Thrombotic disease is a major cause of peripartum morbidity and mortality worldwide. Development of thrombosis in pregnancy is multifactorial due to the physiologic changes of pregnancy—which induce a relative hypercoagulable state—as well as physical changes leading to increased stasis and also the effects of both the inherited and the acquired thrombophilias. In this review, we discuss the impact of each of these factors on the development of thrombosis as well as the evidence for the impact of pregnancy-associated thrombosis on pregnancy outcome. We then discuss the use of both prophylactic and therapeutic anticoagulation during pregnancy and the puerperium. We review the indications and dosing recommendations for administration of anticoagulation in a context of discussing the evidence including the lack of evidence and formal guidelines in this area. We briefly address the role of the new oral anticoagulants in pregnancy and conclude that significant further research in women with thrombophilias and pregnancy-associated thrombosis may help clarify the management of this condition in the future. 1. Introduction The risk of venous thromboembolic events (VTE) is high during pregnancy due to both physiologic changes of pregnancy and the additional impact of the inherited and acquired thrombophilias. The overall rate of venous thromboembolic events in pregnancy is 200 per 100,000 deliveries [1]. The main risk appears to occur in the postpartum period where the incidence increases almost 2.5-fold and is estimated at 500 per 100,000. The majority of these events are deep vein thrombosis as opposed to the more deadly pulmonary embolism. Venous thromboembolic events remain a leading cause of death which has been estimated to range from 1.2 to 4.7 per 100,000 pregnancies. Inherited and acquired thrombophilias contribute further to an increased predisposition to thrombotic events. The overall impact of the inherited and acquired thrombophilias is low in the nonpregnant population, and the majority of patients never experience a thrombotic event. During pregnancy, however, the increased risk of thromboses in patients with inherited and acquired thrombophilias can be substantial and warrants consideration, especially as thrombosis is the leading cause of mortality during pregnancy. Fifty percent of the patients with thrombosis during pregnancy will be found to have an underlying thrombophilia. 2. Pathophysiologic Changes during Pregnancy The physiological changes that occur during pregnancy are mainly responsible for the increased thrombogenicity of the
References
[1]
J. A. Heit, C. E. Kobbervig, A. H. James, T. M. Petterson, K. R. Bailey, and L. J. Melton III, “Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study,” Annals of Internal Medicine, vol. 143, no. 10, pp. 697–706, 2005.
[2]
K. A. Bremme, “Haemostatic changes in pregnancy,” Best Practice and Research, vol. 16, no. 2, pp. 153–168, 2003.
[3]
A. Antovic, M. Blomb？ck, K. Bremme, and S. He, “The assay of overall haemostasis potential used to monitor the low molecular mass (weight) heparin, dalteparin, treatment in pregnant women with previous thromboembolism,” Blood Coagulation and Fibrinolysis, vol. 13, no. 3, pp. 181–186, 2002.
[4]
F. Cerneca, G. Ricci, R. Simeone, M. Malisano, S. Alberico, and S. Guaschino, “Coagulation and fibrinolysis changes in normal pregnancy increased levels of procoagulants and reduced levels of inhibitors during pregnancy induce a hypercoagulable state, combined with a reactive fibrinolysis,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 73, no. 1, pp. 31–36, 1997.
[5]
S. Z. Goldhaber and V. F. Tapson, “A prospective registry of 5,451 patients with ultrasound-confirmed deep vein thrombosis,” American Journal of Cardiology, vol. 93, no. 2, pp. 259–262, 2004.
[6]
N. S. Macklon and I. A. Greer, “The deep venous system in the puerperium: an ultrasound study,” British Journal of Obstetrics and Gynaecology, vol. 104, no. 2, pp. 198–200, 1997.
[7]
J. S. Ginsberg, P. Brill-Edwards, R. F. Burrows et al., “Venous thrombosis during pregnancy: leg and trimester of presentation,” Thrombosis and Haemostasis, vol. 67, no. 5, pp. 519–520, 1992.
[8]
A. H. James, M. G. Jamison, L. R. Brancazio, and E. R. Myers, “Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality,” American Journal of Obstetrics and Gynecology, vol. 194, no. 5, pp. 1311–1315, 2006.
[9]
I. Pabinger, H. Grafenhofer, P. A. Kyrle et al., “Temporary increase in the risk for recurrence during pregnancy in women with a history of venous thromboembolism,” Blood, vol. 100, no. 3, pp. 1060–1062, 2002.
[10]
S. Miyakis, M. D. Lockshin, T. Atsumi et al., “International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS),” Journal of Thrombosis and Haemostasis, vol. 4, no. 2, pp. 295–306, 2006.
[11]
L. Opatrny, M. David, S. R. Kahn, I. Shrier, and E. Rey, “Association between antiphospholipid antibodies and recurrent fetal loss in women without autoimmune disease: a metaanalysis,” Journal of Rheumatology, vol. 33, no. 11, pp. 2214–2221, 2006.
[12]
A. A. Long, J. S. Ginsberg, P. Brill-Edwards et al., “The relationship of antiphospholipid antibodies to thromboembolic disease in systemic lupus erythematosus: a cross-sectional study,” Thrombosis and Haemostasis, vol. 66, no. 5, pp. 520–524, 1991.
[13]
R. M. Bertina, B. P. C. Koeleman, T. Koster et al., “Mutation in blood coagulation factor V associated with resistance to activated protein C,” Nature, vol. 369, no. 6475, pp. 64–67, 1994.
[14]
S. R. Poort, F. R. Rosendaal, P. H. Reitsma, and R. M. Bertina, “A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis,” Blood, vol. 88, no. 10, pp. 3698–3703, 1996.
[15]
C. Otto and W. O. Richter, “Hemostatic factors and the risk of myocardial infarction,” The New England Journal of Medicine, vol. 333, no. 6, pp. 389–390, 1995.
[16]
A. Gerhardt, R. E. Scharf, M. W. Beckmann et al., “Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium,” The New England Journal of Medicine, vol. 342, no. 6, pp. 374–380, 2000.
[17]
S. Middeldorp, E. J. Libourel, K. Hamulyák, J. D. Van Meer, and H. R. Büller, “The risk of pregnancy-related venous thromboembolism in women who are homozygous for factor V Leiden,” British Journal of Haematology, vol. 113, no. 2, pp. 553–555, 2001.
[18]
L. Robertson, O. Wu, P. Langhorne et al., “Thrombophilia in pregnancy: a systematic review,” British Journal of Haematology, vol. 132, no. 2, pp. 171–196, 2006.
[19]
C. Benedetto, L. Marozio, A. M. Tavella, L. Salton, S. Grivon, and F. Di Giampaolo, “Coagulation disorders in pregnancy: acquired and inherited thrombophilias,” Annals of the New York Academy of Sciences, vol. 1205, pp. 106–117, 2010.
[20]
A. M. Cotter, A. M. Molloy, J. M. Scott, and S. F. Daly, “Elevated plasma homocysteine in early pregnancy: a risk factor for the development of severe preeclampsia,” American Journal of Obstetrics and Gynecology, vol. 185, no. 4, pp. 781–785, 2001.
[21]
F. J. M. Van der Meer, T. Koster, J. P. Vandenbroucke, E. Bri？t, and F. R. Rosendaal, “The Leiden Thrombophilia Study (LETS),” Thrombosis and Haemostasis, vol. 78, no. 1, pp. 631–635, 1997.
[22]
J. R. Meinardi, S. Middeldorp, P. J. de Kam et al., “Increased risk for fetal loss in carriers of the factor V Leiden mutation,” Annals of Internal Medicine, vol. 130, no. 9, pp. 736–739, 1999.
[23]
D. Tormene, P. Simioni, P. Prandoni et al., “The risk of fetal loss in family members of probands with factor V Leiden mutation,” Thrombosis and Haemostasis, vol. 82, no. 4, pp. 1237–1239, 1999.
[24]
O. Kocher, C. Cirovic, E. Malynn et al., “Obstetric complications in patients with hereditary thrombophilia identified using the LCx microparticle enzyme immunoassay: a controlled study of 5,000 patients,” American Journal of Clinical Pathology, vol. 127, no. 1, pp. 68–75, 2007.
[25]
G. Sottilotta, V. Oriana, C. Latella et al., “Genetic prothrombotic risk factors in women with unexplained pregnancy loss,” Thrombosis Research, vol. 117, no. 6, pp. 681–684, 2006.
[26]
G. Lissalde-Lavigne, P. Fabbro-Peray, E. Cochery-Nouvellon et al., “Factor V Leiden and prothrombin G20210A polymorphisms as risk factors for miscarriage during a first intended pregnancy: the matched case-control “NOHA First” study,” Journal of Thrombosis and Haemostasis, vol. 3, no. 10, pp. 2178–2184, 2005.
[27]
M. A. Rodger, M. T. Betancourt, P. Clark et al., “The association of factor V leiden and prothrombin gene mutation and placenta-mediated pregnancy complications: a systematic review and meta-analysis of prospective cohort studies,” PLoS Medicine, vol. 7, no. 6, Article ID e1000292, 2010.
[28]
E. Rey, S. R. Kahn, M. David, and I. Shrier, “Thrombophilic disorders and fetal loss: a meta-analysis,” The Lancet, vol. 361, no. 9361, pp. 901–908, 2003.
[29]
F. E. Preston, F. R. Rosendaal, I. D. Walker et al., “Increased fetal loss in women with heritable thrombophilia,” The Lancet, vol. 348, no. 9032, pp. 913–916, 1996.
[30]
H. Roqué, M. J. Paidas, E. F. Funai, E. Kuczynski, and C. J. Lockwood, “Maternal thrombophilias are not associated with early pregnancy loss,” Thrombosis and Haemostasis, vol. 91, no. 2, pp. 290–295, 2004.
[31]
Z. Alfirevic, D. Roberts, and V. Martlew, “How strong is the association between maternal thrombophilia and adverse pregnancy outcome? A systematic review,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 101, no. 1, pp. 6–14, 2002.
[32]
J. G. Ray and C. A. Laskin, “Folic acid and homocyst(e)ine metabolic defects and the risk of placental abruption, pre-eclampsia and spontaneous pregnancy loss: a systematic review,” Placenta, vol. 20, no. 7, pp. 519–529, 1999.
[33]
B. Brenner, N. Lanir, and I. Thaler, “HELLP syndrome associated with factor V R506Q mutation,” British Journal of Haematology, vol. 92, no. 4, pp. 999–1001, 1996.
[34]
M. G. van Pampus, G. A. Dekker, H. Wolf et al., “High prevalence of hemostatic abnormalities in women with a history of severe preeclampsia,” American Journal of Obstetrics and Gynecology, vol. 180, no. 5, pp. 1146–1150, 1999.
[35]
I. P. Kosmas, A. Tatsioni, and J. P. A. Ioannidis, “Association of Leiden mutation in factor V gene with hypertension in pregnancy and pre-eclampsia: a meta-analysis,” Journal of Hypertension, vol. 21, no. 7, pp. 1221–1228, 2003.
[36]
T. Dudding, J. Heron, A. Thakkinstian et al., “Factor V Leiden is associated with pre-eclampsia but not with fetal growth restriction: a genetic association study and meta-analysis,” Journal of Thrombosis and Haemostasis, vol. 6, no. 11, pp. 1868–1875, 2008.
[37]
T. E. Dudding and J. Attia, “The association between adverse pregnancy outcomes and maternal factor V Leiden genotype: a meta-analysis,” Thrombosis and Haemostasis, vol. 91, no. 4, pp. 700–711, 2004.
[38]
J. Lin and P. August, “Genetic thrombophilias and preeclampsia: a meta-analysis,” Obstetrics and Gynecology, vol. 105, no. 1, pp. 182–192, 2005.
[39]
A. V. D'Elia, L. Driul, R. Giacomello et al., “Frequency of factor V, prothrombin and methylenetetrahydrofolate reductase gene variants in preeclampsia,” Gynecologic and Obstetric Investigation, vol. 53, no. 2, pp. 84–87, 2002.
[40]
E. R. Morrison, Z. H. Miedzybrodzka, D. M. Campbell et al., “Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension: results from a large population-based study and systematic review,” Thrombosis and Haemostasis, vol. 87, no. 5, pp. 779–785, 2002.
[41]
R. M. Silver, Y. Zhao, C. Y. Spong et al., “Prothrombin gene G20210A mutation and obstetric complications,” Obstetrics and Gynecology, vol. 115, no. 1, pp. 14–20, 2010.
[42]
American College of Obstetricians and Gynecologists Committee on Practice Bulletins-Obstetrics, “ACOG Practice Bulletin No. 111: inherited thrombophilias in pregnancy,” Obstetrics and Gynecology, vol. 115, no. 4, pp. 877–887, 2010.
[43]
A. E. Fogerty and J. M. Connors, “Management of inherited thrombophilia in pregnancy,” Current Opinion in Endocrinology, Diabetes and Obesity, vol. 16, no. 6, pp. 464–469, 2009.
[44]
L. R. Brancazio, K. A. Roperti, R. Stierer, and S. A. Laifer, “Pharmacokinetics and pharmacodynamics of subcutaneous heparin during the early third trimester of pregnancy,” American Journal of Obstetrics and Gynecology, vol. 173, no. 4, pp. 1240–1245, 1995.
[45]
V. Sephton, R. G. Farquharson, J. Topping et al., “A longitudinal study of maternal dose response to low molecular weight heparin in pregnancy,” Obstetrics and Gynecology, vol. 101, no. 6, pp. 1307–1311, 2003.
[46]
S. M. Bates, A. Greer, S. Middeldorp et al., “VTE, thrombophilia, antithrombotic therapy, and pregnancy—antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines,” Chest, vol. 141, no. 2, pp. e691–e736, 2012.
[47]
A. James and Committee on Practice Bulletins—Obstetrics, “Practice Bulletin 123: thromboembolism in pregnancy,” Obstetrics and Gynecology, vol. 118, pp. 718–729, 2011.
[48]
Y. Dargaud, L. Rugeri, M. C. Vergnes et al., “A risk score for the management of pregnant women with increased risk of venous thromboembolism: a multicentre prospective study,” British Journal of Haematology, vol. 145, no. 6, pp. 825–835, 2009.
[49]
P. Brill-Edwards, J. S. Ginsberg, M. Gent et al., “Safety of withholding heparin in pregnant women with a history of venous thromboembolism,” The New England Journal of Medicine, vol. 343, no. 20, pp. 1439–1444, 2000.
[50]
I. A. Greer and C. Nelson-Piercy, “Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy,” Blood, vol. 106, no. 2, pp. 401–407, 2005.
[51]
J.-C. Gris, E. Mercier, I. Quéré et al., “Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder,” Blood, vol. 103, no. 10, pp. 3695–3699, 2004.
[52]
N. Folkeringa, J. L. P. Brouwer, F. J. Korteweg et al., “Reduction of high fetal loss rate by anticoagulant treatment during pregnancy in antithrombin, protein C or protein S deficient women,” British Journal of Haematology, vol. 136, no. 4, pp. 656–661, 2007.
[53]
M. Coppens, N. Folkeringa, M. J. Teune et al., “Outcome of the subsequent pregnancy after a first loss in women with the factor V Leiden or prothrombin 20210A mutations,” Journal of Thrombosis and Haemostasis, vol. 5, no. 7, pp. 1444–1448, 2007.
[54]
A. M. Badawy, M. Khiary, L. S. Sherif, M. Hassan, A. Ragab, and I. Abdelall, “Low-molecular weight heparin in patients with recurrent early miscarriages of unknown aetiology,” Journal of Obstetrics and Gynaecology, vol. 28, no. 3, pp. 280–284, 2008.
[55]
M. Dolitzky, A. Inbal, Y. Segal, A. Weiss, B. Brenner, and H. Carp, “A randomized study of thromboprophylaxis in women with unexplained consecutive recurrent miscarriages,” Fertility and Sterility, vol. 86, no. 2, pp. 362–366, 2006.
[56]
J. E. Warren, S. E. Simonsen, D. W. Branch, T. F. Porter, and R. M. Silver, “Thromboprophylaxis and pregnancy outcomes in asymptomatic women with inherited thrombophilias,” American Journal of Obstetrics and Gynecology, vol. 200, no. 3, pp. e281–e285, 2009.
[57]
S. Mantha, K. A. Bauer, and J. I. Zwicker, “Low molecular weight heparin to achieve live birth following unexplained pregnancy loss: a systematic review,” Journal of Thrombosis and Haemostasis, vol. 8, no. 2, pp. 263–268, 2010.
[58]
R. Rai, H. Cohen, M. Dave, and L. Regan, “Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies),” British Medical Journal, vol. 314, no. 7076, pp. 253–257, 1997.
[59]
W. H. Kutteh, “Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone,” American Journal of Obstetrics and Gynecology, vol. 174, no. 5, pp. 1584–1589, 1996.
[60]
R. G. Farquharson, S. Quenby, and M. Greaves, “Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment,” Obstetrics and Gynecology, vol. 100, no. 3, pp. 408–413, 2002.
