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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
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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.

Keywords

venous thromboembolism - thrombophilia - pregnancy complications - low-molecular-weight heparin


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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    Thieme ConnectPubMedSearch in Google Scholar
  • 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
    Thieme ConnectPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    Thieme ConnectPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 21 Chan WS, Spencer FA, Ginsberg JS. Anatomic distribution of deep vein thrombosis in pregnancy. CMAJ 2010; 182 (07) 657-660
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 28 Rodger M. Pregnancy and venous thromboembolism: ‘TIPPS’ for risk stratification. Hematology (Am Soc Hematol Educ Program) 2014; 2014 (01) 387-392
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    Thieme ConnectPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 42 Middeldorp S. Inherited thrombophilia: a double-edged sword. Hematology (Am Soc Hematol Educ Program) 2016; 2016 (01) 1-9
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 45 Linnemann B. Antiphospholipid syndrome - an update. Vasa 2018; 47 (06) 451-464
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 47 James AH. Pregnancy-associated thrombosis. Hematology (Am Soc Hematol Educ Program) 2009; 277-285
    CrossrefPubMedSearch in Google Scholar
  • 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
    Search in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 57 Thrombosis Canada. Pregnancy thromboprophylaxis clinical guide. 2021
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    Thieme ConnectPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 69 de Jong PG, Goddijn M, Middeldorp S. Antithrombotic therapy for pregnancy loss. Hum Reprod Update 2013; 19 (06) 656-673
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar