Current Rheumatology Reports

, 16:403 | Cite as

Pregnancy Morbidity in Antiphospholipid Syndrome: What Is the Impact of Treatment?

  • Guilherme R. de JesúsEmail author
  • Gustavo Rodrigues
  • Nilson R. de Jesús
  • Roger A. Levy
Part of the following topical collections:
  1. Topical Collection on Antiphospholipid Syndrome


Women with persistently circulating antiphospholipid antibodies (aPL) have a higher incidence of recurrent abortions, fetal losses, pre-eclampsia, and placental insufficiency. Current treatment of patients with antiphospholipid syndrome (APS) during pregnancy with heparin and aspirin can act by preventing clot formation and improving live birth rates, but other obstetric morbidities remain high, especially in patients with a history of thrombotic events. In addition to the classical thrombotic placental events, other factors involving inflammation and complement activation seem to play a role in certain complications. In this article, we will review how medications interfere in the pathogenic mechanisms of APS, discuss the impact of current recommended treatment on pregnancy morbidity, and analyze new promising therapies.


Antiphospholipid syndrome APS Obstetric APS Obstetric antiphospholipid syndrome Pre-eclampsia Intrauterine growth restriction Prematurity Treatment Abortion Pregnancy loss Fetal death Heparin Aspirin Complement activation Thrombosis Hydroxychloroquine Eculizumab 


Compliance with Ethics Guidelines

Conflict of Interest

Guilherme R. de Jesús and Roger A. Levy have had travel/accommodations expenses covered/reimbursed by APS Action.

Gustavo Rodrigues and Nilson R. de Jesús declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    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(2):295–306.PubMedCrossRefGoogle Scholar
  2. 2.••
    Andreoli L, Chighizola CB, Banzato A et al. The estimated frequency of antiphospholipid antibodies in patients with pregnancy morbidity, stroke, myocardial infarction, and deep vein thrombosis. Arthritis Care Res (Hoboken). 2013. Review of the literature and critical analysis of antiphospholipid antibody frequency in patients with pregnancy morbidity, stroke, myocardial infarction, and deep venous thrombosis.Google Scholar
  3. 3.
    Oku K, Amengual O, Atsumi T. Pathophysiology of thrombosis and pregnancy morbidity in the antiphospholipid syndrome. Eur J Clin Investig. 2012;42(10):1126–35.CrossRefGoogle Scholar
  4. 4.••
    Meroni PL, Borghi MO, Raschi E, Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol. 2011;7(6):330–9. Detalied review of pathogenic mechanisms of thrombosis and pregnancy morbidity related to antiphospholipid antibodies.PubMedCrossRefGoogle Scholar
  5. 5.
    Wijetilleka S, Scoble T, Khamashta M. Novel insights into pathogenesis, diagnosis and treatment of antiphospholipid syndrome. Curr Opin Rheumatol. 2012;24(5):473–81.PubMedCrossRefGoogle Scholar
  6. 6.
    Tincani A, Cavazzana I, Ziglioli T, et al. Complement activation and pregnancy failure. Clin Rev Allergy Immunol. 2010;39(3):153–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Girardi G, Redecha P, Salmon JE. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med. 2004;10(11):1222–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Willis R, Harris EN, Pierangeli SS. Pathogenesis of the antiphospholipid syndrome. Semin Thromb Hemost. 2012;38(4):305–21.PubMedCrossRefGoogle Scholar
  9. 9.
    Marchetti T, Cohen M, de Moerloose P. Obstetrical antiphospholipid syndrome: from the pathogenesis to the clinical and therapeutic implications. Clin Dev Immunol. 2013;2013:159124.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.••
    Han CS, Mulla MJ, Brosens JJ, et al. Aspirin and heparin effect on basal and antiphospholipid antibody modulation of trophoblast function. Obstet Gynecol. 2011;118(5):1021–8. Interesting paper with several in vitro studies about the interference of antiphospholipid antibodies in trophoblast function and the effects of heparin and aspirin.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    D'Ippolito S, Marana R, Di Nicuolo F, et al. Effect of Low Molecular Weight Heparins (LMWHs) on antiphospholipid antibodies (aPL)-mediated inhibition of endometrial angiogenesis. PLoS One. 2012;7(1):e29660.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350(7):672–83.PubMedCrossRefGoogle Scholar
  13. 13.
    Venkatesha S, Toporsian M, Lam C, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med. 2006;12(6):642–9.PubMedCrossRefGoogle Scholar
  14. 14.••
    Thadhani R, Kisner T, Hagmann H, et al. Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia. Circulation. 2011;124(8):940–50. Innovative therapy for treatment of severe pre-eclampsia, allowing maintenance of pregnancy for a period.PubMedCrossRefGoogle Scholar
  15. 15.
    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):253–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Kutteh WH, Ermel LD. A clinical trial for the treatment of antiphospholipid antibody-associated recurrent pregnancy loss with lower dose heparin and aspirin. Am J Reprod Immunol. 1996;35(4):402–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. Obstet Gynecol. 2002;100(3):408–13.PubMedCrossRefGoogle Scholar
  18. 18.
    Laskin CA, Spitzer KA, Clark CA, et al. Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial. J Rheumatol. 2009;36(2):279–87.PubMedCrossRefGoogle Scholar
  19. 19.••
    de Jesus GR, dos Santos FC, Oliveira CS, et al. Management of obstetric antiphospholipid syndrome. Curr Rheumatol Rep. 2012;14(1):79–86. Current recommendations for treatment of obstetric antiphospholipid syndrome.PubMedCrossRefGoogle Scholar
  20. 20.••
    Dadhwal V, Sharma AK, Deka D, et al. The obstetric outcome following treatment in a cohort of patients with antiphospholipid antibody syndrome in a tertiary care center. J Postgrad Med. 2011;57(1):16–9. Gestational outcomes of treated patients with mainly obstetric APS followed in a tertiary center in India.PubMedCrossRefGoogle Scholar
  21. 21.
    Serrano F, Nogueira I, Borges A, Branco J. Primary antiphospholipid syndrome: pregnancy outcome in a portuguese population. Acta Reumatol Port. 2009;34(3):492–7.PubMedGoogle Scholar
  22. 22.
    Alijotas-Reig J. Treatment of refractory obstetric antiphospholipid syndrome: the state of the art and new trends in the therapeutic management. Lupus. 2013;22(1):6–17.PubMedCrossRefGoogle Scholar
  23. 23.
    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(3):148–53.PubMedCrossRefGoogle Scholar
  24. 24.••
    Ruffatti A, Tonello M, Visentin MS, et al. Risk factors for pregnancy failure in patients with anti-phospholipid syndrome treated with conventional therapies: a multicentre, case-control study. Rheumatology (Oxford). 2011;50(9):1684–9. Describes risk factors for pregnancy loss in APS patients who receive adequate treatment. This study may facilitate the identification of patients at high risk for pregnancy loss.CrossRefGoogle Scholar
  25. 25.
    Clark EA, Silver RM, Branch DW. Do antiphospholipid antibodies cause preeclampsia and HELLP syndrome? Curr Rheumatol Rep. 2007;9(3):219–25.PubMedCrossRefGoogle Scholar
  26. 26.
    do Prado AD, Piovesan DM, Staub HL, Horta BL. Association of anticardiolipin antibodies with preeclampsia: a systematic review and meta-analysis. Obstet Gynecol. 2010;116(6):1433–43.PubMedCrossRefGoogle Scholar
  27. 27.
    Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet. 2005;365(9461):785–99.PubMedGoogle Scholar
  28. 28.
    Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 2002;46(4):1019–27.PubMedCrossRefGoogle Scholar
  29. 29.••
    Bramham K, Hunt BJ, Germain S, et al. Pregnancy outcome in different clinical phenotypes of antiphospholipid syndrome. Lupus. 2010;19(1):58–64. This publication shows that treatment does not prevent adverse gestational results in patients with APS, especially those patients with history of thrombotic events.PubMedCrossRefGoogle Scholar
  30. 30.•
    Fischer-Betz R, Specker C, Brinks R, Schneider M. Pregnancy outcome in patients with antiphospholipid syndrome after cerebral ischaemic events: an observational study. Lupus. 2012;21(11):1183–9. Pregnancy outcomes in a singular group of patients.PubMedCrossRefGoogle Scholar
  31. 31.
    Roberge S, Giguère Y, Villa P, et al. Early administration of low-dose aspirin for the prevention of severe and mild preeclampsia: a systematic review and meta-analysis. Am J Perinatol. 2012;29(7):551–6.PubMedGoogle Scholar
  32. 32.
    Bujold E, Roberge S, Lacasse Y, et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol. 2010;116(2 Pt 1):402–14.PubMedCrossRefGoogle Scholar
  33. 33.
    Baschat AA, Cosmi E, Bilardo CM, et al. Predictors of neonatal outcome in early-onset placental dysfunction. Obstet Gynecol. 2007;109(2 Pt 1):253–61.PubMedCrossRefGoogle Scholar
  34. 34.
    Mari G, Hanif F. Intrauterine growth restriction: how to manage and when to deliver. Clin Obstet Gynecol. 2007;50(2):497–509.PubMedCrossRefGoogle Scholar
  35. 35.
    Polzin WJ, Kopelman JN, Robinson RD, et al. The association of antiphospholipid antibodies with pregnancies complicated by fetal growth restriction. Obstet Gynecol. 1991;78(6):1108–11.PubMedGoogle Scholar
  36. 36.
    Yasuda M, Takakuwa K, Tokunaga A, Tanaka K. Prospective studies of the association between anticardiolipin antibody and outcome of pregnancy. Obstet Gynecol. 1995;86(4 Pt 1):555–9.PubMedGoogle Scholar
  37. 37.
    Alfirevic Z, Mousa HA, Martlew V, et al. Postnatal screening for thrombophilia in women with severe pregnancy complications. Obstet Gynecol. 2001;97(5 Pt 1):753–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Kupferminc MJ, Eldor A, Steinman N, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med. 1999;340(1):9–13.PubMedCrossRefGoogle Scholar
  39. 39.
    Milliez J, Lelong F, Bayani N, et al. The prevalence of autoantibodies during third-trimester pregnancy complicated by hypertension or idiopathic fetal growth retardation. Am J Obstet Gynecol. 1991;165(1):51–6.PubMedCrossRefGoogle Scholar
  40. 40.
    Spegiorin LC, Galão EA, De Godoy JM, et al. Antiphospholipid antibodies and growth retardation in intrauterine development. Prague Med Rep. 2007;108(2):185–90.PubMedGoogle Scholar
  41. 41.••
    Andreoli L, Fredi M, Nalli C, et al. Pregnancy implications for systemic lupus erythematosus and the antiphospholipid syndrome. J Autoimmun. 2012;38(2-3):J197–208. Exciting review about all aspects related to pregnancy in patients with lupus and APS.PubMedCrossRefGoogle Scholar
  42. 42.
    Levy RA, Jesús GR, Jesús NR. Obstetric antiphospholipid syndrome: still a challenge. Lupus. 2010;19(4):457–9.PubMedCrossRefGoogle Scholar
  43. 43.•
    Wu XX, Guller S, Rand JH. Hydroxychloroquine reduces binding of antiphospholipid antibodies to syncytiotrophoblasts and restores annexin A5 expression. Am J Obstet Gynecol. 2011;205(6):576.e7–14. Continuation of the work from Rand et al. reporting that aPL can reduce the production of annexin A5 from human syncytiotrophoblasts cells and that hydroxychloroquine can reverse this effect.CrossRefGoogle Scholar
  44. 44.•
    Comarmond C, Cacoub P. Antiphospholipid syndrome: from pathogenesis to novel immunomodulatory therapies. Autoimmun Rev. 2013;12(7):752–7. Discusses new therapies that should be considered for the treatment of APS.PubMedCrossRefGoogle Scholar
  45. 45.
    Ruiz-Irastorza G, Crowther M, Branch W, Khamashta MA. Antiphospholipid syndrome. Lancet. 2010;376(9751):1498–509.PubMedCrossRefGoogle Scholar
  46. 46.
    Rand JH, Wu XX, Quinn AS, Taatjes DJ. The annexin A5-mediated pathogenic mechanism in the antiphospholipid syndrome: role in pregnancy losses and thrombosis. Lupus. 2010;19(4):460–9.PubMedCrossRefGoogle Scholar
  47. 47.••
    Burwick RM, Feinberg BB. Eculizumab for the treatment of preeclampsia/HELLP syndrome. Placenta. 2013;34(2):201–3. Case report of the treatment of a patient with HELLP syndrome using complement blocker, with successful result.PubMedCrossRefGoogle Scholar
  48. 48.
    Haddad B, Sibai BM. Expectant management of severe preeclampsia: proper candidates and pregnancy outcome. Clin Obstet Gynecol. 2005;48(2):430–40.PubMedCrossRefGoogle Scholar
  49. 49.
    Tello-Montoliu A, Seecheran NA, Angiolillo DJ. Successful pregnancy and delivery on prasugrel treatment: considerations for the use of dual antiplatelet therapy during pregnancy in clinical practice. J Thromb Thrombolysis. 2013;36(3):348–51.PubMedCrossRefGoogle Scholar
  50. 50.
    George EM, Cockrell K, Adair TH, Granger JP. Regulation of sFlt-1 and VEGF secretion by adenosine under hypoxic conditions in rat placental villous explants. Am J Physiol Regul Integr Comp Physiol. 2010;299(6):R1629–33.PubMedCrossRefGoogle Scholar
  51. 51.
    Valentine N, Van de Laar FA, van Driel ML. Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2012;11, CD005449.PubMedGoogle Scholar
  52. 52.
    Bilodeau ML, Simon DI. Clopidogrel for the hot patient. Circ Cardiovasc Interv. 2009;2(6):495–6.PubMedCrossRefGoogle Scholar
  53. 53.
    Malloy RJ, Kanaan AO, Silva MA, Donovan JL. Evaluation of antiplatelet agents for secondary prevention of stroke using mixed treatment comparison meta-analysis. Clin Ther. 2013;35(10):1490–500.e7.PubMedCrossRefGoogle Scholar
  54. 54.
    Imseis HM, Zimmerman PD, Samuels P, Kniss DA. Tumour necrosis factor-alpha induces cyclo-oxygenase-2 gene expression in first trimester trophoblasts: suppression by glucocorticoids and NSAIDs. Placenta. 1997;18(7):521–6.PubMedCrossRefGoogle Scholar
  55. 55.
    Daher S, Fonseca F, Ribeiro OG, et al. Tumor necrosis factor during pregnancy and at the onset of labor and spontaneous abortion. Eur J Obstet Gynecol Reprod Biol. 1999;83(1):77–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Yu XW, Yan CF, Jin H, Li X. Tumor necrosis factor receptor 1 expression and early spontaneous abortion. Int J Gynaecol Obstet. 2005;88(1):44–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Berman J, Girardi G, Salmon JE. TNF-alpha is a critical effector and a target for therapy in antiphospholipid antibody-induced pregnancy loss. J Immunol. 2005;174(1):485–90.PubMedGoogle Scholar
  58. 58.
    Girardi G. Pravastatin prevents miscarriages in antiphospholipid antibody-treated mice. J Reprod Immunol. 2009;82(2):126–31.PubMedCrossRefGoogle Scholar
  59. 59.
    Odiari EA, Mulla MJ, Sfakianaki AK, et al. Pravastatin does not prevent antiphospholipid antibody-mediated changes in human first trimester trophoblast function. Hum Reprod. 2012;27(10):2933–40.PubMedCrossRefGoogle Scholar
  60. 60.
    Lockshin MD, Pierangeli SS. Statins for the treatment of obstetric complications in antiphospholipid syndrome? J Reprod Immunol. 2010;84(2):206. author reply -7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Guilherme R. de Jesús
    • 1
    • 4
    Email author
  • Gustavo Rodrigues
    • 1
    • 5
  • Nilson R. de Jesús
    • 1
    • 6
  • Roger A. Levy
    • 2
    • 3
    • 7
  1. 1.Department of Obstetrics, Faculdade de Ciências MédicasUniversidade do Estado do Rio de JaneiroRio de JaneiroBrazil
  2. 2.Department of Rheumatology, Faculdade de Ciências MédicasUniversidade do Estado do Rio de JaneiroRio de JaneiroBrazil
  3. 3.Federico FoundationVaduzLiechtenstein
  4. 4.Rio de JaneiroBrazil
  5. 5.RecreioBrazil
  6. 6.Rio de JaneiroBrazil
  7. 7.Rio de JaneiroBrazil

Personalised recommendations