Antiphospholipid Antibodies in Pregnancy: Maternal and Neonatal Implications

Jean-Christophe Gris; Florence Guillotin; Mathias Chéa; Chloé Bourguignon; Éva Nouvellon; Sylvie Bouvier

doi:10.1055/s-0042-1756193

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2023; 49(04): 337-347
DOI: 10.1055/s-0042-1756193

Review Article

Antiphospholipid Antibodies in Pregnancy: Maternal and Neonatal Implications

Authors

Jean-Christophe Gris

¹Department of Hematology, CHU Nîmes, Univ Montpellier, Nîmes, France

²Department of Hematology, Faculty of Pharmaceutical and Biological Sciences, Montpellier University, France

³UMR UA11 INSERM IDESP - Montpellier University, France

⁴Department of Obstetrics and Gynecology, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
Florence Guillotin

¹Department of Hematology, CHU Nîmes, Univ Montpellier, Nîmes, France
Mathias Chéa

¹Department of Hematology, CHU Nîmes, Univ Montpellier, Nîmes, France
Chloé Bourguignon

¹Department of Hematology, CHU Nîmes, Univ Montpellier, Nîmes, France

³UMR UA11 INSERM IDESP - Montpellier University, France
Éva Nouvellon

¹Department of Hematology, CHU Nîmes, Univ Montpellier, Nîmes, France

³UMR UA11 INSERM IDESP - Montpellier University, France
Sylvie Bouvier

¹Department of Hematology, CHU Nîmes, Univ Montpellier, Nîmes, France

²Department of Hematology, Faculty of Pharmaceutical and Biological Sciences, Montpellier University, France

³UMR UA11 INSERM IDESP - Montpellier University, France

Abstract

Antiphospholipid antibodies (aPL Abs) have long been associated with the occurrence of certain specific pregnancy morbidities, affecting both mother and fetus. Antithrombotic-based prophylactic regimens are the standard of care. Their intensity is modulated by the thrombotic history and has greatly improved the prognosis related to spontaneous morbidity. Observational studies show that this treatment is still associated with the persistence of excess of late-pregnancy placental diseases, calling for new or complementary developments, yet to be validated. Rigorous prospective multicentric validation of clinical and laboratory parameters capable of identifying those women and fetuses at a risk of pejorative evolution, thus early prognosis, is a priority issue. These will make it possible to develop customized treatments and test them. Furthermore, there are still concerns, particularly neurodevelopmental ones, about children born to aPL Ab-positive mothers, and clarification based on regular, more systematic evaluations is required. Even after pregnancy, women with a pure obstetrical antiphospholipid syndrome are at a greater risk of venous and arterial thrombosis over time, and prevention needs to be improved. These women also appear to develop more psychiatric and mood disorders. Central nervous system imaging using high-resolution techniques has shown subtle impairments in the white matter, associated with the most pathogenic aPL Abs and the clinical significance of this is under investigation. These mothers also seem to develop an excess of cancers. The systemic impact of aPL Abs is gradually being suspected, although this requires further evidence, and prevention should be envisaged.

Keywords

antiphospholipid antibodies - pregnancy - placental disease - mother - neonate - thrombosis - psychiatric - cancer

Full Text

References

References
1 Conley CL. Disorders of the blood in disseminated lupus erythematosus. Am J Med 1952; 13 (01) 1-2
2 Feinstein DI, Rapaport SI. Acquired inhibitors of blood coagulation. Prog Hemost Thromb 1972; 1: 75-95
3 Harris EN, Gharavi AE, Boey ML. et al. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 1983; 2 (8361): 1211-1214
4 McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci U S A 1990; 87 (11) 4120-4124
5 Galli M, Comfurius P, Maassen C. et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990; 335 (8705): 1544-1547
6 Bevers EM, Galli M, Barbui T, Comfurius P, Zwaal RF. Lupus anticoagulant IgG's (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin. Thromb Haemost 1991; 66 (06) 629-632
7 Green D. Pathophysiology of antiphospholipid syndrome. Thromb Haemost 2021; 122 (07) 1085-1095
8 Arvieux J, Roussel B, Jacob MC, Colomb MG. Measurement of anti-phospholipid antibodies by ELISA using beta 2-glycoprotein I as an antigen. J Immunol Methods 1991; 143 (02) 223-229
9 Iverson GM, Victoria EJ, Marquis DM. Anti-beta2 glycoprotein I (beta2GPI) autoantibodies recognize an epitope on the first domain of beta2GPI. Proc Natl Acad Sci U S A 1998; 95 (26) 15542-15546
10 Galli M, Beretta G, Daldossi M, Bevers EM, Barbui T. Different anticoagulant and immunological properties of anti-prothrombin antibodies in patients with antiphospholipid antibodies. Thromb Haemost 1997; 77 (03) 486-491
11 Arnout J. The pathogenesis of the antiphospholipid syndrome: a hypothesis based on parallelisms with heparin-induced thrombocytopenia. Thromb Haemost 1996; 75 (04) 536-541
12 Müller-Calleja N, Lackner KJ. Mechanisms of cellular activation in the antiphospholipid syndrome. Semin Thromb Hemost 2018; 44 (05) 483-492
13 Müller-Calleja N, Hollerbach A, Royce J. et al. Lipid presentation by the protein C receptor links coagulation with autoimmunity. Science 2021; 371 (6534): eabc0956
14 Harris EN, Hughes GR, Gharavi AE. Antiphospholipid antibodies: an elderly statesman Dons new garments. J Rheumatol Suppl 1987; 14 (Suppl. 13) 208-213
15 Asherson RA, Khamashta MA, Ordi-Ros J. et al. The “primary” antiphospholipid syndrome: major clinical and serological features. Medicine (Baltimore) 1989; 68 (06) 366-374
16 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
17 Jiang H, Wang CH, Jiang N. et al. Clinical characteristics and prognosis of patients with isolated thrombotic vs. obstetric antiphospholipid syndrome: a prospective cohort study. Arthritis Res Ther 2021; 23 (01) 138
18 Schreiber K, Sciascia S, de Groot PG. et al. Antiphospholipid syndrome. Nat Rev Dis Primers 2018; 4: 17103
19 Viall CA, Chamley LW. Histopathology in the placentae of women with antiphospholipid antibodies: a systematic review of the literature. Autoimmun Rev 2015; 14 (05) 446-471
20 De Angelis V, Scurati S, Raschi E. et al. Pro-inflammatory genotype as a risk factor for aPL-associated thrombosis: report of a family with multiple anti-phospholipid positive members. J Autoimmun 2009; 32 (01) 60-63
21 Agostinis C, Biffi S, Garrovo C. et al. In vivo distribution of β2 glycoprotein I under various pathophysiologic conditions. Blood 2011; 118 (15) 4231-4238
22 Lambrianides A, Carroll CJ, Pierangeli SS. et al. Effects of polyclonal IgG derived from patients with different clinical types of the antiphospholipid syndrome on monocyte signaling pathways. J Immunol 2010; 184 (12) 6622-6628
23 Poulton K, Ripoll VM, Pericleous C. et al. Purified IgG from patients with obstetric but not IgG from non-obstetric antiphospholipid syndrome inhibit trophoblast invasion. Am J Reprod Immunol 2015; 73 (05) 390-401
24 Larosa M, Le Guern V, Guettrot-Imbert G, Morel N, Abisror N, Morati-Hafsaoui C. et al. Evaluation of lupus anticoagulant, damage, and remission as predictors of pregnancy complications in lupus women: the French GR2 study. Rheumatology (Oxford) 2022; Jan 7: keab943
25 Ünlü O, Zuily S, Erkan D. The clinical significance of antiphospholipid antibodies in systemic lupus erythematosus. Eur J Rheumatol 2016; 3 (02) 75-84
26 Garcia D, Erkan D. Diagnosis and management of the antiphospholipid syndrome. N Engl J Med 2018; 378 (21) 2010-2021
27 Hamulyák EN, Scheres LJJ, Goddijn M, Middeldorp S. Antithrombotic therapy to prevent recurrent pregnancy loss in antiphospholipid syndrome-what is the evidence?. J Thromb Haemost 2021; 19 (05) 1174-1185
28 Sevim E, Willis R, Erkan D. Is there a role for immunosuppression in antiphospholipid syndrome?. Hematology (Am Soc Hematol Educ Program) 2019; 2019 (01) 426-432
29 Scambi C, Ugolini S, Tonello M. et al. Complement activation in the plasma and placentas of women with different subsets of antiphospholipid syndrome. Am J Reprod Immunol 2019; 82 (06) e13185
30 Nalli C, Lini D, Andreoli L. et al. Low preconception complement levels are associated with adverse pregnancy outcomes in a multicenter study of 260 pregnancies in 197 women with antiphospholipid syndrome or carriers of antiphospholipid antibodies. Biomedicines 2021; 9 (06) 671
31 Gavriilaki E, Brodsky RA. Complementopathies and precision medicine. J Clin Invest 2020; 130 (05) 2152-2163
32 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
33 Gebhart J, Posch F, Koder S. et al. High risk of adverse pregnancy outcomes in women with a persistent lupus anticoagulant. Blood Adv 2019; 3 (05) 769-776
34 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
35 Popescu F, Jaslow CR, Kutteh WH. Recurrent pregnancy loss evaluation combined with 24-chromosome microarray of miscarriage tissue provides a probable or definite cause of pregnancy loss in over 90% of patients. Hum Reprod 2018; 33 (04) 579-587
36 Chauleur C, Galanaud JP, Alonso S. et al. Observational study of pregnant women with a previous spontaneous abortion before the 10th gestation week with and without antiphospholipid antibodies. J Thromb Haemost 2010; 8 (04) 699-706
37 Page JM, Christiansen-Lindquist L, Thorsten V. et al. Diagnostic tests for evaluation of stillbirth: results from the stillbirth collaborative research network. Obstet Gynecol 2017; 129 (04) 699-706
38 Marchetti T, de Moerloose P, Gris JC. Antiphospholipid antibodies and the risk of severe and non-severe pre-eclampsia: the NOHA case-control study. J Thromb Haemost 2016; 14 (04) 675-684
39 Gibbins KJ, Tebo AE, Nielsen SK, Branch DW. Antiphospholipid antibodies in women with severe preeclampsia and placental insufficiency: a case-control study. Lupus 2018; 27 (12) 1903-1910
40 Foddai SG, Radin M, Cecchi I. et al. The prevalence of antiphospholipid antibodies in women with late pregnancy complications and low-risk for chromosomal abnormalities. J Thromb Haemost 2020; 18 (11) 2921-2928
41 Girardi G, Yarilin D, Thurman JM, Holers VM, Salmon JE. Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J Exp Med 2006; 203 (09) 2165-2175
42 Kim MY, Buyon JP, Guerra MM. et al. Angiogenic factor imbalance early in pregnancy predicts adverse outcomes in patients with lupus and antiphospholipid antibodies: results of the PROMISSE study. Am J Obstet Gynecol 2016; 214 (01) 108.e1-108.e14
43 Cochery-Nouvellon É, Mercier É, Bouvier S. et al. Obstetric antiphospholipid syndrome: early variations of angiogenic factors are associated with adverse outcomes. Haematologica 2017; 102 (05) 835-842
44 Bitsadze V, Bouvier S, Khizroeva J. et al. Early ADAMTS13 testing associates with pre-eclampsia occurrence in antiphospholipid syndrome. Thromb Res 2021; 203: 101-109
45 Bergrem A, Jacobsen EM, Skjeldestad FE, Jacobsen AF, Skogstad M, Sandset PM. The association of antiphospholipid antibodies with pregnancy-related first time venous thrombosis—a population-based case-control study. Thromb Res 2010; 125 (05) e222-e227
46 Walter IJ, Klein Haneveld MJ, Lely AT, Bloemenkamp KWM, Limper M, Kooiman J. Pregnancy outcome predictors in antiphospholipid syndrome: a systematic review and meta-analysis. Autoimmun Rev 2021; 20 (10) 102901
47 Amengual O, Fujita D, Ota E. et al. Primary prophylaxis to prevent obstetric complications in asymptomatic women with antiphospholipid antibodies: a systematic review. Lupus 2015; 24 (11) 1135-1142
48 Fredi M, Andreoli L, Aggogeri E. et al. Risk factors for adverse maternal and fetal outcomes in women with confirmed apl positivity: results from a multicenter study of 283 pregnancies. Front Immunol 2018; 9: 864
49 Sammaritano LR, Bermas BL, Chakravarty EE. et al. 2020 American College of Rheumatology Guideline for the management of reproductive health in rheumatic and musculoskeletal diseases. Arthritis Rheumatol 2020; 72 (04) 529-556
50 Liu L, Sun D. Pregnancy outcomes in patients with primary antiphospholipid syndrome: a systematic review and meta-analysis. Medicine (Baltimore) 2019; 98 (20) e15733
51 Alijotas-Reig J, Esteve-Valverde E, Ferrer-Oliveras R. et al; EUROAPS Study Group. The European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS): a survey of 1000 consecutive cases. Autoimmun Rev 2019; 18 (04) 406-414
52 Chayoua W, Kelchtermans H, Moore GW. et al. Detection of anti-cardiolipin and Anti-β2glycoprotein I antibodies differs between platforms without influence on association with clinical symptoms. Thromb Haemost 2019; 119 (05) 797-806
53 Chayoua W, Kelchtermans H, Gris JC. et al. The (non-)sense of detecting anti-cardiolipin and anti-β2glycoprotein I IgM antibodies in the antiphospholipid syndrome. J Thromb Haemost 2020; 18 (01) 169-179
54 Yin D, Chayoua W, Kelchtermans H. et al. Detection of anti-domain I antibodies by chemiluminescence enables the identification of high-risk antiphospholipid syndrome patients: a multicenter multiplatform study. J Thromb Haemost 2020; 18 (02) 463-478
55 Chayoua W, Yin DM, Kelchtermans H. et al. Is there an additional value in detecting anticardiolipin and anti-β2 glycoprotein I iga antibodies in the antiphospholipid syndrome?. Thromb Haemost 2020; 120 (11) 1557-1568
56 Vandevelde A, Chayoua W, de Laat B. et al. Semiquantitative interpretation of anticardiolipin and antiβ2glycoprotein I antibodies measured with various analytical platforms: communication from the ISTH SSC Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies. J Thromb Haemost 2022; 20 (02) 508-524
57 Abisror N, Nguyen Y, Marozio L, Esteve Valverde E, Udry S, Pleguezuelo DE. et al. Obstetrical outcome and treatments in seronegative primary APS: data from European retrospective study. RMD Open 2020; 6 (02) e001340
58 Alijotas-Reig J, Esteve-Valverde E, Ferrer-Oliveras R. et al; EUROAPS Study Group. Comparative study of obstetric antiphospholipid syndrome (OAPS) and non-criteria obstetric APS (NC-OAPS): report of 1640 cases from the EUROAPS registry. Rheumatology (Oxford) 2020; 59 (06) 1306-1314
59 Tincani A, Rebaioli CB, Andreoli L, Lojacono A, Motta M. Neonatal effects of maternal antiphospholipid syndrome. Curr Rheumatol Rep 2009; 11 (01) 70-76
60 Boffa MC, Lachassinne E. Infant perinatal thrombosis and antiphospholipid antibodies: a review. Lupus 2007; 16 (08) 634-641
61 Nacinovich R, Galli J, Bomba M. et al. Neuropsychological development of children born to patients with antiphospholipid syndrome. Arthritis Rheum 2008; 59 (03) 345-351
62 Abisror N, Mekinian A, Lachassinne E. et al. Autism spectrum disorders in babies born to mothers with antiphospholipid syndrome. Semin Arthritis Rheum 2013; 43 (03) 348-351
63 Mekinian A, Lachassinne E, Nicaise-Roland P. et al. European registry of babies born to mothers with antiphospholipid syndrome. Ann Rheum Dis 2013; 72 (02) 217-222
64 Chighizola CB, Crisafulli F, Hoxha A. et al; SIRyoung. Psychosocial burden in young patients with primary anti-phospholipid syndrome: an Italian nationwide survey (The AQUEOUS study). Clin Exp Rheumatol 2021; 39 (05) 938-946
65 Durigutto P, Grossi C, Borghi MO. et al. New insight into antiphospholipid syndrome: antibodies to β2glycoprotein I-domain 5 fail to induce thrombi in rats. Haematologica 2019; 104 (04) 819-826
66 Gris JC, Bouvier S, Molinari N. 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 (11) 2624-2632
67 Tonello M, Calligaro A, Favaro M. et al. The first thrombotic event in purely obstetric antiphospholipid syndrome patients and in antiphospholipid antibody carriers: comparison of incidence and characteristics. Arch Gynecol Obstet 2021; 303 (02) 455-461
68 Gris JC, Cyprien F, Bouvier S. et al. Antiphospholipid antibodies are associated with positive screening for common mental disorders in women with previous pregnancy loss. The NOHA-PSY observational study. World J Biol Psychiatry 2019; 20 (01) 51-63
69 Pereira FR, Macri F, Jackowski MP. et al. Diffusion tensor imaging in patients with obstetric antiphospholipid syndrome without neuropsychiatric symptoms. Eur Radiol 2016; 26 (04) 959-968
70 Gris JC, Mousty É, Bouvier S. et al. Increased incidence of cancer in the follow-up of obstetric antiphospholipid syndrome within the NOH-APS cohort. Haematologica 2020; 105 (02) 490-497
71 Hamulyák EN, Scheres LJ, Marijnen MC, Goddijn M, Middeldorp S. Aspirin or heparin or both for improving pregnancy outcomes in women with persistent antiphospholipid antibodies and recurrent pregnancy loss. Cochrane Database Syst Rev 2020; 5 (05) CD012852
72 Bao SH, Sheng SL, Liao H, Zhou Q, Frempong ST, Tu WY. Use of D-dimer measurement to guide anticoagulant treatment in recurrent pregnancy loss associated with antiphospholipid syndrome. Am J Reprod Immunol 2017; 78 (06)
73 Mekinian A, Bourrienne MC, Carbillon L. et al. Non-conventional antiphospholipid antibodies in patients with clinical obstetrical APS: Prevalence and treatment efficacy in pregnancies. Semin Arthritis Rheum 2016; 46 (02) 232-237
74 Giacomelli R, Afeltra A, Bartoloni E. et al. The growing role of precision medicine for the treatment of autoimmune diseases; results of a systematic review of literature and Experts' Consensus. Autoimmun Rev 2021; 20 (02) 102738