Preconception anti-annexin A5 antibodies are associated with subsequent live birth in women with recurrent miscarriage: A retrospective study from China.

Publisher: Wiley-Blackwell Country of Publication: Denmark NLM ID: 8912860 Publication Model: Print Cited Medium: Internet ISSN: 1600-0897 (Electronic) Linking ISSN: 10467408 NLM ISO Abbreviation: Am J Reprod Immunol Subsets: MEDLINE

Publication: Copenhagen : Wiley-Blackwell
Original Publication: New York : Alan R. Liss, Inc., c1989-

Live Birth* ; Abortion, Habitual*/epidemiology ; Aziridines* ; Benzoquinones*; Pregnancy ; Female ; Humans ; Retrospective Studies ; Annexin A5 ; China/epidemiology

Problem: To evaluate the correlation between the antiannexin A5 antibodies (aAnxA5) multiples of median (MOM) and subsequent pregnancy outcomes in women with recurrent miscarriage (RM).
Methods: Totally, 310 RM women were included in this study and grouped into tertiles according to their MOM of preconception aAnxA5 circulating levels determined by ELISA. The effect of aAnxA5 on the pregnancy outcomes was performed using multiple logistic regression. The outcomes included early miscarriage (before 10 weeks of gestation), late miscarriage (between 10 and 24 weeks), ongoing pregnancy (beyond 10 weeks), and live birth (after 24 weeks) characterized by pregnancy with fetal heartbeat.
Results: For each unit increase in aAnxA5 MOM, the odds of live birth after 24 weeks and ongoing pregnancy were reduced by 40.2% (OR = .598; 95%CI 0.406-0.882, P = .010) and 38.1% (OR = .619; 95%CI 0.424-0.904, P = .013), respectively, after adjusting for demographic and clinical characteristics. The rise in aAnxA5 MOM was associated with an increased risk of early miscarriage (OR = 1.616; 95%CI 1.106-2.361, P = .013) and miscarriage (early + late miscarriage) (OR = 1.671; 95%CI 1.134-2.464, P = .010). Further subgroup analyses showed a decreased risk of live birth rates after 24 weeks of gestation in the two subgroups: maternal age ≥35 years (OR = .131; 95%CI 0.026-0.652), and previous pregnancy loss ≥ 3 (OR = .381; 95%CI 0.173-0.837).
Conclusions: Higher preconception aAnxA5 MOM levels in women with RM may be linked with a decreased risk of live birth after 24 weeks and an increased risk of early miscarriage, especially in individuals aged ≥35 years or with previous pregnancy losses ≥3.
(© 2024 The Authors. American Journal of Reproductive Immunology published by John Wiley & Sons Ltd.)

RPL EGGo, Bender Atik R, Christiansen OB, et al, RPL EGGo. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2018;2018(2):hoy004.
Green DM, O'Donoghue K. A review of reproductive outcomes of women with two consecutive miscarriages and no living child. J Obstet Gynaecol. 2019;39(6):816-821.
Wu Y, Xin M, Han Q, et al. Extensive serum biomarker analysis in the prethrombotic state of recurrent spontaneous abortion. J Cell Mol Med. 2021;25(14):6679-6694.
Jaslow CR, Carney JL, Kutteh WH. Diagnostic factors identified in 1020 women with two versus three or more recurrent pregnancy losses. Fertil Steril. 2010;93(4):1234-1243.
Shapira E, Ratzon R, Shoham-Vardi I, Serjienko R, Mazor M, Bashiri A. Primary vs. secondary recurrent pregnancy loss-epidemiological characteristics, etiology, and next pregnancy outcome. J Perinat Med. 2012;40(4):389-396.
Wang XH, Song XH, Wang YL, et al. Expanded alleles of the FMR1 gene are related to unexplained recurrent miscarriages. Biosci Rep. 2017;37(6).
Su N, Wang H, Zhang B, et al. Maternal natural killer cell immunoglobulin receptor genes and human leukocyte antigen-C ligands influence recurrent spontaneous abortion in the Han Chinese population. Exp Ther Med. 2018;15(1):327-337.
Morita K, Ono Y, Takeshita T, et al. Risk factors and outcomes of recurrent pregnancy loss in Japan. J Obstet Gynaecol Res. 2019;45(10):1997-2006.
Xu T, Lun W, Wang P, He Y. Analysis of risk factors and pregnancy outcomes in pregnant women with subchorionic hematoma. Medicine (Baltimore). 2023;102(47):e35874.
Tong M, Viall CA, Chamley LW. Antiphospholipid antibodies and the placenta: a systematic review of their in vitro effects and modulation by treatment. Hum Reprod Update. 2015;21(1):97-118.
Abisror N, Nguyen Y, Marozio L, et al. Obstetrical outcome and treatments in seronegative primary APS: data from European retrospective study. RMD Open. 2020;6(2).
Alijotas-Reig J, Esteve-Valverde E, Anunciacion-Llunell A, Marques-Soares J, Pardos-Gea J, Miro-Mur F. Pathogenesis, diagnosis and management of obstetric antiphospholipid syndrome: a comprehensive review. J Clin Med. 2022;11(3).
Rand JH, Arslan AA, Wu XX, et al. Reduction of circulating annexin A5 levels and resistance to annexin A5 anticoagulant activity in women with recurrent spontaneous pregnancy losses. Am J Obstet Gynecol. 2006;194(1):182-188.
Zhang R, Lu W, Wen X, et al. Annexin A5-conjugated polymeric micelles for dual SPECT and optical detection of apoptosis. J Nucl Med. 2011;52(6):958-964.
Chaurio RA, Janko C, Muñoz LE, Frey B, Herrmann M, Gaipl US. Phospholipids: key players in apoptosis and immune regulation. Molecules. 2009;14(12):4892-4914.
Karata S, Aydin Y, Ocer F, Buyru A, Balci H. Hereditary thrombophilia, anti-beta2 glycoprotein 1 IgM, and anti-annexin V antibodies in recurrent pregnancy loss. Am J Reprod Immunol. 2012;67(3):251-255.
Singh NK, Yadav DP, Gupta A, Singh U, Godara M. Role of anti-annexin A5 in pathogenesis of hypercoagulable state in patients with antiphospholipid syndrome. Int J Rheum Dis. 2013;16(3):325-330.
Ueki H, Mizushina T, Laoharatchatathanin T, et al. Loss of maternal annexin A5 increases the likelihood of placental platelet thrombosis and foetal loss. Sci Rep. 2012;2:827.
Rand JH, Wu XX, Lin EY, Griffel A, Gialanella P, McKitrick JC. Annexin A5 binds to lipopolysaccharide and reduces its endotoxin activity. mBio. 2012;3(2).
Bizzaro N, Tonutti E, Villalta D, Tampoia M, Tozzoli R. Prevalence and clinical correlation of anti-phospholipid-binding protein antibodies in anticardiolipin-negative patients with systemic lupus erythematosus and women with unexplained recurrent miscarriages. Arch Pathol Lab Med. 2005;129(1):61-68.
Becarevic M, Singh S, Majkic-Singh N. Oxidized LDL, anti-oxidized LDL and anti-annexin A5 antibodies in primary antiphospholipid syndrome. Clin Lab. 2008;54(3-4):97-101.
Bećarević M, Stojanović L, Ignjatović S, Dopsaj V. The IgM isotype of anti-annexin A5 antibodies and multiple positivity of conventional antiphospholipid antibodies: increasing the number of clinical manifestations of primary antiphospholipid syndrome. Clin Rheumatol. 2016;35(5):1361-1365.
Nojima J, Kuratsune H, Suehisa E, et al. Association between the prevalence of antibodies to beta(2)-glycoprotein I, prothrombin, protein C, protein S, and annexin V in patients with systemic lupus erythematosus and thrombotic and thrombocytopenic complications. Clin Chem. 2001;47(6):1008-1015.
Alijotas-Reig J, Ferrer-Oliveras R, Rodrigo-Anoro MJ, et al. Anti-annexin A5 antibodies in women with spontaneous pregnancy loss. Med Clin (Barc). 2010;134(10):433-438.
Zhang S, Wu Z, Li J, et al. Evaluation of the clinical relevance of anti-annexin-A5 antibodies in Chinese patients with antiphospholipid syndrome. Clin Rheumatol. 2016;36(2):407-412.
Fink AM, Kottas-Heldenberg A, Mayer W, et al. Lupus anticoagulant and venous leg ulceration. Br J Dermatol. 2002;146(2):308-310.
Vranken G, Reynolds T, Van Nueten J. Medians for second-trimester maternal serum markers: geographical differences and variation caused by median multiples-of-median equations. J Clin Pathol. 2006;59(6):639-644.
Magnus MC, Wilcox AJ, Morken NH, Weinberg CR, Håberg SE. Role of maternal age and pregnancy history in risk of miscarriage: prospective register based study. BMJ (Clinical Research ed). 2019;364:l869.
Dimitriadis E, Menkhorst E, Saito S, Kutteh WH, Brosens JJ. Recurrent pregnancy loss. Nat Rev Dis Primers. 2020;6(1):98.
Veleva Z, Tiitinen A, Vilska S, et al. High and low BMI increase the risk of miscarriage after IVF/ICSI and FET. Hum Reprod. 2008;23(4):878-884.
Raatikainen K, Heiskanen N, Heinonen S. Transition from overweight to obesity worsens pregnancy outcome in a BMI-dependent manner. Obesity (Silver Spring, Md). 2006;14(1):165-171.
Bećarević M. The IgG and IgM isotypes of anti-annexin A5 antibodies: relevance for primary antiphospholipid syndrome. J Thromb Thrombolysis. 2016;42(4):552-557.
Gerke V, Moss SE. Annexins: from structure to function. Physiol Rev. 2002;82(2):331-371.
Iaccarino L, Ghirardello A, Canova M, et al. Anti-annexins autoantibodies: their role as biomarkers of autoimmune diseases. Autoimmun Rev. 2011;10(9):553-558.
Irman S, Skarabot M, Muševič I, Rozman B, Božič B. The use of atomic force microscopy to study the pathologic effects of anti-annexin autoantibodies. J Autoimmun. 2011;36(2):98-105.
Esposito G, Tamby MC, Chanseaud Y, Servettaz A, Guillevin L, Mouthon L. Anti-annexin V antibodies: are they prothrombotic? Autoimmun Rev. 2005;4(1):55-60.
Krikun G, Lockwood CJ, Wu XX, et al. The expression of the placental anticoagulant protein, annexin V, by villous trophoblasts: immunolocalization and in vitro regulation. Placenta. 1994;15(6):601-612.
Wang X, Campos B, Kaetzel MA, Dedman JR. Annexin V is critical in the maintenance of murine placental integrity. Am J Obstet Gynecol. 1999;180(4):1008-1016.
Zammiti W, Mtiraoui N, Kallel C, Mercier E, Almawi WY, Mahjoub T. A case-control study on the association of idiopathic recurrent pregnancy loss with autoantibodies against β2-glycoprotein I and annexin V. Reproduction. 2006;131(4):817-822.
Quenby S, Gallos ID, Dhillon-Smith RK, et al. Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss. Lancet. 2021;397(10285):1658-1667.
Bortoletto P, Lucas ES, Melo P, et al. Miscarriage syndrome: linking early pregnancy loss to obstetric and age-related disorders. EBioMedicine. 2022;81:104134.
Schliep KC, Hinkle SN, Kim K, et al. Prospectively assessed perceived stress associated with early pregnancy losses among women with history of pregnancy loss. Hum Reprod. 2022;37(10):2264-2274.
Sugiura-Ogasawara M. Recurrent pregnancy loss and obesity. Best Pract Res Clin Obstet Gynaecol. 2015;29(4):489-497.

071100132 Science Foundation of Lanzhou University; YJS-BD-19 Science Foundation of Lanzhou University Second Hospital; lzuyxcx-2022-137 Medical Innovation and Development Project of Lanzhou University

Keywords: anti-annexin A5 antibodies; live birth; miscarriage; multiples of median; recurrent miscarriage

0 (Annexin A5)
FQL5EUP13W (diaziquone)
0 (Aziridines)
0 (Benzoquinones)

Date Created: 20240226 Date Completed: 20240227 Latest Revision: 20240227

20240227

10.1111/aji.13822

38407361