  Arterioscler Thromb Vasc Biol. http://atvb.ahajournals.org/content/29/3/326 World Wide Web at: The online version of this article, along with updated information and services, is located on the  http://atvb.ahajournals.org//subscriptions/ at: is online  Arteriosclerosis, Thrombosis, and Vascular Biology Information about subscribing to Subscriptions:  http://www.lww.com/reprints Information about reprints can be found online at: Reprints:  document. Question and AnswerPermissions and Rightspage under Services. Further information about this process is available in thewhich permission is being requested is located, click Request Permissions in the middle column of the WebCopyright Clearance Center, not the Editorial Office. Once the online version of the published article for can be obtained via RightsLink, a service of the  Arteriosclerosis, Thrombosis, and Vascular Biology in Requests for permissions to reproduce figures, tables, or portions of articles srcinally published Permissions:  by guest on November 9, 2014http://atvb.ahajournals.org/ Downloaded from by guest on November 9, 2014http://atvb.ahajournals.org/ Downloaded from   Venous Thromboembolism: Mechanisms, Treatment,and Public Awareness Venous Thromboembolism in Pregnancy Andra H. James  Abstract —The purpose of this review is to summarize the epidemiology of venous thromboembolism (VTE) in pregnancyand describe strategies used to prevent and treat it. The main reason for the increased risk of VTE in pregnancy ishypercoagulability. The hypercoagulability of pregnancy, which has likely evolved to protect women from the bleedingchallenges of miscarriage and childbirth, is present as early as the first trimester and so is the increased risk of VTE.Other risk factors include a history of thrombosis, inherited and acquired thrombophilia, certain medical conditions, andcomplications of pregnancy and childbirth. Candidates for anticoagulation are women with a current thrombosis, ahistory of thrombosis, thrombophilia, and a history of poor pregnancy outcome, or postpartum risk factors for VTE. Forfetal reasons, the preferred agents for anticoagulation in pregnancy are heparins. There are no large trials of anticoagulants in pregnancy and recommendations are based on case series and the opinion of experts. Nonetheless,anticoagulants are believed to improve the outcome of pregnancy for women who have or have had VTE.  (  ArteriosclerThromb Vasc Biol  . 2009;29:326-331.)Key Words:  venous thromboembolism    arterial thromboembolism    deep vein thrombosis   pulmonary embolus    pregnancy    anticoagulation W omen are at an increased risk of both venous andarterial thromboembolism during pregnancy. Com-pared to women who are not pregnant, the risk of arterialthromboembolism (strokes and heart attacks) is increased 3-to 4-fold 1,2 and the risk of venous thromboembolism (VTE) isincreased 4- to 5-fold. 3 Postpartum, the risk is even higher(20-fold 3 ). The overall prevalence of thromboembolic eventsduring pregnancy is approximately 2 per 1000 deliveries. 1,2,4 Approximately 20% of these events are arterial, and the other80% are venous. 1,2,4 VTE accounts for 1.1 deaths per 100 000deliveries, 1,2 or 10% of all maternal deaths.Approximately 80% of venous thromboembolic eventsduring pregnancy are deep vein thrombosis (DVT) and 20%are pulmonary emboli. 4 Approximately one third of pregnancy-related DVT and half of pregnancy-related pulmo-nary emboli occur after delivery. 5–8 When DVT occursduring pregnancy, it is more likely to be proximal, 9 massive, 9 and in the left lower extremity. 7,8 Distal thromboses are aslikely to occur on the right as on the left, but proximalthromboses occurring under the influence of estrogen 10,11 aremore likely to be on the left. This left-sided predominance isthought to be attributable to a relative stenosis of the leftcommon iliac vein where it lies between the lumbar vertebralbody and the right common iliac artery, 12 but the truemechanism is unknown. 13 Pelvic vein thromboses, whichaccount for less than 1% of all cases of DVT, 14 are rareoutside of pregnancy or pelvic surgery yet account forapproximately 10% of DVT during pregnancy and the post-partum period. 7 Pregnant women are probably at an increased risk for VTEas a result of hormonally induced decreased venous capaci-tance and decreased venous outflow, 15,16 possibly as a resultof mechanical obstruction by the uterus, 17 and questionably asa result of decreased mobility. 18–21 These factors, along withvascular injury, 17 are important, especially during the post-partum period, but the risk of VTE is as high during the firsttrimester 7,8 as it is during the second and third trimesters.Therefore, the risk of VTE increases before many of theanatomic changes of pregnancy take place, suggesting that,overall, the most important reason for the increased risk of VTE during pregnancy is hypercoagulability.Normal pregnancy is accompanied by increased concen-trations of factors VII, VIII, X, and von Willebrand factor andby pronounced increases in fibrinogen. 22 Factors II, V, and IXare relatively unchanged. 22 Free protein S, the active, un-bound form, is decreased during pregnancy secondary toincreased levels of its binding protein, the complementcomponent C4b. 22 Plasminogen activator inhibitor type 1(PAI-1) levels increase 5-fold. 22 Levels of PAI-2, producedby the placenta, increase dramatically during the third trimes-ter. 23 Markers of thrombin generation such as prothrombinF1  2 and thrombin-antithrombin (TAT) complexes are in-creased. 24–27 These changes, which may not completelyreturn to baseline until more than 8 weeks postpartum, 22 begin with conception. So does the risk of thrombosis. 7,8 Received January 8, 2009; revision accepted January 16, 2009.From the Division of Maternal-Fetal Medicine Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC.Correspondence to Andra H. James, MD, Box 3967 DUMC, Durham, NC 27710. E-mail andra.james@duke.edu© 2009 American Heart Association, Inc.  Arterioscler Thromb Vasc Biol   is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.109.184127  326   by guest on November 9, 2014http://atvb.ahajournals.org/ Downloaded from   The hypercoagulability of pregnancy has likely evolved toprotect women from hemorrhage at the time of miscarriage orchildbirth. Indeed, in the developing world, the leading causeof maternal death is still hemorrhage, 28 but in Western Europeand the United States, where hemorrhage is successfullytreated or prevented, the leading cause of maternal death isthromboembolic disease. 29 Risk Factors for Thrombosis in Pregnancy The most important risk factor for VTE in pregnancy is ahistory of thrombosis. Fifteen to 25% of thromboembolicevents in pregnancy are recurrent events. The risk of recurrentVTE in pregnancy is also increased 3- to 4-fold (relative risk 3.5 [95% confidence interval 1.6, 7.8]). 30 In recent studies,the rate of recurrent VTE in women who did not receiveanticoagulation has been reported to range from 2.4% to12.2%. 31–33 In women who did receive anticoagulation, therate of recurrent VTE has been reported to range from 0 to2.4%. 31,34,35 Besides a history of thrombosis, the most important risk factor for VTE in pregnancy is thrombophilia. 4,7 Othermedical conditions that increase the risk of VTE are heartdisease, sickle cell disease, lupus, obesity, anemia, diabetes,hypertension, and smoking. Pregnancy and delivery compli-cations that increase the risk are multiple gestation, hy-peremesis, disorders of fluid, electrolyte and acid-base bal-ance, antepartum hemorrhage, cesarean delivery, postpartuminfection, postpartum hemorrhage, and transfusion. 4 Oddsratios for these conditions were obtained from an analysis of 14 335 records from the Nationwide Inpatient Sample 4 andare summarized in Table 1. In the same analysis, older ageand black race were also found to be risk factors for VTE.The odds ratio (OR) for women age 35 and older was foundto be 2.1 (2.0, 2.3). 4 After controlling for age, the OR forblack women was still found to be 1.4 (1.2, 1.6). 4 Thrombophilia is present in 20% to 50% 33,36,37 of womenwho experience VTE during pregnancy and the postpartumperiod. Both acquired and inherited thrombophilia increasethe risk. The absolute risk of VTE conferred by type of thrombophilia was systematically reviewed by Robertson etal 38 and is summarized in Table 2. Prevention of Thrombosis in Pregnancy Despite the increased risk of VTE during pregnancy and thepostpartum period, most women do not require anticoagula-tion. In most cases, the risks of anticoagulation outweigh itsbenefits. Women who would benefit from anticoagulation forprevention of thrombosis in pregnancy are those whose risk of VTE is greater than the risk of bleeding complicationsfrom heparin or low-molecular-weight heparin, which hasbeen reported to be as high as 2%. 34,35,39,40 Women whowould benefit are those with a history of thrombosis.Other women who may benefit from anticoagulation inpregnancy are women with inherited or acquired thrombo-philia and a history of poor pregnancy outcome. In theantiphospholipid syndrome, several studies have demon-strated that anticoagulation improves the outcome of preg-nancy 41 and in inherited thrombophilia, case reports, caseseries, and one small randomized trial 42 have also suggestedthat anticoagulation can improve the outcome of pregnancy.Ideally, evaluation of the woman who may require antico-agulation during pregnancy should occur before conception,or at least early in pregnancy. Women with conditions thatplace them at a high risk of maternal mortality because of thrombosis may best be counseled against pregnancy. Theseconditions include mechanical heart valves, 43 chronic throm-boembolic pulmonary hypertension, a history of recurrentthrombosis while fully anticoagulated, and a history of myocardial infarction. Most women with a history of VTE,however, can be counseled that their risks are manageableand are probably reduced with anticoagulation.Women who are already on full anticoagulation willlikely need to continue. They should be counseled aboutthe harmful effects of warfarin on the fetus and offered theopportunity to be converted to low-molecular-weight hep-arin before conception.Women who have not had a complete thrombophiliawork-up may be tested. Although the results of thrombophiliatesting will not alter the general recommendation for antico-agulation in pregnancy, the results may alter the intensity Table 1. Medical Conditions and Complications of Pregnancyand Delivery Associated With an Increased Risk of VenousThromboembolism in Pregnancy Risk Factor Odds Ratio Confidence IntervalMedical conditionsHeart disease 7.1 6.2, 8.3Sickle cell disease 6.7 4.4, 10.1Lupus 8.7 5.8, 13.0Obesity 4.4 3.4, 5.7 Anemia 2.6 2.2, 2.9Diabetes 2.0 1.4, 2.7Hypertension 1.8 1.4, 2.3Smoking 1.7 1.4, 2.1Complications of pregnancy and deliveryMultiple gestation 1.6 1.2, 2.1Hyperemesis 2.5 2.0, 3.2Fluid & electrolyte imbalance 4.9 4.1, 5.9 Antepartum hemorrhage 2.3 1.8, 2.8Cesarean delivery 2.1 1.8, 2.4Postpartum infection 4.1 2.9, 5.7Postpartum hemorrhage 1.3 1.1, 1.6Transfusion 7.6 6.2, 9.4 Table 2. Risk of VTE Conferred by Type of Thrombophilia Thrombophilia Odds RatiosFactor V Leiden–homozygosity 34.40 (9.86, 120.05)Factor V Leiden–heterozygosity 8.32 (5.44, 12.70)Prothrombin gene mutation–homozygosity 26.36 (1.24, 559.29)Prothrombin gene mutation–heterozygosity 6.80 (2.46, 18.77)Protein C deficiency 4.76 (2.15, 10.57)Protein S deficiency 2.19 (1.48, 6.00) Antithrombin deficiency 4.76 (2.15, 10.57) James Venous Thromboembolism in Pregnancy  327   by guest on November 9, 2014http://atvb.ahajournals.org/ Downloaded from   from low or “prophylactic” to full adjusted-dose or “thera-peutic.” Although some experts would recommend thrombo-prophylaxis for all pregnant women with inherited thrombo-philia, anticoagulation is probably not necessary if there is nopersonal history of thromboembolism or poor pregnancyoutcome. 44 The exceptions, because of their especially highrisk of thrombosis, are women with antithrombin deficiency,homozygosity for the factor V Leiden mutation or theprothrombin gene G20210A mutation, or heterozygosity forboth mutations (compound heterozygosity). 44 Anticoagulation and Pregnancy Unique aspects of anticoagulation in pregnancy include bothmaternal and fetal issues. Warfarin, the preferred agent forlong-term anticoagulation outside of pregnancy, has harmfulfetal effects. Warfarin taken during the critical period fororganogenesis, the 4th to the 8th week after conception., 45 isassociated with a 14.6% to 56% reported risk of miscar-riage 49–55 and, depending on the case series, carries up to a30% risk of congenital anomalies. 46–52 Placental transfer of warfarin later in pregnancy can result in fetal bleeding 52,53 orstillbirth. 47,49,50,54 Long-term sequelae include a 14% reportedrisk of adverse neurological outcome 55 and a 4% reported risk of low intelligence quotient (IQ). 55 The preferred agents for anticoagulation in pregnancyare heparin compounds. 44 Neither heparin 56–58 nor low-molecular-weight heparin 57,58 cross the placenta, and bothare considered safe in pregnancy. 35,39 Unique aspects of anticoagulation in pregnancy include an increase in mater-nal blood volume of 40% to 50% 15 and an increase in thevolume of distribution. An increase in glomerular filtra-tion 15 results in increased renal excretion of heparincompounds, which are eliminated by this route. Addition-ally, there is an increase in protein binding of heparin.During pregnancy, both unfractionated heparin 59 and low-molecular-weight heparins 60–64 have shorter half-lives andlower peak plasma concentrations, usually necessitatinghigher doses and more frequent administration.Disadvantages of unfractionated heparin include the neces-sity of parenteral administration, a risk of major bleeding, 39 arisk of reduced bone density, 65–67 a risk of vertebral frac-ture, 68 and a risk of heparin-induced thrombocytopenia(HIT). 44 Although the risk of HIT is low in pregnancy andmay be lower than in nonpregnant patients, 69 the actual risk isunknown. 44 There are few comparative studies in pregnancy, but innonpregnant patients, low-molecular-weight heparin has beenassociated with fewer side effects than unfractionated hepa-rin. 70 Potential advantages of low-molecular-weight heparinare less bleeding, a more predictable response, a lower risk of HIT (no cases were confirmed in two large reviews of the useof low-molecular-weight heparin in pregnancy 34,40 ), a longerhalf-life, and less bone loss. 71 However, in a randomized trialof low-dose unfractionated heparin versus enoxaparin (alow-molecular-weight heparin) for thromboprophylaxis inpregnancy, there was no difference in the incidence of clinically significant bone loss (which was 2 to 2.5%)between women who took unfractionated heparin comparedto those who took enoxaparin, 67 and another study found thatbone loss in women who took low-molecular-weight heparinwas approximately 4%, the same as in controls. 72 An advan-tage of enoxaparin, and probably other low-molecular-weightheparins as well, is less bruising at injection sites. 73 Adisadvantage of low-molecular-weight heparins, besides theircost, is their longer half-life, which is an issue at the time of delivery.Fondaparinux is a new selective factor Xa inhibitor usedfor thromboprophylaxis. Data on its use in pregnancy arelimited. Although Lagrange et al 74 observed no transplacentalpassage of fondaparinux using a perfused cotyledon model,Dempfle et al 75 found transplacental passage of fondaparinuxin 5 women who took it for 1 to 101 days because of heparinallergy. Antifactor Xa levels in umbilical cord plasma of newborns were found to be one tenth the concentration of maternal plasma. The clinical significance of this finding isunknown, but no adverse effects were noted in thenewborns. 75 Fondaparinux may not be effective in reducing the risk of pregnancy loss in women for whom it is prescribed for thatindication, such as women with the antiphospholipid syn-drome. Unlike heparin or low-molecular-weight heparin,fondaparinux does not prevent fetal death in mice withantiphospholipid antibodies. 76 At the present time there areinsufficient data to justify the routine use of fondaparinux forprophylaxis of VTE in pregnancy. Nonetheless, fondaparinuxis probably the anticoagulant of choice in cases of severecutaneous allergies or HIT in pregnancy 75,77 where danap-aroid (a nonheparin containing heparanoid composed of heparin sulfate, dermatan sulfate and chondroitin sulfate) isunavailable, such as in the United States.There are no large trials of anticoagulants in pregnancy,and recommendations for their use are based on case seriesand the opinion of experts. Full-dose (adjusted dose) antico-agulation is recommended 44,78 for women with either a needfor life-long anticoagulation or antiphospholipid syndromewith a history of thrombosis. Full-dose (adjusted dose) or anintermediate or moderate dose is recommended 44,78 forwomen with either antithrombin deficiency or homozygosityfor the factor V Leiden mutation, the prothrombin geneG20210A mutation, or compound heterozygosity for bothmutations. Low-dose anticoagulation is recommended 44,79 forwomen with a history of unprovoked thrombosis. In oneseries, women with a history of thrombosis in the setting of transient risk factors had a rate of recurrence in pregnancysimilar to that of other women with a history of thrombosis, 32 but close observation (assessment of signs and symptoms of thrombosis at routine prenatal visits) may be an option forwomen with a history of thrombosis in the setting of transientrisk factors such as injury or immobility. 44 Nonetheless, if these women do not receive anticoagulation during preg-nancy, they should be considered for thromboprophylaxispostpartum. New Onset DVT and Pulmonary Embolismin Pregnancy The two most common initial symptoms, present in more than80% of women with pregnancy-related DVT, are pain andswelling in an extremity. 7 When signs or symptoms suggest  328 Arterioscler Thromb Vasc Biol   March 2009  by guest on November 9, 2014http://atvb.ahajournals.org/ Downloaded from 
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