Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter December 13, 2013

Risk factors for pregnancy-associated venous thromboembolism: a review

Barry Kevane, Jennifer Donnelly, Mary D’Alton, Sharon Cooley, Roger J.S. Preston and Fionnuala Ní Áinle

Abstract

Aim: To critically evaluate current understanding of risk factors for pregnancy-associated venous thromboembolism (VTE) and to describe underlying molecular mechanisms.

Methods: A literature search was undertaken using the national library of medicine PubMed database. The search terms used were “pregnancy” and “venous thromboembolism”. Following exclusion of unsuitable data sources, studies were identified that described specific risk factors for pregnancy-associated VTE and suggested possible underlying molecular mechanisms. Adjusted odds ratios and incident rate ratios for these specific risk factors were identified in each study and tabulated.

Results: A series of mainly retrospective cohort and case control studies over the past two decades have reported specific risk factors for pregnancy-associated VTE. Recent published literature has highlighted the interaction between commonly occurring risk factors, particularly the potential for a multiplicative effect on overall VTE risk, and have led to improvements in our understanding of the molecular mechanisms underlying these risk factors.

Conclusion: Mortality from pregnancy associated VTE continues despite prevention strategies. A detailed understanding of specific risk factors, their interactions and underlying molecular mechanisms is required to identify women at highest risk and to guide development of thromboprophylaxis strategies.


Corresponding author: Dr Fionnuala Ní Áinle, Rotunda Hospital, Parnell St, Dublin 1, Ireland and Mater Misericordiae University Hospital, Dublin 7, Ireland, E-mail:

References

[1] Ay L, Kopp HP, Brix JM, Ay C, Quehenberger P, Schernthaner GH, et al. Thrombin generation in morbid obesity: significant reduction after weight loss. J Thromb Haemost. 2010;8:759–65.10.1111/j.1538-7836.2010.03766.xSearch in Google Scholar

[2] Badeanlou L, Furlan-Freguia C, Yang G, Ruf W, Samad F. Tissue factor-protease-activated receptor 2 signaling promotes diet-induced obesity and adipose inflammation. Nat Med. 2011;17:1490–7.10.1038/nm.2461Search in Google Scholar

[3] Baglin T, Gray E, Greaves M, Hunt BJ, Keeling D, Machin S, et al. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol. 2010;149:209–20.10.1111/j.1365-2141.2009.08022.xSearch in Google Scholar

[4] Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO, 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. 2012; 141(2 Suppl):e691S–736S.10.1378/chest.11-2300Search in Google Scholar

[5] Bezemer ID, van der Meer FJ, Eikenboom JC, Rosendaal FR, Doggen CJ. The value of family history as a risk indicator for venous thrombosis. Arch Intern Med. 2009;169:610–5.10.1001/archinternmed.2008.589Search in Google Scholar

[6] Biron-Andreani C, Schved JF, Daures JP. Factor V Leiden mutation and pregnancy-related venous thromboembolism: what is the exact risk? Results from a meta-analysis. Thromb Haemost. 2006;96:14–8.10.1160/TH06-02-0086Search in Google Scholar

[7] Blondon M. Thromboprophylaxis after cesarean section: decision analysis. Thromb Res. 2011;127(Suppl 3):S9–12.10.1016/S0049-3848(11)70004-4Search in Google Scholar

[8] Brill-Edwards P, Ginsberg JS, Gent M, Hirsh J, Burrows R, Kearon C, et al. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of Clot in This Pregnancy Study Group. N Engl J Med. 2000;343:1439–44.10.1056/NEJM200011163432002Search in Google Scholar PubMed

[9] British Committee for Standards in Haematology, Stainsby D, MacLennan S, Thomas D, Isaac J, Hamilton PJ. Guidelines on the management of massive blood loss. Br J Haematol. 2006;135:634–41.10.1111/j.1365-2141.2006.06355.xSearch in Google Scholar PubMed

[10] Bucciarelli P, Mannucci PM. The hemostatic system through aging and menopause. Climacteric. 2009;12(Suppl 1):47–51.10.1080/13697130903006365Search in Google Scholar PubMed

[11] Cantwell R, Clutton-Brock T, Cooper G, Dawson A, Drife J, Garrod D, et al. Saving mothers’ lives: reviewing maternal deaths to make motherhood safer: 2006–2008. The eighth report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. BJOG. 2011;118(Suppl 1):1–203.10.1111/j.1471-0528.2010.02847.xSearch in Google Scholar PubMed

[12] Chan LY, Tam WH, Lau TK. Venous thromboembolism in pregnant Chinese women. Obstet Gynecol. 2001;98(3):471–5.Search in Google Scholar

[13] Cirillo P, De Rosa S, Pacileo M, Gargiulo A, Leonardi A, Angri V, et al. Nicotine induces tissue factor expression in cultured endothelial and smooth muscle cells. J Thromb Haemost. 2006;4:453–8.10.1111/j.1538-7836.2006.01741.xSearch in Google Scholar PubMed

[14] Coughlin SR. Thrombin signalling and protease-activated receptors. Nature. 2000;407:258–64.10.1038/35025229Search in Google Scholar PubMed

[15] Danilenko-Dixon DR, Heit JA, Silverstein MD, Yawn BP, Petterson TM, Lohse CM, et al. Risk factors for deep vein thrombosis and pulmonary embolism during pregnancy or post partum: a population-based, case-control study. Am J Obstet Gynecol. 2001;184:104–10.10.1067/mob.2001.107919Search in Google Scholar PubMed

[16] Darvall KA, Sam RC, Silverman SH, Bradbury AW, Adam DJ. Obesity and thrombosis. Eur J Vasc Endovasc Surg. 2007;33:223–33.10.1016/j.ejvs.2006.10.006Search in Google Scholar PubMed

[17] de Jong PG, Coppens M, Middeldorp S. Duration of anticoagulant therapy for venous thromboembolism: balancing benefits and harms on the long term. Br J Haematol. 2012;158:433–41.10.1111/j.1365-2141.2012.09196.xSearch in Google Scholar PubMed

[18] De Stefano V, Martinelli I, Rossi E, Battaglioli T, Za T, Mannuccio Mannucci P, et al. The risk of recurrent venous thromboembolism in pregnancy and puerperium without antithrombotic prophylaxis. Br J Haematol. 2006;135:386–91.10.1111/j.1365-2141.2006.06317.xSearch in Google Scholar PubMed

[19] Delluc A, Le Moigne E, Tromeur C, Noel-Savina E, Couturaud F, Mottier D, et al. Site of venous thromboembolism and prothrombotic mutations according to body mass index. Results from the EDITH study. Br J Haematol. 2011;154:486–91.10.1111/j.1365-2141.2011.08592.xSearch in Google Scholar PubMed

[20] Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol. 2013;13:34–45.10.1038/nri3345Search in Google Scholar PubMed

[21] Gardiner C, Tannetta DS, Simms CA, Harrison P, Redman CW, Sargent IL. Syncytiotrophoblast microvesicles released from pre-eclampsia placentae exhibit increased tissue factor activity. PLoS One. 2011;6:e26313.10.1371/journal.pone.0026313Search in Google Scholar PubMed PubMed Central

[22] Gould MK, Garcia DA, Wren SM, Karanicolas PJ, Arcelus JI, Heit JA, et al. Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 Suppl):e227S–77S.10.1378/chest.11-2297Search in Google Scholar PubMed PubMed Central

[23] Gris JC, Bouvier S, Molinari N, Galanaud JP, Cochery-Nouvellon E, Mercier E, et al. Comparative incidence of a first thrombotic event in purely obstetric antiphospholipid syndrome with pregnancy loss: the NOH-APS observational study. Blood. 2012;119:2624–32.10.1182/blood-2011-09-381913Search in Google Scholar PubMed

[24] Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ, 3rd. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med. 2005;143: 697–706.10.7326/0003-4819-143-10-200511150-00006Search in Google Scholar PubMed

[25] Heit JA, Leibson CL, Ashrani AA, Petterson TM, Bailey KR, Melton LJ, 3rd. Is diabetes mellitus an independent risk factor for venous thromboembolism?: a population-based case-control study. Arterioscler Thromb Vasc Biol. 2009;29:1399–405.10.1161/ATVBAHA.109.189290Search in Google Scholar PubMed PubMed Central

[26] Hung J, Lam JY, Lacoste L, Letchacovski G. Cigarette smoking acutely increases platelet thrombus formation in patients with coronary artery disease taking aspirin. Circulation. 1995;92:2432–6.10.1161/01.CIR.92.9.2432Search in Google Scholar PubMed

[27] Jacobsen AF, Skjeldestad FE, Sandset PM. Ante- and postnatal risk factors of venous thrombosis: a hospital-based case-control study. J Thromb Haemost. 2008;6:905–12.10.1111/j.1538-7836.2008.02961.xSearch in Google Scholar PubMed

[28] Jacobsen AF, Skjeldestad FE, Sandset PM. Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium-a register-based case-control study. Am J Obstet Gynecol. 2008;198:233.e1–7.10.1016/j.ajog.2007.08.041Search in Google Scholar PubMed

[29] James AH, Jamison MG, Brancazio LR, Myers ER. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol. 2006;194:1311–5.10.1016/j.ajog.2005.11.008Search in Google Scholar PubMed

[30] Kane EV, Calderwood C, Dobbie R, Morris C, Roman E, Greer IA. A population-based study of venous thrombosis in pregnancy in Scotland 1980–2005. Eur J Obstet Gynecol Reprod Biol. 2013;169:223–9.10.1016/j.ejogrb.2013.03.024Search in Google Scholar PubMed

[31] Keeling D, Mackie I, Moore GW, Greer IA, Greaves M, British Committee for Standards in H. Guidelines on the investigation and management of antiphospholipid syndrome. Br J Haematol. 2012;157:47–58.10.1111/j.1365-2141.2012.09037.xSearch in Google Scholar PubMed

[32] Kopp CW, Kopp HP, Steiner S, Kriwanek S, Krzyzanowska K, Bartok A, et al. Weight loss reduces tissue factor in morbidly obese patients. Obes Res. 2003;11:950–6.10.1038/oby.2003.131Search in Google Scholar

[33] Kingdom JC, Drewlo S. Is heparin a placental anticoagulant in high-risk pregnancies? Blood. 2011;118:4780–8.10.1182/blood-2011-07-319749Search in Google Scholar

[34] Larsen TB, Johnsen SP, Gislum M, Moller CA, Larsen H, Sorensen HT. ABO blood groups and risk of venous thromboembolism during pregnancy and the puerperium. A population-based, nested case-control study. J Thromb Haemost. 2005;3:300–4.10.1111/j.1538-7836.2005.01195.xSearch in Google Scholar

[35] Larsen TB, Sorensen HT, Gislum M, Johnsen SP. Maternal smoking, obesity, and risk of venous thromboembolism during pregnancy and the puerperium: a population-based nested case-control study. Thromb Res. 2007;120:505–9.10.1016/j.thromres.2006.12.003Search in Google Scholar

[36] Lee KW, Lip GY. Effects of lifestyle on hemostasis, fibrinolysis, and platelet reactivity: a systematic review. Arch Intern Med. 2003;163:2368–92.10.1001/archinte.163.19.2368Search in Google Scholar

[37] Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol. 2009;145:24–33.10.1111/j.1365-2141.2009.07600.xSearch in Google Scholar

[38] Lindqvist P, Dahlback B, Marsal K. Thrombotic risk during pregnancy: a population study. Obstet Gynecol. 1999;94:595–9.10.1097/00006250-199910000-00021Search in Google Scholar

[39] Liu S, Rouleau J, Joseph KS, Sauve R, Liston RM, Young D, et al. Epidemiology of pregnancy-associated venous thromboembolism: a population-based study in Canada. J Obstet Gynaecol Can. 2009;31:611–20.10.1016/S1701-2163(16)34240-2Search in Google Scholar

[40] Lussana F, Coppens M, Cattaneo M, Middeldorp S. Pregnancy-related venous thromboembolism: risk and the effect of thromboprophylaxis. Thromb Res. 2012;129:673–80.10.1016/j.thromres.2012.01.017Search in Google Scholar PubMed

[41] Macey MG, Bevan S, Alam S, Verghese L, Agrawal S, Beski S, et al. Platelet activation and endogenous thrombin potential in pre-eclampsia. Thromb Res. 2010;125:e76–81.10.1016/j.thromres.2009.09.013Search in Google Scholar PubMed

[42] McDonald AP, Meier TR, Hawley AE, Thibert JN, Farris DM, Wrobleski SK, et al. Aging is associated with impaired thrombus resolution in a mouse model of stasis induced thrombosis. Thromb Res. 2010;125:72–8.10.1016/j.thromres.2009.06.005Search in Google Scholar PubMed

[43] McLintock C, Brighton T, Chunilal S, Dekker G, McDonnell N, McRae S, et al. Recommendations for the prevention of pregnancy-associated venous thromboembolism. Aust N Z J Obstet Gynaecol. 2012;52:3–13.10.1111/j.1479-828X.2011.01357.xSearch in Google Scholar PubMed

[44] Miller GJ, Bauer KA, Cooper JA, Rosenberg RD. Activation of the coagulant pathway in cigarette smokers. Thromb Haemost. 1998;79:549–53.10.1055/s-0037-1614942Search in Google Scholar

[45] Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295–306.10.1111/j.1538-7836.2006.01753.xSearch in Google Scholar PubMed

[46] Newby DE, Wright RA, Labinjoh C, Ludlam CA, Fox KA, Boon NA, et al. Endothelial dysfunction, impaired endogenous fibrinolysis, and cigarette smoking: a mechanism for arterial thrombosis and myocardial infarction. Circulation. 1999;99:1411–5.10.1161/01.CIR.99.11.1411Search in Google Scholar

[47] Ni Ainle F, O’Donnell JS, Johnson JA, Brown L, Gleeson EM, Smith OP, et al. Activated protein C N-linked glycans modulate cytoprotective signaling function on endothelial cells. J Biol Chem. 2011;286:1323–30.10.1074/jbc.M110.159475Search in Google Scholar PubMed PubMed Central

[48] Pabinger I, Grafenhofer H, Kaider A, Kyrle PA, Quehenberger P, Mannhalter C, et al. Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis. J Thromb Haemost. 2005;3:949–54.10.1111/j.1538-7836.2005.01307.xSearch in Google Scholar PubMed

[49] Palomo I, Alarcon M, Moore-Carrasco R, Argiles JM. Hemostasis alterations in metabolic syndrome (review). Int J Mol Med. 2006;18:969–74.10.3892/ijmm.18.5.969Search in Google Scholar

[50] Pomp ER, Lenselink AM, Rosendaal FR, Doggen CJ. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost. 2008;6:632–7.10.1111/j.1538-7836.2008.02921.xSearch in Google Scholar PubMed

[51] Reducing the risk of thrombosis and embolism during pregnancy and the puerperium. Royal College of Obstetricians and Gynaecologists Green-top Guideline No 37a; 2009.Search in Google Scholar

[52] Robertson L, Wu O, Langhorne P, Twaddle S, Clark P, Lowe GD, et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol. 2006;132:171–96.10.1111/j.1365-2141.2005.05847.xSearch in Google Scholar PubMed

[53] Sauls DL, Banini AE, Boyd LC, Hoffman M. Elevated prothrombin level and shortened clotting times in subjects with type 2 diabetes. J Thromb Haemost. 2007;5:638–9.10.1111/j.1538-7836.2007.02366.xSearch in Google Scholar

[54] Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet. 2005;365:785–99.10.1016/S0140-6736(05)17987-2Search in Google Scholar

[55] Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ, 3rd. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998;158:585–93.10.1001/archinte.158.6.585Search in Google Scholar

[56] Simpson EL, Lawrenson RA, Nightingale AL, Farmer RD. Venous thromboembolism in pregnancy and the puerperium: incidence and additional risk factors from a London perinatal database. BJOG. 2001;108:56–60.Search in Google Scholar

[57] Sultan AA, Tata LJ, West J, Fiaschi L, Fleming KM, Nelson-Piercy C, et al. Risk factors for first venous thromboembolism around pregnancy: a population based cohort study from the United Kingdom. Blood. 2013;121:3953–61.10.1182/blood-2012-11-469551Search in Google Scholar

[58] Sultan AA, West J, Tata LJ, Fleming KM, Nelson-Piercy C, Grainge MJ. Risk of first venous thromboembolism in and around pregnancy: a population-based cohort study. Br J Haematol. 2012;156:366–73.10.1111/j.1365-2141.2011.08956.xSearch in Google Scholar

[59] Tripodi A, Branchi A, Chantarangkul V, Clerici M, Merati G, Artoni A, et al. Hypercoagulability in patients with type 2 diabetes mellitus detected by a thrombin generation assay. J Thromb Thrombolysis. 2011;31:165–72.10.1007/s11239-010-0506-0Search in Google Scholar

[60] Tully L, Gates S, Brocklehurst P, McKenzie-McHarg K, Ayers S. Surgical techniques used during caesarean section operations: results of a national survey of practice in the UK. Eur J Obstet Gynecol Reprod Biol. 2002;102:120–6.10.1016/S0301-2115(01)00589-9Search in Google Scholar

[61] Won HS, Kim do Y, Yang MS, Lee SJ, Shin HH, Park JB. Pregnancy-induced hypertension, but not gestational diabetes mellitus, is a risk factor for venous thromboembolism in pregnancy. Korean Circ J. 2011;41:23–7.10.4070/kcj.2011.41.1.23Search in Google Scholar PubMed PubMed Central

The authors stated that there are no conflicts of interest regarding the publication of this article.

Received: 2013-8-8
Accepted: 2013-11-18
Published Online: 2013-12-13
Published in Print: 2014-7-1

©2014 by Walter de Gruyter Berlin/Boston

Scroll Up Arrow