Thromb Haemost 2018; 118(04): 639-646
DOI: 10.1055/s-0038-1632388
Coagulation and Fibrinolysis
Schattauer GmbH Stuttgart

Effect of Additional Treatments Combined with Conventional Therapies in Pregnant Patients with High-Risk Antiphospholipid Syndrome: A Multicentre Study

Amelia Ruffatti
1   Rheumatology Unit, Department of Medicine, University of Padua, Padua, Italy
,
Marta Tonello
1   Rheumatology Unit, Department of Medicine, University of Padua, Padua, Italy
,
Ariela Hoxha
1   Rheumatology Unit, Department of Medicine, University of Padua, Padua, Italy
,
Savino Sciascia
2   Louise Coote Lupus Unit, Guy's and St Thomas' NHS Foundation Trust, St Thomas' Hospital, London, United Kingdom
,
Maria J. Cuadrado
2   Louise Coote Lupus Unit, Guy's and St Thomas' NHS Foundation Trust, St Thomas' Hospital, London, United Kingdom
,
José O. Latino
3   Autoimmune,Thrombophilic Diseases and Pregnancy Division, Dr. Carlos G Durand Hospital, Buenos Aires, Argentina
,
Sebastian Udry
3   Autoimmune,Thrombophilic Diseases and Pregnancy Division, Dr. Carlos G Durand Hospital, Buenos Aires, Argentina
,
Tatiana Reshetnyak
4   Department of Systemic Rheumatic Disease, V.A. Nasonova Research Institute of Rheumatology, Moscow, Russia
,
Nathalie Costedoat-Chalumeau
5   AP-HP, Cochin Hospital, Internal Medicine Department, Centre de Référence Maladies Auto-immunes et Systémiques Rares, Paris, France
6   Université Paris Descartes, Sorbonne Paris Cité, Paris, France
7   INSERM U 1153, Centre for Epidemiology and Statistics, Sorbonne Paris Cité (CRESS), Paris, France
,
Nathalie Morel
5   AP-HP, Cochin Hospital, Internal Medicine Department, Centre de Référence Maladies Auto-immunes et Systémiques Rares, Paris, France
6   Université Paris Descartes, Sorbonne Paris Cité, Paris, France
,
Luca Marozio
8   Department of Obstetrics and Gynaecology, Università di Torino, Torino, Italy
,
Angela Tincani
9   Rheumatology and Clinical Immunology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili, Brescia, Italy
,
Laura Andreoli
9   Rheumatology and Clinical Immunology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili, Brescia, Italy
,
Ewa Haladyj
10   Department of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
,
Pier L. Meroni
11   Division of Rheumatology, G. Pini Institute, Milan
12   Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
13   Istituto Auxologico IRCCS, Milan, Italy
,
Maria Gerosa
11   Division of Rheumatology, G. Pini Institute, Milan
12   Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
13   Istituto Auxologico IRCCS, Milan, Italy
,
Jaume Alijotas-Reig
14   Systemic Autoimmune Diseases Unit, Department of Medicine, Vall d'Hebron University Hospital, Barcelona, Spain
15   Department of Medicine, Faculty of Medicine, Universitat Autònoma, Barcelona, Spain
,
Sara Tenti
16   Department of Medicine, Surgery and Neuroscience, Rheumatology Unit, University of Siena, Siena, Italy
,
Karoline Mayer-Pickel
17   Department of Obstetrics, Medical University Graz, Graz, Austria
,
Michal J. Simchen
18   Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Sheba Medical Centre, Tel Hashomer, Israel
,
Maria T. Bertero
19   Clinical Immunology, AO Ordine Mauriziano, Torino, Italy
,
Sara De Carolis
20   Department of Obstetrics and Gynecology, Catholic University of Sacred Heart, Rome, Italy
,
Véronique Ramoni
21   Division of Rheumatology, IRCCS Policlinico S. Matteo, Pavia, Italy
,
Arsène Mekinian
22   Service de Médecine Interne et l'inflammation-(DHU i2B), Hôpital Saint-Antoine, Université Paris 06, Paris, France
,
Elvira Grandone
23   Atherosclerosis and Thrombosis Unit, I.R.C.C.S. Casa Sollievo della Sofferenza, S. Giovanni Rotondo, Foggia, Italy
,
Aldo Maina
24   Servizio di Medicina Interna, Ospedale Sant'Anna, Torino, Italy
,
Fátima Serrano
25   Department of Obstetrics and Gynecology, Centro Hospitalar de Lisboa Central, NOVA Medical School, Universidade Nova de Lisboa, Lisbon, Portugal
,
Vittorio Pengo
1   Rheumatology Unit, Department of Medicine, University of Padua, Padua, Italy
26   Cardiology Clinic, Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy
,
Munther A. Khamashta
2   Louise Coote Lupus Unit, Guy's and St Thomas' NHS Foundation Trust, St Thomas' Hospital, London, United Kingdom
27   Lupus Research Unit, The Rayne Institute, Division of Women's Health, St Thomas Hospital, London, United Kingdom
28   Department of Rheumatology, Dubai Hospital, Dubai, United Arab Emirates
› Institutsangaben
Funding None.
Weitere Informationen

Publikationsverlauf

23. August 2017

05. Januar 2018

Publikationsdatum:
28. Februar 2018 (online)

Abstract

The effect of additional treatments combined with conventional therapy on pregnancy outcomes was examined in high-risk primary antiphospholipid syndrome (PAPS) patients to identify the most effective treatment strategy. The study's inclusion criteria were (1) positivity to lupus anticoagulant alone or associated with anticardiolipin and/or anti-β2 glycoprotein I antibodies; (2) a history of severe maternal–foetal complications (Group I) or a history of one or more pregnancies refractory to conventional therapy leading to unexplained foetal deaths not associated with severe maternal–foetal complications (Group II). Two different additional treatments were considered: oral—low-dose steroids (10–20 mg prednisone daily) and/or 200 to 400 mg daily doses of hydroxychloroquine and parenteral—intravenous immunoglobulins at 2 g/kg per month and/or plasma exchange. The study's primary outcomes were live birth rates and pregnancy complications. A total of 194 pregnant PAPS patients attending 20 tertiary centres were retrospectively enrolled. Hydroxychloroquine was found to be linked to a significantly higher live birth rate with respect to the other oral treatments in the Group II patients. The high (400 mg) versus low (200 mg) doses of hydroxychloroquine (p = 0.036) and its administration before versus during pregnancy (p = 0.021) were associated with a significantly higher live birth rate. Hydroxychloroquine therapy appeared particularly efficacious in the PAPS patients without previous thrombosis. Parenteral treatments were associated with a significantly higher live birth rate with respect to the oral ones (p = 0.037), particularly in the Group I patients. In conclusion, some additional treatments were found to be safe and efficacious in high-risk PAPS pregnant women.

 
  • References

  • 1 Lassere M, Empson M. Treatment of antiphospholipid syndrome in pregnancy--a systematic review of randomized therapeutic trials. Thromb Res 2004; 114 (5-6): 419-426
  • 2 Sailer T, Zoghlami C, Kurz C. , et al. Anti-beta2-glycoprotein I antibodies are associated with pregnancy loss in women with the lupus anticoagulant. Thromb Haemost 2006; 95 (05) 796-801
  • 3 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) 1183-1189
  • 4 Matsuki Y, Atsumi T, Yamaguchi K. , et al. Clinical features and pregnancy outcome in antiphospholipid syndrome patients with history of severe pregnancy complications. Mod Rheumatol 2015; 25 (02) 215-218
  • 5 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 (03) 337-341
  • 6 Ruffatti A, Tonello M, Cavazzana A, Bagatella P, Pengo V. Laboratory classification categories and pregnancy outcome in patients with primary antiphospholipid syndrome prescribed antithrombotic therapy. Thromb Res 2009; 123 (03) 482-487
  • 7 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 (09) 1684-1689
  • 8 Latino JO, Udry S, Aranda FM, Perés Wingeyer SDA, Fernández Romero DS, de Larrañaga GF. Pregnancy failure in patients with obstetric antiphospholipid syndrome with conventional treatment: the influence of a triple positive antibody profile. Lupus 2017; 26 (09) 983-988
  • 9 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
  • 10 Nodler J, Moolamalla SR, Ledger EM, Nuwayhid BS, Mulla ZD. Elevated antiphospholipid antibody titers and adverse pregnancy outcomes: analysis of a population-based hospital dataset. BMC Pregnancy Childbirth 2009; 9: 11
  • 11 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 (12) 1428-1433
  • 12 Lima F, Khamashta MA, Buchanan NM, Kerslake S, Hunt BJ, Hughes GR. A study of sixty pregnancies in patients with the antiphospholipid syndrome. Clin Exp Rheumatol 1996; 14 (02) 131-136
  • 13 Bramham K, Hunt BJ, Germain S. , et al. Pregnancy outcome in different clinical phenotypes of antiphospholipid syndrome. Lupus 2010; 19 (01) 58-64
  • 14 de Jesús GR, Rodrigues G, de Jesús NR, Levy RA. Pregnancy morbidity in antiphospholipid syndrome: what is the impact of treatment?. Curr Rheumatol Rep 2014; 16 (02) 403
  • 15 Bowman ZS, Wünsche V, Porter TF, Silver RM, Branch DW. Prevalence of antiphospholipid antibodies and risk of subsequent adverse obstetric outcomes in women with prior pregnancy loss. J Reprod Immunol 2015; 107: 59-63
  • 16 Danowski A, de Azevedo MN, de Souza Papi JA, Petri M. Determinants of risk for venous and arterial thrombosis in primary antiphospholipid syndrome and in antiphospholipid syndrome with systemic lupus erythematosus. J Rheumatol 2009; 36 (06) 1195-1199
  • 17 Ruffatti A, Hoxha A, Favaro M. , et al. Additional treatments for high-risk obstetric antiphospholipid syndrome: a comprehensive review. Clin Rev Allergy Immunol 2017; 53 (01) 28-39
  • 18 Ruffatti A, Salvan E, Del Ross T. , et al. Treatment strategies and pregnancy outcomes in antiphospholipid syndrome patients with thrombosis and triple antiphospholipid positivity. A European multicentre retrospective study. Thromb Haemost 2014; 112 (04) 727-735
  • 19 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
  • 20 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 (5-6): 553-558
  • 21 Reber G, Tincani A, Sanmarco M, de Moerloose P, Boffa MC. ; Standardization Group of the European Forum on Antiphospholipid Antibodies. Proposals for the measurement of anti-beta2-glycoprotein I antibodies. Standardization group of the European Forum on Antiphospholipid Antibodies. J Thromb Haemost 2004; 2 (10) 1860-1862
  • 22 Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulant. Thromb Haemost 1995; 74 (04) 1185-1190
  • 23 Pengo V, Tripodi A, Reber G. , et al; Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost 2009; 7 (10) 1737-1740
  • 24 Mekinian A, Lazzaroni MG, Kuzenko A. , et al; SNFMI and the European Forum on Antiphospholipid Antibodies. The efficacy of hydroxychloroquine for obstetrical outcome in anti-phospholipid syndrome: Data from a European multicenter retrospective study. Autoimmun Rev 2015; 14 (06) 498-502
  • 25 Sciascia S, Hunt BJ, Talavera-Garcia E, Lliso G, Khamashta MA, Cuadrado MJ. The impact of hydroxychloroquine treatment on pregnancy outcome in women with antiphospholipid antibodies. Am J Obstet Gynecol 2016; 214 (02) 273.e1-273.e8
  • 26 Kaplan YC, Ozsarfati J, Nickel C, Koren G. Reproductive outcomes following hydroxychloroquine use for autoimmune diseases: a systematic review and meta-analysis. Br J Clin Pharmacol 2016; 81 (05) 835-848
  • 27 Cherin P, Marie I, Michallet M. , et al. Management of adverse events in the treatment of patients with immunoglobulin therapy: a review of evidence. Autoimmun Rev 2016; 15 (01) 71-81
  • 28 El-Haieg DO, Zanati MF, El-Foual FM. Plasmapheresis and pregnancy outcome in patients with antiphospholipid syndrome. Int J Gynaecol Obstet 2007; 99 (03) 236-241
  • 29 Ruffatti A, Favaro M, Hoxha A. , et al. Apheresis and intravenous immunoglobulins used in addition to conventional therapy to treat high-risk pregnant antiphospholipid antibody syndrome patients. A prospective study. J Reprod Immunol 2016; 115: 14-19
  • 30 Reber G, Tincani A, Sanmarco M, de Moerloose P, Boffa MC. ; European Forum on Antiphospholipid Antibodies Standardization Group. Variability of anti-beta2 glycoprotein I antibodies measurement by commercial assays. Thromb Haemost 2005; 94 (03) 665-672
  • 31 Pengo V, Biasiolo A, Bison E, Chantarangkul V, Tripodi A. ; Italian Federation of Anticoagulation Clinics (FCSA). Antiphospholipid antibody ELISAs: survey on the performance of clinical laboratories assessed by using lyophilized affinity-purified IgG with anticardiolipin and anti-beta2-Glycoprotein I activity. Thromb Res 2007; 120 (01) 127-133
  • 32 Favaloro EJ, Wheatland L, Jovanovich S, Roberts-Thomson P, Wong RC. Internal quality control and external quality assurance in testing for antiphospholipid antibodies: Part I--Anticardiolipin and anti-β2-glycoprotein I antibodies. Semin Thromb Hemost 2012; 38 (04) 390-403