Pregnancy Outcome in Women with Antiphospholipid Antibodies: Report on a Retrospective Study

ABSTRACT

Antiphospholipid syndrome (APS) represents a serious risk factor in pregnancy resulting in several complications, leading to fetal loss and hemostatic complications. In this dedicated report, we describe our experiences in the treatment of pregnancies in patients with APS. The retrospective data from 140 pregnant women were investigated, and the treatment results of 121 patients were recorded. We studied two groups of patients receiving different treatment. The first group (n = 78) received the standard therapy with low-weight-molecular heparin (dalteparin 5000 U or certoparin 3000 U daily) and aspirin (100 mg daily) and in the second group (n = 43) an additional 0.2 g/kg intravenous immunoglobulin (IVIG). Outcomes were 74.3% and 83.7% live births in the first group and in the second group, respectively. The abortion rate was similar in both groups (11.5% vs. 11.6%). The late complication rate was lower in the second group (5.8% vs. 14.1%, p < 0.05) than in the group with standard therapy. Interestingly, we found a trend to higher percentage (> 12%) of natural killer (NK) cells in patients with pregnancy complications (60% vs. 12%, p < 0.05). Our retrospective data shows an improvement of late pregnancy complications by additional use of IVIG. It is possible that IVIG influences higher NK cell activity in patients with previous pregnancy complications.

KEYWORDS

Antiphospholipid syndrome - pregnancy - low-molecular-weight heparin - certoparin - dalteparin - intravenous immunoglobulins

REFERENCES

• 1 Birdsall M A, Lockwood G M, Ledger W L. Antiphospholipid antibodies in women having in-vitro fertilization.  Hum Reprod. 1996;  11 1185-1189
• 2 Carp H JA. Antiphospholipid syndrome in pregnancy.  Curr Opin Obstet Gynecol. 2004;  16 129-135
• 3 Cervera R, Piette J C, Font J, Khamashta M A. for the Euro-Phospholipid project group . Antiphospholipid syndrome.  Arthritis Rheum. 2002;  46 1019-1027
• 4 Katano K, Aoki A, Sasa H et al.. β 2-glykoprotein1-dependent anticardiolipin antibodies as a predictor of adverse pregnancy outcomes in healthy pregnant women.  Hum Reprod. 1996;  11 509-512
• 5 Pattison N S, Chamley L W, McKay E J et al.. Antiphospholipid-antibodies in pregnancy: prevalence and clinical association.  Br J Obstet Gynaecol. 1993;  100 909-913
• 6 Schleussner E. Impact of the antiphospholipid syndrome on complications during pregnancy.  Transfus Med Hemother. 2006;  33 486-492
• 7 Yasuda M, Takakuwa K, Tokunaga A, Tanaka K. Prospective studies of the association between anticardiolipin antibody and outcome of pregnancy.  Obstet Gynecol. 1995;  86 555-559
• 8 Carp H JA. Intravenous immunoglobulin: effect on infertility and recurrent pregnancy loss.  Israel Medical Association Journal. 2007;  9 877-880
• 9 Clark D A, Coulam C B, Stricker R B. Is intravenous immunoglobulins (IVIG) efficacious in early pregnancy failure? A critical review and metaanalysis for patients who fail in vitro fertilization and embryo transfer(IVF).  J Assist Reprod Genet. 2006;  23 1-13
• 10 Canesi B, Brucato A. Antiphospholipid antibodies and pregnancy.  Haematologica Reports. 2005;  1 6-12
• 11 Galli M, Barbui T. Antiphospholipid antibodies and pregnancy.  Best Pract Res Clin Haematol. 2003;  16 211-225
• 12 Salmon J E, de Groot P G. Pathogenic role of antiphospholipid antibodies.  Lupus. 2008;  17 405-411
• 13 Kutteh W H. 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
• 14 Vashisht A, Regan L. Antiphospholipid syndrome in pregnancy—an update.  J R Coll Physicians (Edinburg). 2005;  35 337-339
• 15 Bates S M, Greer I A, Hirsh J, Ginsberg J S. Use of antithrombotic agents during pregnancy: the Seventh ACCP Conference on antithrombotic and thrombolytic therapy.  Chest. 2004;  127(suppl 3) 627-644
• 16 Empson M, Lassere M, Craig J C, Scott J R. Recurrent pregnancy loss with antiphospholipid antibody. A systematic review of therapeutic trials.  Obstet Gynecol. 2002;  99 135-144
• 17 Stephenson M D, Ballem P J, Tsang P et al.. Treatment of antiphospholipid antibody syndrome (APS) in pregnancy: a randomized pilot trial comparing low molecular heparin to unfractionated heparin.  J Obstet Gynaecol Canada. 2004;  26 729-734
• 18 Branch W, Khamashta M A. Antiphospholipid syndrome: obstetric diagnosis. Management and controversies.  Obstet Gynecol. 2003;  101 1333-1344
• 19 Brandt J T, Triplett D A, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update.  Thromb Haemost. 1995;  74 1185-1190
• 20 Lim W, Crowther M A, Eikelboom J W. Management of antiphospholipid antibody syndrome: a systematic review.  JAMA. 2006;  295 1050-1057
• 21 Lynch A M, Rutledge J H, Stephens J K et al.. Longitudinal measurement of anti-cardiolipin antibodies during normal pregnancy:a prospective study.  Lupus. 1995;  4 365-369
• 22 Tincani A, Bazzani C, Zingarelli S, Lojacono A. Lupus and the antiphopsholipid syndrome in pregnancy and obstectrics: clinical characteristics, diagnosis, pathogenesis and treatment.  Semin Thromb Hemost. 2008;  34 267-273
• 23 Pierangeli S S, Chen P P, Raschi E et al.. Antiphospholipid antibodies and the antiphospholipid syndrome: pathogenic mechanisms.  Semin Thromb Hemost. 2008;  34 236-250
• 24 Ogasawara M, Sasa H, Katano K et al.. Recurrent abortion and moderate or strong antiphospholipid antibody production.  Int J Gynaecol Obstet. 1998;  62 183-188
• 25 Tincani A, Branch W, Levy R A et al.. Treatment of patients with antiphospholipid syndrome.  Lupus. 2003;  12 524-529
• 26 Backos M, Rai R, Baxter N. Pregnancy complications in women with recurrent miscarriage associated with antiphospholipid antibodies treated with low dose aspirin and heparin.  Br J Obstet Gynaecol. 1999;  106 102-107
• 27 Cowchock S. Prevention of fetal death in the antiphospholipid antibody syndrome.  Lupus. 1996;  5 467-472
• 28 Clark A L, Branch D W, Silver R M. Pregnancy complicated by the antiphospholipid syndrome: outcomes with intravenous immunoglobulin therapy.  Obstet Gynecol. 1999;  93 437-441
• 29 Alarcon-Segovia D, Boffa M C, Branch W et al.. Prophylaxis of the antiphospholipid syndrome: a consensus report.  Lupus. 2003;  12 499-503
• 30 Greaves M, Cohen H, MacHin S J, Mackie I. Guidelines on the investigation and management of the antiphospholipid syndrome.  Br J Haematol. 2000;  109 704-715
• 31 Chang P, Millar D, Tsang P et al.. Intravenous immunoglobulin in antiphospholipid syndrome and maternal floor infarction when standard treatment fails: a case report.  Am J Perinatol. 2006;  23 125-129
• 32 Cowchock S. Treatment of antiphospholipid syndrome in pregnancy.  Lupus. 1998;  17 95-97
• 33 Farquharson R G, Jauniaux E, Exalto N. Updated and revised nomenclature for description of early pregnancy events.  Hum Reprod. 2005;  20 3008-3011
• 34 Huong D LT, Wechsler B, Bletry O, Vaunthier-Brouzes D, Lefebvre G, Piette J-C. A study of 75 pregnancies in patients with antiphospholipid syndrome.  J Rheumatol. 2001;  28 2025-2030
• 35 Carp H JA, Asherson R A, Shoenfeld Y. Intravenous immunglobulin in pregnancies complicated by the antiphospholipid syndrome: what is its role.  J Clin Rheumatol. 2001;  7 291-294
• 36 Perricone C, Carolis C D, Giacomelli R et al.. High levels of NK cells in the peripheral blood of patients affected with antiphospholipid syndrome and recurrent spontaneous abortion: a potential new hypothesis.  Rheumatology. 2007;  46 1574-1578
• 37 Aoki K, Hayashi Y, Hirao Y, Yagami Y. Specific antiphospholipid antibodies as a predictive variable in patients with recurrent pregnancy loss.  Am J Reprod Immunol. 1993;  29 82-87
• 38 Emmer P M, Nelen W LDM, Steegers E AP, Hendriks J CM, Veerkoek M, Joosten I. Peripheral natural killer cell cytotoxicity and CD56pos CD16 pos cells increase during early pregnancy in women with a history of recurrent spontaneous abortion.  Hum Reprod. 2000;  15 1163-1169
• 39 Van den Heuvel M J, Crystal G P, Hatta K, Han V K, Clark D A. Decline in number of elevated blood CD3+ CD56+ NKT cells in response to intravenous immunoglobulin treatment correlates with successful pregnancy.  Am J Reprod Immunol. 2007;  58 447-459
• 40 Veenstra van Nieuwenhoven A L, Heinemann M J, Faas M M. The immunology of successful pregnancy.  Hum Reprod Update. 2003;  9 347-357
• 41 Beer A E, Kwaak T Y, Ruiz J E. Immunophenotypic profiles of peripheral blood lymphocytes in women with recurrent pregnancy loss and infertile women with multiple failed in vitro fertilization cycles.  Am J Reprod Immunol. 1996;  35 376-382
• 42 Coulam C B, Beaman K D. Reciprocal alteration in circulating TJ6+ CD19+ and TJ6+ CD56+ leukocytes in early pregnancy predict success or miscarriage.  Am J Reprod Immunol. 1995;  34 219-224
• 43 Kwak-Kim J, Gillman-Sachs A. Clinical implication of natural killer cells and reproduction.  Am J Reprod Immunol. 2008;  59 388-400
• 44 Vila P, Hernandez M C, Lopez-Fernandez M F. Prevalence, follow-up and clinical significance of the anticardiolipin antibodies in normal subjects.  Thromb Haemost. 1994;  72 209-213
• 45 Keskin D B, David S, Allan J et al.. TGFß promotes conversion of CD16+ peripheral blood NK cells into CD16-NK cells with similarities to decidual NK cells.  Proc Natl Acad Sci U S A. 2007;  104 3378-3383
• 46 Sacks G, Fay L, Smith S, Russell P, Chapman M. NK cells analysis in women with recurrent reproductive failure; there is a clinical correlation between peripheral blood and endometrial biopsy samples.  The Royal Australian and New Zeeland College of Obstetricians and Gynecologists. 2007;  47(Suppl 1) A27-28
• 47 Varla-Leftherioti M, Spyropoulou-Vlachou M, Niokou D et al.. Natural killer (NK) cell receptors repertoire in couples with recurrent spontaneous abortions.  Am J Reprod Immunol. 2003;  49 183-191
• 48 Varla-Leftherioti M, Spyropoulou-Vlachou M, Keramitsoglou T. Lack of the appropriate natural killer cell inhibitory receptors in women with spontaneous abortion.  Hum Immunol. 2005;  66 65-71
• 49 Wilson W A, Harris N. Management of antiphospholipid syndrome in pregnancy. In: Carp HJA Recurrent Pregnancy Loss. London, United Kingdom; Informa Healthcare 2007: 119-125
• 50 Vacca P, Pietra G, Falco M et al.. Analysis of natural killer cells isolated from human decidua: evidence that 2B4(CD244) functions as an inhibitory receptor and blocks NK-.cell function.  Blood. 2006;  108 4078-4085
• 51 Yamada H, Shimada S, Kato E H et al.. Decrease in a specific killer cell immunoglobulin-like receptor on peripheral natural killer cells in women with recurrent spontaneous abortion of unexplained etiology.  Am J Reprod Immunol. 2004;  51 241-247
• 52 Yamada H, Shimada S, Morikawa M et al.. Divergence of natural killer cell receptor and related molecule in the decidua from sporatic miscarriage with normal chromosome karyotype.  Mol Hum Reprod. 2005;  11 451-457
• 53 Hiby S E, Regan L, Lo W, Farrell L, Carrington M, Moffet A. Association of maternal killer-cell immunoglobulin-like receptor and parental HLA-C genotypes with recurrent miscarriage.  Hum Reprod. 2008;  23 972-976
• 54 Witt C S, Goodridge J, Gerbase-Delina M G, Daher S, Christiansen F T. Maternal KIR repertoire is not associated with recurrent spontaneous abortion.  Hum Reprod. 2004;  19 2653-2657
• 55 Wilson W A, Gharavi A E, Koike T et al.. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome. Report of an international workshop.  Arthritis Rheum. 1999;  42 1309-1311
• 56 Lockshin M D, Sammaritano L R, Schwartzman S. Validation of the Sapporo criteria for antiphospholipid syndrome.  Arthritis Rheum. 2000;  43 440-443
• 57 Bertolaccini M L, Khamashta M A. Laboratory diagnosis and management challenges in the antiphospholipid syndrome.  Lupus. 2006;  15 172-178
• 58 Franklin R D, Hollier N, Kutteh W H. β2-Glycoprotein 1 as a marker of antiphospholipid syndrome in women with recurrent pregnancy loss.  Fertil Steril. 2000;  73 531-535
• 59 Carmo-Pereira S, Bertolaccini M L, Escudero-Contres A et al.. Value of IgA anticardiolipin and anti-B-2 glycoprotein 1 antibody testing in patients with pregnancy morbidity.  Ann Rheum Dis. 2003;  62 540-543
• 60 Chong P, Matzner W, Ching W. Correlation between beta-2-glycoprotein antibodies and antiphospholipid antibodies in patients with reproductive failure.  Am J Reprod Immunol. 1998;  40 414-417
• 61 Kiprov D D, Nachtigall R D, Weavers R C, Jacobson A, Main E K, Garvoy M R. The use of intravenous immunoglobulin in recurrent pregnancy loss associated with combined alloimmune and autoimmune abnormalities.  Am J Reprod Immunol. 1996;  36 228-234
• 62 Stojanovich L, Mikovic Z, Mandic V, Popvid-Kuzmanovic D. Treatment of antiphospholipid-syndrome in pregnancy with low dose of intravenous immunoglobulin.  Isr Med Assoc J. 2007;  9 555-556
• 63 Lynch A, Mariar R, Murphy J et al.. Antiphospholipid antibodies in predicting adverse pregnancy outcome.  Ann Intern Med. 1994;  120 470-475
• 64 Kaira S, Tuli A, Goyal U, Choudhary R, Raheja S. Correlation of antiphospholipid antibody IgM with first trimester recurrent abortion.  J Anat Soc India. 2002;  51 10-13
• 65 Lockwood C J, Omero R, Feinburg R F, Clyne L P, Coster B, Hobbins J C. The prevalence and biologic significance of lupus anticoagulant and anticardiolipin antibodies in a general population.  Am J Obstet Gynecol. 1989;  161 369-373
• 66 Fialova L, Mikolikova L, Matous-Malbohan I, Benesova O, Zwinger A. Prevalence of various antiphospholipid antibodies in pregnant women.  Physiol Res. 2000;  49 299-305
• 67 Branch D W, Andres R, Digre K B, Rote N S, Scott J R. The association of antiphospholipid antibodies with severe preeclampsia.  Obstet Gynecol. 1989;  73 541-545
• 68 Barbui T, Cortelazzo S, Galli M et al.. Antiphospholipid antibodies in early repeated abortions: a case-controlled study.  Fertil Steril. 1988;  50 589-592
• 69 Soltesz P, Veres K, Lakos G, Kiss E, Muszbek L, Szegedi G. Evaluation of clinical and laboratory features of antiphospholipid syndrome: a retrospective study of 637 patients.  Lupus. 2003;  12 302-307
• 70 Konova E, Ivanova I, Petrova P et al.. Effect of intravenous gamma-globulin therapy on lymphocyte population in pregnant women with antiphospholipid antibodies.  Akush Ginekol (Sofiia). 2004;  43 3-10
• 71 Branch D W, Peacman A M, Druzin M. A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. The pregnancy loss study group.  Am J Obstet Gynecol. 2000;  182 122-127
• 72 Vaquero E, Lazzarin N, Valensise H. Pregnancy outcome in recurrent spontaneous abortion associated with antiphospholipid antibodies: a comparative study of intravenous immunoglobulin versus prednisone plus low dose aspirin.  Am J Reprod Immunol. 2001;  45 174-179
• 73 Valensise H, Vaquero E, de Carolis C. Normal fetal growth in women with antiphospholipid syndrome treated with high dose intravenous immunoglobulin (IVIG).  Prenat Diagn. 1995;  15 97-102
• 74 Giannakopoulos B, Passam F, Rahgozar S, Krilis S A. Current concepts on the pathogenesis of the antiphospholipid syndrome.  Blood. 2007;  109 422-425
• 75 Wang S, Zhao Y R, Jiao Y L et al.. Increased activating killer immunoglobulin-like receptor genes and decreased specific HLA-C alleles in couples with recurrent spontaneous abortion.  Biochem Biophys Res Commun. 2007;  360 696-701
• 76 Caruso A D, Carolis S, Simone N. Antiphospholipid antibodies in obstetrics: new complexities and sites of action.  Hum Reprod. 1999;  5 267-276
• 77 Perricone C, Carolis C D, Giacomelli R et al.. High levels of NK cells in the peripheral blood of patients affected with antiphospholipid syndrome and recurrent spontaneous abortion: a potential new hypothesis.  Rheumatology. 2007;  46 1574-1578
• 78 Sargent I L, Borzychowski A M, Redman C WG. NK cells and preeclampsia.  J Reprod Immunol. 2007;  76 40-44
• 79 Radder C M, Roelen D L, van de Meer-Prind E M et al.. The immunologic profile of infants born after maternal immunoglobulin treatment and intrauterine platelet transfusion for fetal/alloimmune thrombozytopenia.  Am J Obstet Gynecol. 2004;  191 815-820