Download PDF
Thromb Haemost 2020; 120(01): 036-043
DOI: 10.1055/s-0039-1697665
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

Upgrading Therapy Strategy Improves Pregnancy Outcome in Antiphospholipid Syndrome: A Cohort Management Study

Ariela Hoxha   *
1   Department of Medicine-DIMED, Rheumatology Unit, University of Padua, Padua, Italy
2   Department of Medicine, Internal Medicine Unit, San Bortolo Hospital, Vicenza, Italy
,
Maria Favaro‡   *
1   Department of Medicine-DIMED, Rheumatology Unit, University of Padua, Padua, Italy
,
Antonia Calligaro
1   Department of Medicine-DIMED, Rheumatology Unit, University of Padua, Padua, Italy
,
Teresa Del Ross
1   Department of Medicine-DIMED, Rheumatology Unit, University of Padua, Padua, Italy
,
Alessandra Teresa Ruffatti
3   Obstetrics and Gynaecology Unit, University Hospital Padua, Padua, Italy
,
Chiara Infantolino
3   Obstetrics and Gynaecology Unit, University Hospital Padua, Padua, Italy
,
Marta Tonello
1   Department of Medicine-DIMED, Rheumatology Unit, University of Padua, Padua, Italy
,
Elena Mattia
1   Department of Medicine-DIMED, Rheumatology Unit, University of Padua, Padua, Italy
,
Amelia Ruffatti
1   Department of Medicine-DIMED, Rheumatology Unit, University of Padua, Padua, Italy
› Author Affiliations Funding None.
Further Information

Publication History

10 December 2018

16 August 2019

Publication Date:
21 October 2019 (online)

Also available at
    Permissions and Reprints

Abstract

The current study evaluates the efficacy and safety of different treatment strategies for pregnant patients with antiphospholipid syndrome. One hundred twenty-seven consecutive pregnancies were assessed; 87 (68.5%) with a history of pregnancy morbidity alone were treated with prophylactic low molecular weight heparin (LMWH) + low-dose aspirin (LDA, 100 mg) (group I) and 40 (31.5%) with a history of thrombosis and/or severe pregnancy complications with therapeutic LMWH + LDA (group II). LMWH doses were increased throughout the pregnancies depending on the patients' weight gain, and treatment was switched to a more intensive one at the first sign of maternal/fetal complications. The study's primary outcome was live births. There were no significant differences in live birth rate between group I (95.4%) and group II (87.5%). Even fetal complication rate was similar in the two groups; group II nevertheless had a higher prevalence of maternal and neonatal complications (p = 0.0005 and p = 0.01, respectively) and registered a significantly lower gestational age at delivery and birth weight (p = 0.0001 and p = 0.0005, respectively). Two patients in group I switched to group II therapy, six patients in group II switched to a more intensive treatment strategy (weekly plasma exchange + fortnightly intravenous immunoglobulins in addition to therapeutic LMWH + LDA). The multivariate analysis uncovered that triple antiphospholipid antibodies positivity was an independent factor leading to a more intensive therapy. All eight switched patients achieved a live birth. Study results revealed that adjusted LMWH doses and switching therapy at first signs of severe pregnancy complications led to a high rate of live births in antiphospholipid syndrome patients.

Keywords

obstetric antiphospholipid syndrome - low molecular weight heparin - low-dose aspirin - plasma exchange - intravenous immunoglobulins - pregnancy

Ethical Approval

The Institutional Review Board for observational studies and the Audit Committee of the University-Hospital of Padua approved the study protocol (Protocol Number: 6894/2013, February 7, 2013).


* The first two authors contributed equally to the study.


 

  • References

  • 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 (02) 295-306
    CrossrefPubMedGoogle Scholar
  • 2 Hughes GRV. Thrombosis, abortion, cerebral disease, and the lupus anticoagulant. Br Med J (Clin Res Ed) 1983; 287 (6399): 1088-1089
    CrossrefPubMedGoogle Scholar
  • 3 de Jesus GR, Agmon-Levin N, Andrade CA. , et al. 14th International Congress on Antiphospholipid Antibodies Task Force report on obstetric antiphospholipid syndrome. Autoimmun Rev 2014; 13 (08) 795-813
    CrossrefPubMedGoogle Scholar
  • 4 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 (05) 1584-1589
    CrossrefPubMedGoogle Scholar
  • 5 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
    CrossrefPubMedGoogle Scholar
  • 6 Empson M, Lassere M, Craig J, Scott J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev 2005; 2 (02) CD002859
    PubMedGoogle Scholar
  • 7 Mak A, Cheung MW, Cheak AA, Ho RC. 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 (Oxford) 2010; 49 (02) 281-288
    CrossrefPubMedGoogle Scholar
  • 8 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
    CrossrefPubMedGoogle Scholar
  • 9 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
    CrossrefPubMedGoogle Scholar
  • 10 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
    CrossrefPubMedGoogle Scholar
  • 11 Bramham K, Thomas M, Nelson-Piercy C, Khamashta M, Hunt BJ. First-trimester low-dose prednisolone in refractory antiphospholipid antibody-related pregnancy loss. Blood 2011; 117 (25) 6948-6951
    CrossrefPubMedGoogle Scholar
  • 12 Sciascia S, Branch DW, Levy RA. , et al. The efficacy of hydroxychloroquine in altering pregnancy outcome in women with antiphospholipid antibodies. Evidence and clinical judgment. Thromb Haemost 2016; 115 (02) 285-290
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 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
    CrossrefPubMedGoogle Scholar
  • 14 Ruffatti A, Tonello M, Hoxha A. , et al. Effect of additional treatments combined with conventional therapies in pregnant patients with high-risk antiphospholipid syndrome: a multicentre study. Thromb Haemost 2018; 118 (04) 639-646
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Chighizola CB, Gerosa M, Trespidi L. , et al. Update on the current recommendations and outcomes in pregnant women with antiphospholipid syndrome. Expert Rev Clin Immunol 2014; 10 (11) 1505-1517
    CrossrefPubMedGoogle Scholar
  • 16 Andreoli L, Bertsias GK, Agmon-Levin N. , et al. EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Ann Rheum Dis 2017; 76 (03) 476-485
    CrossrefPubMedGoogle Scholar
  • 17 Ruffatti A, Gervasi MT, Favaro M, Ruffatti AT, Hoxha A, Punzi L. Adjusted prophylactic doses of nadroparin plus low dose aspirin therapy in obstetric antiphospholipid syndrome. A prospective cohort management study. Clin Exp Rheumatol 2011; 29 (03) 551-554
    PubMedGoogle Scholar
  • 18 Ruffatti A, Favaro M, Tonello M. , et al. Efficacy and safety of nadroparin in the treatment of pregnant women with antiphospholipid syndrome: a prospective cohort study. Lupus 2005; 14 (02) 120-128
    CrossrefPubMedGoogle Scholar
  • 19 Ruffatti A, Olivieri S, Tonello M. , et al. Influence of different IgG anticardiolipin antibody cut-off values on antiphospholipid syndrome classification. J Thromb Haemost 2008; 6 (10) 1693-1696
    CrossrefPubMedGoogle Scholar
  • 20 Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulant. Thromb Haemost 1995; 74 (04) 1185-1190
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 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
    CrossrefPubMedGoogle Scholar
  • 22 Roberts JM, August PA, Bakris G. , et al; American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013; 122 (05) 1122-1131
    CrossrefPubMedGoogle Scholar
  • 23 Galan H, Grobman W. ; American College of Obstetricians and Gynecologists. ACOG Practice bulletin no. 134: fetal growth restriction. Obstet Gynecol 2013; 121 (05) 1122-1133
    CrossrefPubMedGoogle Scholar
  • 24 von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. ; STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 2007; 370 (9596): 1453-1457
    CrossrefPubMedGoogle Scholar
  • 25 Barbour LA, Smith JM, Marlar RA. Heparin levels to guide thromboembolism prophylaxis during pregnancy. Am J Obstet Gynecol 1995; 173 (06) 1869-1873
    CrossrefPubMedGoogle Scholar
  • 26 Casele HL, Laifer SA, Woelkers DA, Venkataramanan R. Changes in the pharmacokinetics of the low-molecular-weight heparin enoxaparin sodium during pregnancy. Am J Obstet Gynecol 1999; 181 (5 Pt 1): 1113-1117
    CrossrefPubMedGoogle Scholar
  • 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 (Oxford) 2011; 50 (09) 1684-1689
    CrossrefPubMedGoogle Scholar
  • 28 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 Obstet Gynecol 2017; 216 (05) 525.e1-525.e12
    CrossrefPubMedGoogle Scholar
  • 29 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
    CrossrefPubMedGoogle Scholar
  • 30 De Carolis S, Botta A, Garofalo S. , et al. Uterine artery velocity waveforms as predictors of pregnancy outcome in patients with antiphospholipid syndrome: a review. Ann N Y Acad Sci 2007; 1108: 530-539
    CrossrefPubMedGoogle Scholar
  • 31 Alfirevic Z, Stampalija T, Gyte GM. Fetal and umbilical Doppler ultrasound in high-risk pregnancies. Cochrane Database Syst Rev 2013; 11 (11) CD007529
    PubMedGoogle Scholar
  • 32 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
    CrossrefPubMedGoogle Scholar
  • 33 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Marson P, Gervasi MT, Tison T, Colpo A, De Silvestro G. Therapeutic apheresis in pregnancy: General considerations and current practice. Transfus Apheresis Sci 2015; 53 (03) 256-261
    CrossrefPubMedGoogle Scholar