Treatment strategies and pregnancy outcomes in antiphospholipid syndrome patients with thrombosis and triple antiphospholipid positivity

Amelia Ruffatti; Elisa Salvan; Teresa Del Ross; Maria Gerosa; Laura Andreoli; Aldo Maina; Jaume Alijotas-Reig; Sara De Carolis; Arsene Mekinian; Maria Tiziana Bertero; Valentina Canti; Antonio Brucato; Katarina Bremme; Véronique Ramoni; Marta Mosca; Emma Di Poi; Paola Caramaschi; Mauro Galeazzi; Angela Tincani; Pier Luigi Meroni

doi:10.1160/TH14-03-0191

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2014; 112(04): 727-735
DOI: 10.1160/TH14-03-0191

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Treatment strategies and pregnancy outcomes in antiphospholipid syndrome patients with thrombosis and triple antiphospholipid positivity

A European multicentre retrospective study

Authors

Amelia Ruffatti

¹Rheumatology Unit, Department of Medicine, University Hospital, Padua, Italy
Elisa Salvan

¹Rheumatology Unit, Department of Medicine, University Hospital, Padua, Italy
Teresa Del Ross

¹Rheumatology Unit, Department of Medicine, University Hospital, Padua, Italy
Maria Gerosa

²Department of Clinical Sciences and Community Health, University of Milan, Istituto G. Pini and IRCCS Istituto Auxologico Italiano, Milan, Italy
Laura Andreoli

³Rheumatology and Clinical Immunology Units, University Hospital, Brescia, Italy
Aldo Maina

⁴Department of Internal Medicine, University Hospital, Turin, Italy
Jaume Alijotas-Reig

⁵Systemic Autoimmune Diseases Unit, Department of Internal Medicine-1, Vall d’Hebron University Hospital, Barcelona, Spain
Sara De Carolis

⁶Department of Obstetrics and Gynecology, Catholic University of Sacred Hearth, Rome, Italy
Arsene Mekinian

⁷Service de Médecine Interne, Université Paris 13, AP-HP, Hôpital Jean Verdier, Bondy, France
Maria Tiziana Bertero

⁸Clinical Immunology and Allergology Units, Mauriziano Hospital, Turin, Italy
Valentina Canti

⁹San Raffaele Scientific Institute, University of Milan, Milan, Italy
Antonio Brucato

¹⁰Department of Internal Medicine, Hospital of Bergamo, Bergamo, Italy
Katarina Bremme

¹¹Department of Women´s and Children´s Health, Division of Obstetrics and Gynecology, Karolinska Institutet, Stockholm, Sweden
Véronique Ramoni

¹²Rheumatology Unit, IRCCS Policlinico S. Matteo Foundation, University of Pavia, Pavia, Italy
Marta Mosca

¹³Rheumatology Unit, University of Pisa, Pisa, Italy
Emma Di Poi

¹⁴Division of Rheumatology, DPMSC, School of Medicine, University of Udine, Udine, Italy
Paola Caramaschi

¹⁵Rheumatology Unit, AOUI, Verona, Italy
Mauro Galeazzi

¹⁶Rheumatology Unit, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy
Angela Tincani

³Rheumatology and Clinical Immunology Units, University Hospital, Brescia, Italy
Pier Luigi Meroni

²Department of Clinical Sciences and Community Health, University of Milan, Istituto G. Pini and IRCCS Istituto Auxologico Italiano, Milan, Italy

Abstract

Summary

Previous thrombosis, diagnosis of systemic lupus erythematosus (SLE) and triple antiphospholipid (aPL) antibody positivity have recently been found to be independent factors associated to pregnancy failure during conventional therapy in women with antiphospholipid syndrome (APS). This study aimed to assess the effect of various treatment strategies on pregnancy outcomes in women with APS and the risk factors for pregnancy failure. One hundred ninety-six pregnancies of 156 patients diagnosed with APS were analysed: 118 (60.2%) of these had previous thrombosis, 81 (41.3%) were diagnosed with SLE, and 107 (54.6%) had triple aPL positivity. One hundred seventy-five (89.3%) were treated with conventional therapies (low-dose aspirin [LDA] or prophylactic doses of heparin + LDA or therapeutic doses of heparin + LDA), while 21 (10.7%) were prescribed other treatments in addition to conventional therapy. The pregnancies were classified into seven risk profiles depending on the patients’ risk factors – thrombosis, SLE, and triple aPL positivity – and their single, double or triple combinations. It was possible to find significant difference in outcomes correlated to treatments only in the thrombosis plus triple aPL positivity subset, and logistic regression analysis showed that additional treatments were the only independent factor associated to a favourable pregnancy outcome (odds ratio=9.7, 95% confidence interval= 1.1–88.9, p-value<0.05). On the basis of this retrospective study, we found that APS pregnant patients with thrombosis and triple aPL positivity treated with additional therapy had a significant higher livebirth rate with respect to those receiving conventional therapy alone.

Keywords

Antiphospholipid antibodies - antiphospholipid syndrome - pregnancy - risk factors - treatment

Full Text

References

References
1 Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol 1996; 174: 1584-1589.
2 Rai R, Cohen H, Dave M. et al. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). Br Med J 1997; 314: 253-257.
3 Franklin RD, Kutteh WH. Antiphospholipid antibodies (APA) and recurrent pregnancy loss: treating a unique APA positive population. Hum Reprod 2002; 17: 2981-2985.
4 Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. Obstet Gynecol 2002; 100: 408-413.
5 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: 279-287.
6 Mak A, Cheung MW, Cheak AA. et al. Combination of heparin and aspirin is superior to aspirin alone in enhancing live births in patients with recurrent pregnancy loss and positive anti-phospholipid antibodies: a meta-analysis of randomized controlled trials and meta-regression. Rheumatology 2010; 9: 281-288.
7 Szodoray P, Bacskó G, Lakos G. et al. Combined therapy in pregnancy with primary antiphospholipid syndrome. Orv Hetil 2003; 144: 2411-2413.
8 Chang P, Millar D, Tsang P. et al. Intravenous immunoglobulin in antiphospholipid syndrome and maternal floor infarction when standard treatment fails: a case report. Am J Perinatol 2006; 23: 125-129.
9 Kaaja R, Julkunen H, Ammälä P. et al. Intravenous immunoglobulin treatment of pregnant patients with recurrent pregnancy losses associated with antiphospholipid antibodies. Acta Obstet Gynecol Scand 1993; 72: 63-66.
10 Branch DW, Peaceman AM, Druzin M. et al. A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study Group. Am J Obstet Gynecol 2000; 182: 122-127.
11 Xiao J, Xiong J, Zhu F. et al. Effect of prednisone, aspirin, low molecular weight heparin and intravenous immunoglobulin on outcome of pregnancy in women with antiphospholipid syndrome. Exp Ther Med 2013; 5: 287-291.
12 Bramham K, Thomas M, Nelson-Piercy C. et al. First-trimester low-dose prednisolone in refractory antiphospholipid antibody-related pregnancy loss. Blood 2011; 117: 6948-6951.
13 Frampton G, Cameron JS, Thom M. et al. Successful removal of anti-phospholipid antibody during pregnancy using plasma exchange and low-dose prednisolone. Lancet 1987; 2: 1023-1024.
14 El-Haieg DO, Zanati MF, El-Foual FM. Plasmapheresis and pregnancy outcome in patients with antiphospholipid syndrome. Int J Gynaecol Obstet 2007; 99: 236-241.
15 Nakamura Y, Yoshida K, Itoh S. et al. Immunoadsorption plasmapheresis as a treatment for pregnancy complicated by systemic lupus erythematosus with positive antiphospholipid antibodies. Am J Reprod Immunol 1999; 41: 307-311.
16 Kobayashi S, Tamura N, Tsuda H. et al. Immunoadsorbent plasmapheresis for a patient with antiphospholipid syndrome during pregnancy. Ann Rheum Dis 1992; 51: 399-401.
17 Ruffatti A, Marson P, Pengo V. et al. Plasma exchange in the management of high risk pregnant patients with primary antiphospholipid syndrome. A report of 9 cases and a review of the literature. Autoimmun Rev 2007; 6: 196-202.
18 Bortolati M, Marson P, Chiarelli S. et al. Case reports of the use of immunoadsorption or plasma exchange in high-risk pregnancies of women with anti-phospholipid syndrome. Ther Apher Dial 2009; 13: 157-160.
19 Ruffatti A, Tonello M, Del Ross T. et al. Antibody profile and clinical course in primary antiphospholipid syndrome with pregnancy morbidity. Thromb Haemost 2006; 96: 337-341.
20 Bramham K, Hunt BJ, Germain S. et al. Pregnancy outcome in different clinical phenotypes of antiphospholipid syndrome. Lupus 2010; 19: 58-64.
21 Fischer-Betz R, Specker C, Brinks R. et al. Pregnancy outcome in patients with antiphospholipid syndrome after cerebral ischaemic events: an observational study. Lupus 2012; 21: 1183-1189.
22 Ruffatti A, Tonello M, Cavazzana A. et al. Laboratory classification categories and pregnancy outcome in patients with primary antiphospholipid syndrome prescribed antithrombotic therapy. Thromb Res 2009; 123: 482-487.
23 Simchen MJ, Dulitzki M, Rofe G. et al. High positive antibody titers and adverse pregnancy outcome in women with antiphospholipid syndrome. Acta Obstet Gynecol Scand 2011; 90: 1428-1433.
24 Danowski A, de Azevedo MN, de Souza Papi JA. et al. Determinants of risk for venous and arterial thrombosis in primary antiphospholipid syndrome and in antiphospholipid syndrome with systemic lupus erythematosus. J Rheumatol 2009; 36: 1195-1199.
25 Carmona F, Font J, Azulay M. et al. Risk factors associated with fetal losses in treated antiphospholipid syndrome pregnancies: a multivariate analysis. Am J Reprod Immunol 2001; 46: 274-279.
26 De Carolis S, Botta A, Santucci S. et al. Predictors of pregnancy outcome in anti-phospholipid syndrome: a review. Clin Rev Allerg Immunol 2010; 38: 116-124.
27 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 2011; 50: 1684-1689.
28 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: 295-306.
29 Tincani A, Allegri F, Balestrieri G. et al. Minimal requirements for antiphospholipid antibodies ELISAs proposed by the European Forum on antiphospholipid antibodies. Thromb Res 2004; 114: 553-558.
30 Reber G, Tincani A, Sanmarco M. et al. Proposal for the measurement of anti-2-Glycoprotein I antibodies. Standardization Group of the European Forum on Antiphospholipid Antibodies. J Thromb Haemost 2004; 2: 1860-1862.
31 Brandt JT, Triplett DA, Alvin B. et al. Criteria for the diagnosis of lupus anticoagulant. Thromb Haemost 1995; 74: 1185-1190.
32 Pengo V, Tripodi A, Reber G. et al. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2009; 7: 1737-1740.
33 Wijetilleka S, Scoble T, Khamashta M. Novel insights into pathogenesis, diagnosis and treatment of antiphospholipid syndrome. Curr Opin Rheumatol 2012; 24: 473-481.
34 Alijotas-Reig J. Treatment of refractory obstetric antiphospholipid syndrome: the state of the art and new trends in the therapeutic management. Lupus 2013; 22: 6-17.
35 Vaquero E, Lazzarin N, Valensise H. et al. Pregnancy outcome in recurrent spontaneous abortion associated with antiphospholipid antibodies: a comparative study of intravenous immunoglobulin versus prednisone plus low-dose aspirin. Am J Reprod Immunol 2001; 45: 174-179.
36 Triolo G, Ferrante A, Ciccia F. et al. Randomized study of subcutaneous low molecular weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies. Arthritis Rheum 2003; 48: 728-731.
37 Dendrinos S, Sakkas E, Makrakis E. Low-molecular-weight heparin versus intravenous immunoglobulin for recurrent abortion associated with antiphospholipid antibody syndrome. Int J Gynaecol Obstet 2009; 104: 223-225.
38 Scoble T, Wijetilleka S, Khamashta MA. Management of refractory anti-phospholipid syndrome. Autoimmun Rev 2011; 10: 669-673.
39 Hauser AC, Hauser L, Pabinger-Fasching I. et al. The course of anticardiolipin antibody levels under immunoadsorption therapy. Am J Kidney Dis 2005; 46: 446-454.
40 Bontadi A, Ruffatti A, Marson P. et al. Plasma exchange and immunoadsorption effectively remove antiphospholipid antibodies in pregnant patients with anti-phospholipid syndrome. J Clin Apher 2012; 27: 200-204.