Hamostaseologie 2020; 40(03): 356-363
DOI: 10.1055/a-1184-8388
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Understanding and Preventing Placenta-Mediated Pregnancy Complications

Leslie Skeith
1   Division of Hematology and Hematological Malignancies, Department of Medicine, University of Calgary, Calgary, Canada
Marc Blondon
2   Division of Angiology and Hemostasis, Department of Specialties of Medicine, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland
Fionnuala Ní Áinle
3   Department of Haematology, School of Medicine, University College Dublin, Rotunda Hospital and Mater University Hospital, Irish Network for VTE Research (INViTE), Dublin, Ireland
› Author Affiliations
Further Information

Publication History

02 February 2020

21 May 2020

Publication Date:
29 July 2020 (online)


Placenta-mediated pregnancy complications are clinically important conditions and include preeclampsia, placental abruption, intrauterine growth restriction, and late fetal loss. Pathophysiology is complex, and may be linked to prothrombotic disorders such as antiphospholipid syndrome, whose understanding is still evolving. In this narrative review, we will present the latest evidence to better understand hemostatic mechanisms of preeclampsia, as well as in women with placenta-mediated pregnancy complications and inherited thrombophilia or antiphospholipid antibodies. Using four clinical scenarios, the mixed results of preventive efforts through the use of antithrombotic drugs (aspirin, heparin) will be discussed. We will also review knowledge gaps and ongoing research.


All authors (L.S., M.B., F.N.A.) contributed to writing the first and subsequent drafts of the manuscript.

  • References

  • 1 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
  • 2 Mosca L, Benjamin EJ, Berra K. , et al; American Heart Association. Effectiveness-based guidelines for the prevention of cardiovascular disease in women–2011 update: a guideline from the American Heart Association. J Am Coll Cardiol 2011; 57 (12) 1404-1423
  • 3 Mongraw-Chaffin ML, Cirillo PM, Cohn BA. Preeclampsia and cardiovascular disease death: prospective evidence from the child health and development studies cohort. Hypertension 2010; 56 (01) 166-171
  • 4 Saving Lives, Improving Mothers' Care: Lessons Learned to Inform Maternity Care from the UK and Ireland Confidential Enquiries into Maternal Deaths and Morbidity 2013–2015. 2017;1–104. https://www.npeu.ox.ac.uk/downloads/files/mbrrace-uk/reports/MBRRACE-UK%20Maternal%20Report%202017%20-%20Web.pdf
  • 5 Monteith C, Egan K, O'Connor H. , et al. Early onset preeclampsia is associated with an elevated mean platelet volume (MPV) and a greater rise in MPV from time of booking compared with pregnant controls: results of the CAPE study. J Perinat Med 2018; 46 (09) 1010-1015
  • 6 Jacobsen AF, Skjeldestad FE, Sandset PM. Ante- and postnatal risk factors of venous thrombosis: a hospital-based case-control study. J ThrombHaemost 2008; 6 (06) 905-912
  • 7 Scheres LJJ, Lijfering WM, Groenewegen NFM. , et al. Hypertensive complications of pregnancy and risk of venous thromboembolism. Hypertension 2020; 75 (03) 781-787
  • 8 Fisher SJ. Why is placentation abnormal in preeclampsia?. Am J ObstetGynecol 2015; 213 (4, Suppl): S115-S122
  • 9 Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia: pathophysiology, challenges, and perspectives. Circ Res 2019; 124 (07) 1094-1112
  • 10 Redman CW, Sargent IL. Immunology of pre-eclampsia. Am J Reprod Immunol 2010; 63 (06) 534-543
  • 11 Huppertz B. Placental origins of preeclampsia: challenging the current hypothesis. Hypertension 2008; 51 (04) 970-975
  • 12 English FA, Kenny LC, McCarthy FP. Risk factors and effective management of preeclampsia. Integr Blood Press Control 2015; 8: 7-12
  • 13 Levine RJ, Lam C, Qian C. , et al; CPEP Study Group. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med 2006; 355 (10) 992-1005
  • 14 Venkatesha S, Toporsian M, Lam C. , et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 2006; 12 (06) 642-649
  • 15 Schmella MJ, Roberts JM, Conley YP. , et al. Endoglin pathway genetic variation in preeclampsia: a validation study in Norwegian and Latina cohorts. Pregnancy Hypertens 2018; 12: 144-149
  • 16 Chau K, Hennessy A, Makris A. Placental growth factor and pre-eclampsia. J Hum Hypertens 2017; 31 (12) 782-786
  • 17 Pinheiro MB, Martins-Filho OA, Mota AP. , et al. Severe preeclampsia goes along with a cytokine network disturbance towards a systemic inflammatory state. Cytokine 2013; 62 (01) 165-173
  • 18 Regal JF, Burwick RM, Fleming SD. The complement system and preeclampsia. Curr Hypertens Rep 2017; 19 (11) 87
  • 19 Macey MG, Bevan S, Alam S. , et al. Platelet activation and endogenous thrombin potential in pre-eclampsia. Thromb Res 2010; 125 (03) e76-e81
  • 20 Egan K, O'Connor H, Kevane B. , et al. Elevated plasma TFPI activity causes attenuated TF-dependent thrombin generation in early onset preeclampsia. ThrombHaemost 2017; 117 (08) 1549-1557
  • 21 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
  • 22 Parsons MEM, Szklanna PB, Guerrero JA. , et al. Platelet releasate proteome profiling reveals a core set of proteins with low variance between healthy adults. Proteomics 2018; 18 (15) e1800219
  • 23 Sato Y, Fujiwara H, Konishi I. Role of platelets in placentation. Med Mol Morphol 2010; 43 (03) 129-133
  • 24 Al Obaidly M, Regan C, Lwaleed BMN. A role for platelets in normal pregnancy. The non-thrombotic role of platelets in health and disease. InTech; 2015. https://www.intechopen.com/books/the-non-thrombotic-role-of-platelets-in-health-and-disease/a-role-for-platelets-in-normal-pregnancy
  • 25 Vantroyen B, Vanstraelen D. Management of essential thrombocythemia during pregnancy with aspirin, interferon alpha-2a and no treatment. A comparative analysis of the literature. Acta Haematol 2002; 107 (03) 158-169
  • 26 Falconer J, Pineo G, Blahey W, Bowen T, Docksteader B, Jadusingh I. Essential thrombocythemia associated with recurrent abortions and fetal growth retardation. Am J Hematol 1987; 25 (03) 345-347
  • 27 Morrison R, Crawford J, MacPherson M, Heptinstall S. Platelet behaviour in normal pregnancy, pregnancy complicated by essential hypertension and pregnancy-induced hypertension. ThrombHaemost 1985; 54 (03) 607-611
  • 28 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
  • 29 Szklanna PB, Parsons ME, Wynne K. , et al. The platelet releasate is altered in human pregnancy. Proteomics Clin Appl 2019; 13 (03) e1800162
  • 30 Szklanna PB, Parsons MEM, Wynne K, O'Connor H, Egan K, Ni Ainle FMP. The platelet releasate is a “barcode” for the health status of an individual. Res Pr ThrombHaemost 2017; 1 (Suppl. 01) 1-1451
  • 31 Tannetta D, Masliukaite I, Vatish M, Redman C, Sargent I. Update of syncytiotrophoblast derived extracellular vesicles in normal pregnancy and preeclampsia. J Reprod Immunol 2017; 119: 98-106
  • 32 Tannetta DS, Dragovic RA, Gardiner C, Redman CW, Sargent IL. Characterisation of syncytiotrophoblast vesicles in normal pregnancy and pre-eclampsia: expression of Flt-1 and endoglin. PLoS One 2013; 8 (02) e56754
  • 33 Missfelder-Lobos H, Teran E, Lees C, Albaiges G, Nicolaides KH. Platelet changes and subsequent development of pre-eclampsia and fetal growth restriction in women with abnormal uterine artery Doppler screening. Ultrasound ObstetGynecol 2002; 19 (05) 443-448
  • 34 Kohli S, Ranjan S, Hoffmann J. , et al. Maternal extracellular vesicles and platelets promote preeclampsia through inflammasome activation in embryonic trophoblast. Blood 2016; 128 (17) 2153-2164
  • 35 Duley L, Meher S, Hunter KE, Seidler AL, Askie LM. Antiplatelet agents for preventing pre-eclampsia and its complications. (Review) Cochrane Database Syst Rev 2019; 2019 (10) 1-281
  • 36 Rolnik DL, Wright D, Poon LC. , et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med 2017; 377 (07) 613-622
  • 37 Hoffman MK, Goudar SS, Kodkany BS. , et al; ASPIRIN Study Group. Low-dose aspirin for the prevention of preterm delivery in nulliparous women with a singleton pregnancy (ASPIRIN): a randomised, double-blind, placebo-controlled trial. Lancet 2020; 395 (10220): 285-293
  • 38 Roberge S, Bujold E, Nicolaides KH. Meta-analysis on the effect of aspirin use for prevention of preeclampsia on placental abruption and antepartum hemorrhage. Am J ObstetGynecol 2018; 218 (05) 483-489
  • 39 Rothwell PM, Cook NR, Gaziano JM. , et al. Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials. Lancet 2018; 392 (10145): 387-399
  • 40 Akolekar R, Syngelaki A, Poon L, Wright D, Nicolaides KH. Competing risks model in early screening for preeclampsia by biophysical and biochemical markers. Fetal Diagn Ther 2013; 33 (01) 8-15
  • 41 LeFevre ML. ; U.S. Preventive Services Task Force. Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014; 161 (11) 819-826
  • 42 Webster K, Fishburn S, Maresh M, Findlay SC, Chappell LC. ; Guideline Committee. Diagnosis and management of hypertension in pregnancy: summary of updated NICE guidance. BMJ 2019; 366: l5119
  • 43 Al-Rubaie ZT, Askie LM, Hudson HM, Ray JG, Jenkins G, Lord SJ. Assessment of NICE and USPSTF guidelines for identifying women at high risk of pre-eclampsia for tailoring aspirin prophylaxis in pregnancy: an individual participant data meta-analysis. Eur J Obstet Gynecol Reprod Biol 2018; 229: 159-166
  • 44 Hossain N, Paidas MJ. Adverse pregnancy outcome, the uteroplacental interface, and preventive strategies. SeminPerinatol 2007; 31 (04) 208-212
  • 45 Martinelli I, Taioli E, Cetin I. , et al. Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med 2000; 343 (14) 1015-1018
  • 46 Rodger MA, Walker MC, Smith GN. , et al. Is thrombophilia associated with placenta-mediated pregnancy complications? A prospective cohort study. J ThrombHaemost 2014; 12 (04) 469-478
  • 47 Rodger MA, Betancourt MT, Clark P. , 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 Med 2010; 7 (06) e1000292
  • 48 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
  • 49 Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361 (9361): 901-908
  • 50 Lin J, August P. Genetic thrombophilias and preeclampsia: a meta-analysis. ObstetGynecol 2005; 105 (01) 182-192
  • 51 Howley HEA, Walker M, Rodger MA. A systematic review of the association between factor V Leiden or prothrombin gene variant and intrauterine growth restriction. Am J ObstetGynecol 2005; 192 (03) 694-708
  • 52 Lykke JA, Bare LA, Olsen J. , et al. Thrombophilias and adverse pregnancy outcomes: results from the Danish National Birth Cohort. J ThrombHaemost 2012; 10 (07) 1320-1325
  • 53 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
  • 54 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
  • 55 Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos A-M, 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
  • 56 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
  • 57 Miyakis S, Lockshin MD, Atsumi T. , et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome. J ThrombHaemost 2006; 42: 295-306
  • 58 Branch DW. What's new in obstetric antiphospholipid syndrome. Hematology (Am Soc Hematol Educ Program) 2019; 2019 (01) 421-425
  • 59 Abou-Nassar K, Carrier M, Ramsay T, Rodger MA. The association between antiphospholipid antibodies and placenta mediated complications: a systematic review and meta-analysis. Thromb Res 2011; 128 (01) 77-85
  • 60 Skeith L, Abou-Nassar KE, Walker M. , et al. Are anti-β 2 glycoprotein 1 antibodies associated with placenta-mediated pregnancy complications? A nested case-control study. Am J Perinatol 2018; 35 (11) 1093-1099
  • 61 Yelnik CM, Laskin CA, Porter TF. , et al. Lupus anticoagulant is the main predictor of adverse pregnancy outcomes in aPL-positive patients: validation of PROMISSE study results. Lupus Sci Med 2016; 3 (01) e000131
  • 62 Bouvier S, Cochery-Nouvellon E, Lavigne-Lissalde G. , et al. Comparative incidence of pregnancy outcomes in treated obstetric antiphospholipid syndrome: the NOH-APS observational study. Blood 2014; 123 (03) 404-413
  • 63 Saccone G, Berghella V, Maruotti GM. , et al; PREGNANTS (PREGNancy in women with ANTiphospholipid Syndrome) working group. Antiphospholipid antibody profile based obstetric outcomes of primary antiphospholipid syndrome: the PREGNANTS study. Am J ObstetGynecol 2017; 216 (05) 525.e1-525.e12
  • 64 Chaturvedi S, McCrae KR. Diagnosis and management of the antiphospholipid syndrome. Blood Rev 2017; 31 (06) 406-417
  • 65 Agostinis C, Biffi S, Garrovo C. , et al. In vivo distribution of β2 glycoprotein I under various pathophysiologic conditions. Blood 2011; 118 (15) 4231-4238
  • 66 Di Simone N, Raschi E, Testoni C. , et al. Pathogenic role of anti-β 2-glycoprotein I antibodies in antiphospholipid associated fetal loss: characterisation of β 2-glycoprotein I binding to trophoblast cells and functional effects of anti-β 2-glycoprotein I antibodies in vitro. Ann Rheum Dis 2005; 64 (03) 462-467
  • 67 Di Simone N, Meroni PL, de Papa N. , et al. Antiphospholipid antibodies affect trophoblast gonadotropin secretion and invasiveness by binding directly and through adhered beta2-glycoprotein I. Arthritis Rheum 2000; 43 (01) 140-150
  • 68 Chaturvedi S, Brodsky RA, McCrae KR. Complement in the pathophysiology of the antiphospholipid syndrome. Front Immunol 2019; 10: 449
  • 69 Kim MY, Guerra MM, Kaplowitz E. , et al. Complement activation predicts adverse pregnancy outcome in patients with systemic lupus erythematosus and/or antiphospholipid antibodies. Ann Rheum Dis 2018; 77 (04) 549-555
  • 70 Girardi G, Berman J, Redecha P. , et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest 2003; 112 (11) 1644-1654
  • 71 Holers VM, Girardi G, Mo L. , et al. Complement C3 activation is required for antiphospholipid antibody-induced fetal loss. J Exp Med 2002; 195 (02) 211-220
  • 72 Larsen JB, Andersen AS, Hvas CL. , et al. Lectin pathway proteins of the complement system in normotensive pregnancy and pre-eclampsia. Am J ReprodImmunol 2019; 81 (04) e13092
  • 73 Chaturvedi S, Braunstein EM, Yuan X. , et al. Complement activity and complement regulatory gene mutations are associated with thrombosis in APS and CAPS. Blood 2020; 135 (04) 239-251
  • 74 Tektonidou MG, Andreoli L, Limper M. , et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum 2019; 0: 1-9
  • 75 Choi M, Butler E, Clarke A, Girard LP, Gibson P, Skeith L. Managing pregnancy-associated clinical emergencies in systemic lupus erythematosus: a case-based approach. Expert Rev Clin Immunol 2020; 16 (01) 5-22
  • 76 Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J ObstetGynecol 1996; 174 (05) 1584-1589
  • 77 Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. ObstetGynecol 2002; 100 (03) 408-413
  • 78 Goel N, Tuli A, Choudhry R. The role of aspirin versus aspirin and heparin in cases of recurrent abortions with raised anticardiolipin antibodies. Med Sci Monit 2006; 12 (03) CR132-CR136
  • 79 Laskin CA, Bombardier C, Hannah ME. , et al. Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. N Engl J Med 1997; 337 (03) 148-153
  • 80 Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997; 314 (7076): 253-257
  • 81 van Hoorn ME, Hague WM, van Pampus MG, Bezemer D, de Vries JIP. ; FRUIT Investigators. Low-molecular-weight heparin and aspirin in the prevention of recurrent early-onset pre-eclampsia in women with antiphospholipid antibodies: the FRUIT-RCT. Eur J Obstet Gynecol Reprod Biol 2016; 197: 168-173
  • 82 Hansen AT, Sandager P, Ramsing M. , et al. Tinzaparin for the treatment of foetal growth retardation: an open-labelled randomized clinical trial. Thromb Res 2018; 170: 38-44
  • 83 Lockshin MD, Kim M, Laskin CA. , et al. Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies. Arthritis Rheum 2012; 64 (07) 2311-2318
  • 84 Sciascia S, Branch DW, Levy RA. , et al. The efficacy of hydroxychloroquine in altering pregnancy outcome in women with antiphospholipid syndrome. ThrombHaemost 2016; 115: 285-290
  • 85 Schreiber K, Breen K, Cohen H. , et al. HYdroxychloroquine to improve pregnancy outcome in women with AnTIphospholipid Antibodies (HYPATIA) protocol: a multinational randomized controlled trial of hydroxychloroquine versus placebo in addition to standard treatment in pregnant women with antiphospholipid syndrome or antibodies. Semin ThrombHemost 2017; 43 (06) 562-571