VTE Risk Assessment and Prevention in Pregnancy

Abstract

Venous thromboembolism (VTE) remains the leading cause of maternal mortality in pregnancy and the postpartum period. In addition to the higher pregnancy-associated baseline VTE risk, there are several well-established risk factors that can further increase the risk of VTE. At present, a thorough interrogation of these risk factors remains our only tool for estimating which pregnant people may be at an increased risk of VTE, and thus potentially benefit from thromboprophylaxis. However, an important knowledge gap still exists surrounding the duration of increased risk and the interaction of risk factors with each other. Furthermore, up to now, once significant risk has been established, prevention strategies have been largely based on expert opinion rather than high-quality data. Recent trials have successfully bridged a proportion of this knowledge gap; however, the challenge of conducting high-quality clinical trials with pregnant people remains. In this article, we provide an update on the recent evidence surrounding VTE risk factors in pregnancy while concurrently outlining knowledge gaps and current approaches to VTE prevention.

Keywords

venous thromboembolism - pregnancy - risk assessment

Publication History

Received: 07 September 2023

Accepted: 02 January 2024

Article published online:
26 February 2024

• References

• 1 Berg CJ, Callaghan WM, Syverson C, Henderson Z. Pregnancy-related mortality in the United States, 1998 to 2005. Obstet Gynecol 2010; 116 (06) 1302-1309
• 2 Knight M. Saving Lives, Improving Mothers' Care: Lessons learned to inform maternity care from the UK and Ireland Confidential Enquiries into Maternal Deaths and Morbidity 2014–16. Oxford, UK: National Perinatal Epidemiology Unit; 2018
• 3 Konstantinides SV, Meyer G, Becattini C. et al. ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2019; 41 (04) 543-603
• 4 Abdul Sultan A, Tata LJ, Grainge MJ, West J. The incidence of first venous thromboembolism in and around pregnancy using linked primary and secondary care data: a population based cohort study from England and comparative meta-analysis. PLoS One 2013; 8 (07) e70310
• 5 Wiegers HMG, Körmendiné Farkas D, Horváth-Puhó E, Middeldorp S, van Es N, Sørensen HT. Incidence and prognosis of superficial vein thrombosis during pregnancy and the post-partum period: a Danish nationwide cohort study. Lancet Haematol 2023; 10 (05) e359-e366
• 6 Kevane B, Donnelly J, D'Alton M, Cooley S, Preston RJ, Ní Ainle F. Risk factors for pregnancy-associated venous thromboembolism: a review. J Perinat Med 2014; 42 (04) 417-425
• 7 Rodger M. Pregnancy and venous thromboembolism: ‘TIPPS’ for risk stratification. Hematology (Am Soc Hematol Educ Program) 2014; 2014 (01) 387-392
• 8 Egan K, O'Connor H, Kevane B. et al. Elevated plasma TFPI activity causes attenuated TF-dependent thrombin generation in early onset preeclampsia. Thromb Haemost 2017; 117 (08) 1549-1557
• 9 Haire G, Egan K, Parmar K. et al. Alterations in fibrin formation and fibrinolysis in early onset-preeclampsia: association with disease severity. Eur J Obstet Gynecol Reprod Biol 2019; 241: 19-23
• 10 Morrison R, Crawford J, MacPherson M, Heptinstall S. Platelet behaviour in normal pregnancy, pregnancy complicated by essential hypertension and pregnancy-induced hypertension. Thromb Haemost 1985; 54 (03) 607-611
• 11 Heijnen HF, Schiel AE, Fijnheer R, Geuze HJ, Sixma JJ. Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood 1999; 94 (11) 3791-3799
• 12 Nurden AT. Platelets, inflammation and tissue regeneration. Thromb Haemost 2011; 105 (Suppl. 01) S13-S33
• 13 Szklanna PB, Parsons ME, Wynne K. et al. The platelet releasate is altered in human pregnancy. Proteomics Clin Appl 2019; 13 (03) e1800162
• 14 Lindqvist P, Dahlbäck B, Marŝál K. Thrombotic risk during pregnancy: a population study. Obstet Gynecol 1999; 94 (04) 595-599
• 15 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 (06) 905-912
• 16 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 (05) 1311-1315
• 17 Liu S, Rouleau J, Joseph KS. et al. Epidemiology of pregnancy-associated venous thromboembolism: a population-based study in Canada. J Obstet Gynaecol Can 2009; 31 (07) 611-620
• 18 Danilenko-Dixon DR, Heit JA, Silverstein MD. 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 (02) 104-110
• 19 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 (01) 56-60
• 20 Sultan AA, West J, Grainge MJ. et al. Development and validation of risk prediction model for venous thromboembolism in postpartum women: multinational cohort study. BMJ 2016; 355: i6253
• 21 Sultan AA, Tata LJ, West J. et al. Risk factors for first venous thromboembolism around pregnancy: a population-based cohort study from the United Kingdom. Blood 2013; 121 (19) 3953-3961
• 22 Royal College of Obstetricians and Gynaecologists. Reducing the Risk of Venous Thromboembolism during Pregnancy and the Puerperium. RCOG Green-top Guideline No. 37a. London: Royal College of Obstetricians and Gynaecologists; 2015
• 23 Ewins K, Ní Ainle F. VTE risk assessment in pregnancy. Res Pract Thromb Haemost 2019; 4 (02) 183-192
• 24 O'Shaughnessy F, O'Reilly D, Ní Áinle F. Current opinion and emerging trends on the treatment, diagnosis, and prevention of pregnancy-associated venous thromboembolic disease: a review. Transl Res 2020; 225: 20-32
• 25 O'Shaughnessy F, Donnelly JC, Bennett K, Damkier P, Áinle FN, Cleary BJ. Prevalence of postpartum venous thromboembolism risk factors in an Irish urban obstetric population. J Thromb Haemost 2019; 17 (11) 1875-1885
• 26 Bates SM, Rajasekhar A, Middeldorp S. et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv 2018; 2 (22) 3317-3359
• 27 Robertson L, Wu O, Langhorne P. et al; Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006; 132 (02) 171-196
• 28 Martinelli I, Legnani C, Bucciarelli P, Grandone E, De Stefano V, Mannucci PM. Risk of pregnancy-related venous thrombosis in carriers of severe inherited thrombophilia. Thromb Haemost 2001; 86 (03) 800-803
• 29 Gerhardt A, Scharf RE, Greer IA, Zotz RB. Hereditary risk factors for thrombophilia and probability of venous thromboembolism during pregnancy and the puerperium. Blood 2016; 128 (19) 2343-2349
• 30 Middeldorp S, Henkens CM, Koopman MM. et al. The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis. Ann Intern Med 1998; 128 (01) 15-20
• 31 Bleker SM, Buchmüller A, Chauleur C. et al. Low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy: rationale and design of the Highlow study, a randomised trial of two doses. Thromb Res 2016; 144: 62-68
• 32 Brill-Edwards P, Ginsberg JS, Gent M. et al; Recurrence of Clot in This Pregnancy Study Group. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. N Engl J Med 2000; 343 (20) 1439-1444
• 33 De Stefano V, Martinelli I, Rossi E. et al. The risk of recurrent venous thromboembolism in pregnancy and puerperium without antithrombotic prophylaxis. Br J Haematol 2006; 135 (03) 386-391
• 34 Pabinger I, Grafenhofer H, Kaider A. et al. Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis. J Thromb Haemost 2005; 3 (05) 949-954
• 35 White RH, Chan WS, Zhou H, Ginsberg JS. Recurrent venous thromboembolism after pregnancy-associated versus unprovoked thromboembolism. Thromb Haemost 2008; 100 (02) 246-252
• 36 Abdul Sultan A, Grainge MJ, West J, Fleming KM, Nelson-Piercy C, Tata LJ. Impact of risk factors on the timing of first postpartum venous thromboembolism: a population-based cohort study from England. Blood 2014; 124 (18) 2872-2880
• 37 Bain E, Wilson A, Tooher R, Gates S, Davis LJ, Middleton P. Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period. Cochrane Database Syst Rev 2014; (02) CD001689
• 38 Oakes MC, Reese M, Colditz GA. et al. Efficacy of postpartum pharmacologic thromboprophylaxis: a systematic review and meta-analysis. Obstet Gynecol 2023; 141 (04) 697-710
• 39 Bistervels IM, Buchmüller A, Wiegers HMG. et al; Highlow Block writing committee, Highlow Investigators. Intermediate-dose versus low-dose low-molecular-weight heparin in pregnant and post-partum women with a history of venous thromboembolism (Highlow study): an open-label, multicentre, randomised, controlled trial. Lancet 2022; 400 (10365): 1777-1787
• 40 James A. Practice bulletin no. 123: thromboembolism in pregnancy. Obstet Gynecol 2011; 118 (03) 718-729
• 41 Bates SM, Greer IA, Middeldorp S. 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-e736S
• 42 McLintock C, Brighton T, Chunilal S. et al; Councils of the Society of Obstetric Medicine of Australia and New Zealand, Australasian Society of Thrombosis and Haemostasis. Recommendations for the prevention of pregnancy-associated venous thromboembolism. Aust N Z J Obstet Gynaecol 2012; 52 (01) 3-13
• 43 Kotaska A. Postpartum venous thromboembolism prophylaxis may cause more harm than benefit: a critical analysis of international guidelines through an evidence-based lens. BJOG 2018; 125 (09) 1109-1116
• 44 Arya R. Postpartum venous thromboembolism prophylaxis: harm versus benefit. BJOG 2018; 125 (09) 1117
• 45 Chauleur C, Gris JC, Laporte S. et al; STRATHEGE Investigators and The STRATHEGE Group. Benefit of risk score-guided prophylaxis in pregnant women at risk of thrombotic events: a controlled before-and-after implementation study. Thromb Haemost 2018; 118 (09) 1564-1571
• 46 Rodger MA, Phillips P, Kahn SR, James AH, Konkle BA. PROSPER Investigators. Low-molecular-weight heparin to prevent postpartum venous thromboembolism. A pilot randomised placebo-controlled trial. Thromb Haemost 2015; 113 (01) 212-216
• 47 Rodger MA, Phillips P, Kahn SR. et al; PROSPER Investigators: Tim Ramsay, Dean Fergusson, Anne McLeod, Wee Shian Chan, Rshmi Khurana, Kara Narenberg, Haim Abenhaim, John Heit, Ghada Bourjeilly, Paul Gibson, Kent Bailey. Low molecular weight heparin to prevent postpartum venous thromboembolism: a pilot study to assess the feasibility of a randomized, open-label trial. Thromb Res 2016; 142: 17-20
• 48 Chan WS, Rey E, Kent NE. et al; VTE in Pregnancy Guideline Working Group, Society of Obstetricians and Gynecologists of Canada. Venous thromboembolism and antithrombotic therapy in pregnancy. J Obstet Gynaecol Can 2014; 36 (06) 527-553
• 49 Lindqvist PG, Hellgren M. Obstetric thromboprophylaxis: the Swedish guidelines. Adv Hematol 2011; 2011: 157483
• 50 Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 2005; 106 (02) 401-407
• 51 Ferres MA, Olivarez SA, Trinh V, Davidson C, Sangi-Haghpeykar H, Aagaard-Tillery KM. Rate of wound complications with enoxaparin use among women at high risk for postpartum thrombosis. Obstet Gynecol 2011; 117 (01) 119-124
• 52 Blondon M, Lansiaux M, Bryan S. et al. Preferences of pregnant women for postpartum thromboprophylaxis: the bicentric PREFER-PP study. Res Pract Thromb Haemost 2023; 7 (Suppl): 1117
• 53 American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Obstetrics. ACOG practice bulletin no. 196: thromboembolism in pregnancy. Obstet Gynecol 2018; 132 (01) e1-e17
• 54 Gassmann N, Viviano M, Righini M, Fontana P, Martinez de Tejada B, Blondon M. Estimating the risk thresholds used by guidelines to recommend postpartum thromboprophylaxis. J Thromb Haemost 2021; 19 (02) 452-459
• 55 Daei M, Khalili H, Heidari Z. Direct oral anticoagulant safety during breastfeeding: a narrative review. Eur J Clin Pharmacol 2021; 77 (10) 1465-1471
• 56 Simes J, Becattini C, Agnelli G. et al; INSPIRE Study Investigators (International Collaboration of Aspirin Trials for Recurrent Venous Thromboembolism). Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration. Circulation 2014; 130 (13) 1062-1071
• 57 Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: pulmonary embolism prevention (PEP) trial. Lancet 2000; 355 (9212): 1295-1302
• 58 Robison E, Heyborne K, Allshouse AA, Valdez C, Metz TD. Implementation of a risk-based heparin protocol for postpartum venous thromboembolism prevention. Obstet Gynecol 2017; 130 (02) 262-269
• 59 DʼAlton ME, Friedman AM, Smiley RM. et al. National partnership for maternal safety: consensus bundle on venous thromboembolism. Obstet Gynecol 2016; 128 (04) 688-698