Diagnosis and management of non-criteria obstetric antiphospholipid syndrome

Summary

Accurate diagnosis of obstetric antiphospholipid syndrome (APS) is a prerequisite for optimal clinical management. The international consensus (revised Sapporo) criteria for obstetric APS do not include low positive anticardiolipin (aCL) and anti β₂ glycoprotein I (aβ₂GPI) antibodies (> 99th centile) and/or certain clinical criteria such as two unexplained miscarriages, three non-consecutive miscarriages, late preeclampsia, placental abruption, late premature birth, or two or more unexplained in vitro fertilisation failures. In this review we examine the available evidence to address the question of whether patients who exhibit non-criteria clinical and/or laboratory manifestations should be included within the spectrum of obstetric APS. Prospective and retrospective cohort studies of women with pregnancy morbidity, particularly recurrent pregnancy loss, suggest that elimination of aCL and/or IgM aβ2GPI, or low positive positive aCL or aβ2GPI from APS laboratory diagnostic criteria may result in missing the diagnosis in a sizeable number of women who could be regarded to have obstetric APS. Such prospective and retrospective studies also suggest that women with non-criteria obstetric APS may benefit from standard treatment for obstetric APS with low-molecular-weight heparin plus low-dose aspirin, with good pregnancy outcomes. Thus, non-criteria manifestations of obstetric APS may be clinically relevant, and merit investigation of therapeutic approaches. Women with obstetric APS appear to be at a higher risk than other women of pre-eclampsia, placenta- mediated complications and neonatal mortality, and also at increased long-term risk of thrombotic events. The applicability of these observations to outcomes in women with non-criteria obstetric APS remains to be determined.

Keywords

Antiphospholipid syndrome - international consensus criteria - obstetric APS - low titre aPL - recurrent miscarriages - heparin - aspirin

• References

• 1 Wilson WA. et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999; 42: 1309-1311.
• 2 Miyakis S. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Hae-most 2006; 04: 295-306.
• 3 Stirrat GM. Recurrent miscarriage. Lancet 1990; 336: 673-675.
• 4 Horne AW, Alexander CI. Recurrent miscarriage. J Fam Plann Reprod Health Care 2005; 31: 103-107.
• 5 Rai R, Regan L. Recurrent miscarriage. Lancet 2006; 368: 601-611.
• 6 Porter TF, Scott JR. Evidence-based care of recurrent miscarriage. Best Pract Res Clin Obstet Gynaecol 2005; 19: 85-101.
• 7 Stephenson MD. Frequency of factors associated with habitual abortion in 197 couples. Fertil Steril 1996; 66: 24-29.
• 8 Cohn DM. et al. Recurrent miscarriage and antiphospholipid antibodies: prognosis of subsequent pregnancy. J Thromb Haemost 2010; 08: 2208-2213.
• 9 Boffa MC. et al. European registry of babies born to mothers with antiphosp-holipid syndrome: a result update. Lupus 2009; 18: 900-904.
• 10 Gardiner C. et al. Diagnosis of antiphospholipid syndrome in routine clinical practice. Lupus 2013; 22: 18-25.
• 11 Craig M. et al. Psychiatric morbidity among patients with recurrent miscarriage. J Psychosom Obstet Gynaecol 2002; 23: 157-164.
• 12 Keeling D. et al. Guidelines on the investigation and management of antiphospholipid syndrome. Br J Haematol 2012; 157: 47-58.
• 13 Mekinian A. et al. Outcomes and treatment of obstetrical antiphospholipid syndrome in women with low antiphospholipid antibody levels. J Reprod Immunol 2012; 94: 222-226.
• 14 Alijotas-Reig J, Ferrer-Oliveras R. The European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS): a preliminary first year report. Lupus 2012; 21: 766-768.
• 15 Rand JH. et al. Pregnancy loss in the antiphospholipid-antibody syndrome-- a possible thrombogenic mechanism. N Engl J Med 1997; 337: 154-160.
• 16 Sammaritano LR. et al. Phospholipid binding of antiphospholipid antibodies and placental anticoagulant protein. J Clin Immunol 1992; 12: 27-35.
• 17 Magid MS. et al. Placental pathology in systemic lupus erythematosus: a prospective study. Am J Obstet Gynecol 1998; 179: 226-234.
• 18 Cervera R. et al. Morbidity and mortality in the antiphospholipid syndrome during a 5-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis 2009; 68: 1428-1432.
• 19 Gris JC. et al. Comparative incidence of a first thrombotic event in purely obstetric antiphospholipid syndrome with pregnancy loss: the NOH-APS observational study. Blood 2012; 119: 2624-2632.
• 20 Rai RS. et al. Antiphospholipid antibodies and beta 2-glycoprotein-I in 500 women with recurrent miscarriage: results of a comprehensive screening approach. Hum Reprod 1995; 10: 2001-2005.
• 21 Robertson L. et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006; 132: 171-196.
• 22 Andreoli L. et al. Estimated frequency of antiphospholipid antibodies in patients with pregnancy morbidity, stroke, myocardial infarction, and deep vein thrombosis: a critical review of the literature. Arthritis Care Res (Hoboken) 2013; 65: 1869-1873.
• 23 Galli M. et al. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood 2003; 101: 1827-1832.
• 24 Opatrny L. et al. Association between antiphospholipid antibodies and recurrent fetal loss in women without autoimmune disease: a metaanalysis. J Rheumatol 2006; 33: 2214-2221.
• 25 Out HJ. et al. Histopathological findings in placentae from patients with intra-uterine fetal death and anti-phospholipid antibodies. Eur J Obstet Gynecol Re-prod Biol 1991; 41: 179-186..
• 26 Rand JH. et al. Pregnancy loss in the antiphospholipid-antibody syndrome-- a possible thrombogenic mechanism. N Engl J Med 1997; 337: 154-160.
• 27 Agostinis C. et al. In vivo distribution of beta2 glycoprotein I under various pa-thophysiologic conditions. Blood 2011; 118: 4231-4238.
• 28 La RL. et al. Beta 2 glycoprotein I and placental anticoagulant protein I in placentae from patients with antiphospholipid syndrome. J Rheumatol 1994; 21: 1684-1693.
• 29 Girardi G. Role of tissue factor in the maternal immunological attack of the embryo in the antiphospholipid syndrome. Clin Rev Allergy Immunol 2010; 39: 160-165.
• 30 Breen KA. et al. Complement activation in patients with isolated antiphospholi-pid antibodies or primary antiphospholipid syndrome. Thromb Haemost 2012; 107: 423-429.
• 31 Xu C. et al. A critical role for murine complement regulator crry in fetomaternal tolerance. Science 2000; 287: 498-501.
• 32 Girardi G. et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest 2003; 112: 1644-1654.
• 33 Holers VM. et al. Complement C3 activation is required for antiphospholipid antibody-induced fetal loss. J Exp Med 2002; 195: 211-220.
• 34 Girardi G. et al. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med 2004; 10: 1222-1226.
• 35 Branch DW. et al. Antiphospholipid antibodies in women at risk for preeclampsia. Am J Obstet Gynecol 2001; 184: 825-832.
• 36 Branch W. Report of the Obstetric APS Task Force: 13th International Congress on Antiphospholipid Antibodies, 13th April 2010. Lupus 2011; 20: 158-164.
• 37 Bouvier S. et al. Comparative incidence of pregnancy outcomes in treated obstetric antiphospholipid syndrome: the NOH-APS observational study. Blood 2014; 123: 404-413.
• 38 Laskin 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.
• 39 van den Boogaard E. et al. Number and sequence of preceding miscarriages and maternal age for the prediction of antiphospholipid syndrome in women with recurrent miscarriage. Fertil Steril 2013; 99: 188-192.
• 40 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.
• 41 Porter TF, Scott JR. Evidence-based care of recurrent miscarriage. Best Pract Res Clin Obstet Gynaecol 2005; 19: 85-101.
• 42 Galli M. et al. Invitation to a debate on the serological criteria that define the antiphospholipid syndrome. J Thromb Haemost 2008; 06: 399-401.
• 43 Nash MJ. et al. The anticardiolipin assay is required for sensitive screening for antiphospholipid antibodies. J Thromb Haemost 2004; 02: 1077-81.
• 44 Wahl D. et al. Pursuing the debate on the serologic criteria that define the anti-phospholipid syndrome. J Thromb Haemost 2008; 06: 1433-1435.
• 45 Boffa MC. et al. Laboratory criteria of the obstetrical antiphospholipid syndrome. Data from a multicentric prospective European women cohort. Thromb Haemost 2009; 102: 25-28.
• 46 Ruffatti A. et al. Antibody profile and clinical course in primary antiphospholi-pid syndrome with pregnancy morbidity. Thromb Haemost 2006; 96: 337-341.
• 47 Ruffatti A. et al. Influence of different IgG anticardiolipin antibody cut-off values on antiphospholipid syndrome classification. J Thromb Haemost 2008; 06: 1693-1696.
• 48 Jones DW. et al. Reduced factor XII levels in patients with the antiphospholipid syndrome are associated with antibodies to factor XII. Br J Haematol 2000; 110: 721-726.
• 49 Fleck RA. et al. Anti-prothrombin antibodies and the lupus anticoagulant. Blood 1988; 72: 512-519.
• 50 Lakos G. et al. International consensus guidelines on anticardiolipin and anti-beta2-glycoprotein I testing: report from the 13th International Congress on Antiphospholipid Antibodies. Arthritis Rheum 2012; 64: 1-10.
• 51 Pierangeli SS, Harris EN. A protocol for determination of anticardiolipin antibodies by ELISA. Nat Protoc 2008; 03: 840-848.
• 52 Wong RC. et al. Consensus guidelines on anti-cardiolipin antibody testing and reporting. Pathology 2004; 36: 63-68.
• 53 Wong RC. et al. Consensus guidelines on anti-beta 2 glycoprotein I testing and reporting. Pathology 2008; 40: 58-63.
• 54 Tincani A. et al. Minimal requirements for antiphospholipid antibodies ELISAs proposed by the European Forum on antiphospholipid antibodies. Thromb Res 2004; 114: 553-558.
• 55 Topping J. et al. Marked variation in antiphospholipid antibodies during pregnancy: relationships to pregnancy outcome. Hum Reprod 1999; 14: 224-228.
• 56 Kwak JY. et al. Biological basis of fetoplacental antigenic determinants in the induction of the antiphospholipid antibody syndrome and recurrent pregnancy loss. Ann NY Acad Sci 1994; 731: 242-245.
• 57 Bertolaccini ML. et al. ‘Non-criteria’ aPL tests: report of a task force and precon-ference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, TX, USA, April 2010. Lupus 2011; 20: 191-205.
• 58 Bertolaccini ML. et al. Revisiting antiphospholipid antibodies: from targeting phospholipids to phospholipid binding proteins. Clin Lab 2004; 50: 653-665.
• 59 Nayfe R. et al. Seronegative antiphospholipid syndrome. Rheumatology 2013; 52: 1358-1367.
• 60 Rai R. 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.
• 61 Goel N. et al. The role of aspirin versus aspirin and heparin in cases of recurrent abortions with raised anticardiolipin antibodies. Med Sci Monit 2006; 12: CR132-CR136.
• 62 Farquharson RG. et al. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. Obstet Gynecol 2002; 100: 408-413.
• 63 Rai RS. et al. High prospective fetal loss rate in untreated pregnancies of women with recurrent miscarriage and antiphospholipid antibodies. Hum Reprod 1995; 10: 3301-3304.
• 64 Mak A. 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; 49: 281-288.
• 65 Bates SM. et al. 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: e691S-e736S.