Hamostaseologie 2022; 42(01): 054-064
DOI: 10.1055/a-1717-7663
Review Article

Thrombophilia, Thrombosis and Thromboprophylaxis in Pregnancy: For What and in Whom?

Saskia Middeldorp
1   Department of Internal Medicine, Radboud Institute of Health Sciences (RIHS), Radboud University Medical Center, Nijmegen, The Netherlands
,
Christiane Naue
2   Division of Hematology, Department of Medicine I, University Hospital “Carl Gustav Carus” Dresden, Dresden, Germany
,
Christina Köhler
2   Division of Hematology, Department of Medicine I, University Hospital “Carl Gustav Carus” Dresden, Dresden, Germany
› Author Affiliations

Abstract

Compared with nonpregnant women, pregnancy carries a four- to fivefold higher risk of venous thromboembolism (VTE). Despite increasing use of heparin prophylaxis in identified high-risk patients, pulmonary embolism still is the leading cause of maternal mortality in the western world. However, evidence on optimal use of thromboprophylaxis is scarce. Thrombophilia, the hereditary or acquired tendency to develop VTE, is also thought to be associated with complications in pregnancy, such as recurrent miscarriage and preeclampsia. In this review, the current evidence on optimal thromboprophylaxis in pregnancy is discussed, focusing primarily on VTE prevention strategies but also discussing the potential to prevent recurrent pregnancy complications with heparin in pregnant women with thrombophilia.



Publication History

Received: 22 November 2021

Accepted: 08 December 2021

Article published online:
23 February 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Konstantinides SV, Meyer G, Becattini C. et al; ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020; 41 (04) 543-603
  • 2 Naess IA, Christiansen SC, Romundstad P, Cannegieter SC, Rosendaal FR, Hammerstrøm J. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost 2007; 5 (04) 692-699
  • 3 Delluc A, Tromeur C, Le Ven F. et al; EPIGETBO Study Group. Current incidence of venous thromboembolism and comparison with 1998: a community-based study in Western France. Thromb Haemost 2016; 116 (05) 967-974
  • 4 Heit JA, Ashrani A, Crusan DJ, McBane RD, Petterson TM, Bailey KR. Reasons for the persistent incidence of venous thromboembolism. Thromb Haemost 2017; 117 (02) 390-400
  • 5 Patel P, Patel P, Bhatt M. et al. Systematic review and meta-analysis of outcomes in patients with suspected deep vein thrombosis. Blood Adv 2020; 4 (12) 2779-2788
  • 6 Roach RE, Lijfering WM, Tait RC. et al. Sex difference in the risk of recurrent venous thrombosis: a detailed analysis in four European cohorts. J Thromb Haemost 2015; 13 (10) 1815-1822
  • 7 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 (04) 632-637
  • 8 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
  • 9 Ray JG, Chan WS. Deep vein thrombosis during pregnancy and the puerperium: a meta-analysis of the period of risk and the leg of presentation. Obstet Gynecol Surv 1999; 54 (04) 265-271
  • 10 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 (02) 233.e1-233.e7
  • 11 Hart C, Bauersachs R, Scholz U. et al. Prevention of venous thromboembolism during pregnancy and the puerperium with a special focus on women with hereditary thrombophilia or prior VTE - Position Paper of the Working Group in Women's Health of the Society of Thrombosis and Haemostasis (GTH). Hamostaseologie 2020; 40 (05) 572-590
  • 12 Parunov LA, Soshitova NP, Ovanesov MV, Panteleev MA, Serebriyskiy II. Epidemiology of venous thromboembolism (VTE) associated with pregnancy. Birth Defects Res C Embryo Today 2015; 105 (03) 167-184
  • 13 Kourlaba G, Relakis J, Kontodimas S, Holm MV, Maniadakis N. A systematic review and meta-analysis of the epidemiology and burden of venous thromboembolism among pregnant women. Int J Gynaecol Obstet 2016; 132 (01) 4-10
  • 14 Bates SM, Middeldorp S, Rodger M, James AH, Greer I. Guidance for the treatment and prevention of obstetric-associated venous thromboembolism. J Thromb Thrombolysis 2016; 41 (01) 92-128
  • 15 Jackson E, Curtis KM, Gaffield ME. Risk of venous thromboembolism during the postpartum period: a systematic review. Obstet Gynecol 2011; 117 (03) 691-703
  • 16 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 (03) 366-373
  • 17 Kamel H, Navi BB, Sriram N, Hovsepian DA, Devereux RB, Elkind MS. Risk of a thrombotic event after the 6-week postpartum period. N Engl J Med 2014; 370 (14) 1307-1315
  • 18 Abbasi N, Balayla J, Laporta DP, Kezouh A, Abenhaim HA. Trends, risk factors and mortality among women with venous thromboembolism during labour and delivery: a population-based study of 8 million births. Arch Gynecol Obstet 2014; 289 (02) 275-284
  • 19 Say L, Chou D, Gemmill A. et al. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health 2014; 2 (06) e323-e333
  • 20 Creanga AA, Syverson C, Seed K, Callaghan WM. Pregnancy-related mortality in the United States, 2011-2013. Obstet Gynecol 2017; 130 (02) 366-373
  • 21 Chan WS, Spencer FA, Ginsberg JS. Anatomic distribution of deep vein thrombosis in pregnancy. CMAJ 2010; 182 (07) 657-660
  • 22 Wik HS, Enden TR, Jacobsen AF, Sandset PM. Long-term quality of life after pregnancy-related deep vein thrombosis and the influence of socioeconomic factors and comorbidity. J Thromb Haemost 2011; 9 (10) 1931-1936
  • 23 Wik HS, Jacobsen AF, Sandvik L, Sandset PM. Prevalence and predictors for post-thrombotic syndrome 3 to 16 years after pregnancy-related venous thrombosis: a population-based, cross-sectional, case-control study. J Thromb Haemost 2012; 10 (05) 840-847
  • 24 Kahn SR, Shrier I, Julian JA. et al. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med 2008; 149 (10) 698-707
  • 25 Tick LW, Kramer MH, Rosendaal FR, Faber WR, Doggen CJ. Risk factors for post-thrombotic syndrome in patients with a first deep venous thrombosis. J Thromb Haemost 2008; 6 (12) 2075-2081
  • 26 Pabinger I, Grafenhofer H, Kyrle PA. et al. Temporary increase in the risk for recurrence during pregnancy in women with a history of venous thromboembolism. Blood 2002; 100 (03) 1060-1062
  • 27 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
  • 28 Rodger M. Pregnancy and venous thromboembolism: ‘TIPPS’ for risk stratification. Hematology (Am Soc Hematol Educ Program) 2014; 2014 (01) 387-392
  • 29 Larsen TB, Sørensen 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 (04) 505-509
  • 30 Blondon M, Harrington LB, Boehlen F, Robert-Ebadi H, Righini M, Smith NL. Pre-pregnancy BMI, delivery BMI, gestational weight gain and the risk of postpartum venous thrombosis. Thromb Res 2016; 145: 151-156
  • 31 Rova K, Passmark H, Lindqvist PG. Venous thromboembolism in relation to in vitro fertilization: an approach to determining the incidence and increase in risk in successful cycles. Fertil Steril 2012; 97 (01) 95-100
  • 32 Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. 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
  • 33 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
  • 34 Blondon M, Casini A, Hoppe KK, Boehlen F, Righini M, Smith NL. Risks of venous thromboembolism after cesarean sections: a meta-analysis. Chest 2016; 150 (03) 572-596
  • 35 Dargaud Y, Rugeri L, Fleury C. et al. Personalized thromboprophylaxis using a risk score for the management of pregnancies with high risk of thrombosis: a prospective clinical study. J Thromb Haemost 2017; 15 (05) 897-906
  • 36 Bauersachs RM, Dudenhausen J, Faridi A. et al; EThIG Investigators. Risk stratification and heparin prophylaxis to prevent venous thromboembolism in pregnant women. Thromb Haemost 2007; 98 (06) 1237-1245
  • 37 Nelson-Piercy C, MacCallum P, Mackillop L. Royal College of Obstetricians and Gynaecologists. Reducing the Risk of Venous Thromboembolism during Pregnancy and the Puerperium Green-top Guideline No. 37a;. 2015 . Accessed December 30, 2021 at: https://www.rcog.org.uk/globalassets/documents/guidelines/gtg-37a.pdf
  • 38 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
  • 39 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
  • 40 Jacobsen AF, Dahm A, Bergrem A, Jacobsen EM, Sandset PM. Risk of venous thrombosis in pregnancy among carriers of the factor V Leiden and the prothrombin gene G20210A polymorphisms. J Thromb Haemost 2010; 8 (11) 2443-2449
  • 41 Bistervels IM, Scheres LJJ, Hamulyák EN, Middeldorp S. Sex matters: practice 5P's when treating young women with venous thromboembolism. J Thromb Haemost 2019; 17 (09) 1417-1429
  • 42 Middeldorp S. Inherited thrombophilia: a double-edged sword. Hematology (Am Soc Hematol Educ Program) 2016; 2016 (01) 1-9
  • 43 Miyakis S, Lockshin MD, Atsumi T. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4 (02) 295-306
  • 44 Devreese KMJ, Ortel TL, Pengo V, de Laat B. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies. Laboratory criteria for antiphospholipid syndrome: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (04) 809-813
  • 45 Linnemann B. Antiphospholipid syndrome - an update. Vasa 2018; 47 (06) 451-464
  • 46 Quenby S, Farquharson RG, Dawood F, Hughes AM, Topping J. Recurrent miscarriage and long-term thrombosis risk: a case-control study. Hum Reprod 2005; 20 (06) 1729-1732
  • 47 James AH. Pregnancy-associated thrombosis. Hematology (Am Soc Hematol Educ Program) 2009; 277-285
  • 48 Beyer-Westendorf J, Tittl L, Bistervels I. et al. Safety of direct oral anticoagulant exposure during pregnancy: a retrospective cohort study. Lancet Haematol 2020; 7 (12) e884-e891
  • 49 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
  • 50 Green D, Hirsh J, Heit J, Prins M, Davidson B, Lensing AW. Low molecular weight heparin: a critical analysis of clinical trials. Pharmacol Rev 1994; 46 (01) 89-109
  • 51 Nurmohamed MT, Rosendaal FR, Büller HR. et al. Low-molecular-weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis. Lancet 1992; 340 (8812): 152-156
  • 52 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
  • 53 Nelson-Piercy C, Powrie R, Borg JY. et al. Tinzaparin use in pregnancy: an international, retrospective study of the safety and efficacy profile. Eur J Obstet Gynecol Reprod Biol 2011; 159 (02) 293-299
  • 54 Galambosi PJ, Kaaja RJ, Stefanovic V, Ulander VM. Safety of low-molecular-weight heparin during pregnancy: a retrospective controlled cohort study. Eur J Obstet Gynecol Reprod Biol 2012; 163 (02) 154-159
  • 55 Mitić G, Kovac M, Povazan L. et al. Efficacy and safety of nadroparin and unfractionated heparin for the treatment of venous thromboembolism during pregnancy and puerperium. Srp Arh Celok Lek 2010; 138 (Suppl. 01) 18-22
  • 56 Lindqvist PG, Bremme K, Hellgren M. Working Group on Hemostatic Disorders (Hem-ARG), Swedish Society of Obstetrics and Gynecology. Efficacy of obstetric thromboprophylaxis and long-term risk of recurrence of venous thromboembolism. Acta Obstet Gynecol Scand 2011; 90 (06) 648-653
  • 57 Thrombosis Canada. Pregnancy thromboprophylaxis clinical guide. 2021
  • 58 Romualdi E, Dentali F, Rancan E. et al. Anticoagulant therapy for venous thromboembolism during pregnancy: a systematic review and a meta-analysis of the literature. J Thromb Haemost 2013; 11 (02) 270-281
  • 59 Cox S, Eslick R, McLintock C. Effectiveness and safety of thromboprophylaxis with enoxaparin for prevention of pregnancy-associated venous thromboembolism. J Thromb Haemost 2019; 17 (07) 1160-1170
  • 60 Gándara E, Carrier M, Rodger MA. Intermediate doses of low-molecular-weight heparin for the long-term treatment of pregnancy thromboembolism. A systematic review. Thromb Haemost 2014; 111 (03) 559-561
  • 61 Gates S, Brocklehurst P, Ayers S, Bowler U. Thromboprophylaxis in Pregnancy Advisory Group. Thromboprophylaxis and pregnancy: two randomized controlled pilot trials that used low-molecular-weight heparin. Am J Obstet Gynecol 2004; 191 (04) 1296-1303
  • 62 Howell R, Fidler J, Letsky E, de Swiet M. The risks of antenatal subcutaneous heparin prophylaxis: a controlled trial. Br J Obstet Gynaecol 1983; 90 (12) 1124-1128
  • 63 Roeters van Lennep JE, Meijer E, Klumper FJ, Middeldorp JM, Bloemenkamp KW, Middeldorp S. Prophylaxis with low-dose low-molecular-weight heparin during pregnancy and postpartum: is it effective?. J Thromb Haemost 2011; 9 (03) 473-480
  • 64 Middleton P, Shepherd E, Gomersall JC. Venous thromboembolism prophylaxis for women at risk during pregnancy and the early postnatal period. Cochrane Database Syst Rev 2021; 3 (03) CD001689
  • 65 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
  • 66 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
  • 67 Hamulyák EN, Scheres LJ, Marijnen MC, Goddijn M, Middeldorp S. Aspirin or heparin or both for improving pregnancy outcomes in women with persistent antiphospholipid antibodies and recurrent pregnancy loss. Cochrane Database Syst Rev 2020; 5 (05) CD012852
  • 68 Hamulyák EN, Scheres LJJ, Goddijn M, Middeldorp S. Antithrombotic therapy to prevent recurrent pregnancy loss in antiphospholipid syndrome - What is the evidence?. J Thromb Haemost 2021; 19 (05) 1174-1185
  • 69 de Jong PG, Goddijn M, Middeldorp S. Antithrombotic therapy for pregnancy loss. Hum Reprod Update 2013; 19 (06) 656-673
  • 70 Skeith L, Carrier M, Kaaja R. et al. A meta-analysis of low-molecular-weight heparin to prevent pregnancy loss in women with inherited thrombophilia. Blood 2016; 127 (13) 1650-1655
  • 71 Rodger MA, Gris JC, de Vries JIP. et al; Low-Molecular-Weight Heparin for Placenta-Mediated Pregnancy Complications Study Group. Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials. Lancet 2016; 388 (10060): 2629-2641
  • 72 de Jong PG, Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S. Aspirin and/or heparin for women with unexplained recurrent miscarriage with or without inherited thrombophilia. Cochrane Database Syst Rev 2014; 2014 (07) CD004734
  • 73 Mazzolai L, Ageno W, Alatri A. et al. Second consensus document on diagnosis and management of acute deep vein thrombosis: updated document elaborated by the ESC Working Group on aorta and peripheral vascular diseases and the ESC Working Group on pulmonary circulation and right ventricular function. Eur J Prev Cardiol 2021; zwab088
  • 74 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
  • 75 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
  • 76 Rodger MA, Hague WM, Kingdom J. et al; TIPPS Investigators. Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open-label randomised trial. Lancet 2014; 384 (9955): 1673-1683