Elsevier

Autoimmunity Reviews

Volume 13, Issue 8, August 2014, Pages 795-813
Autoimmunity Reviews

Review
14th International Congress on Antiphospholipid Antibodies Task Force Report on Obstetric Antiphospholipid Syndrome

https://doi.org/10.1016/j.autrev.2014.02.003Get rights and content

Abstract

Pregnancy morbidity is one of the clinical manifestations used for classification criteria of antiphospholipid syndrome (APS). During the 14th International Congress on Antiphospholipid Antibodies (aPL), a Task Force with internationally-known experts was created to carry out a critical appraisal of the literature available regarding the association of aPL with obstetric manifestations present in actual classification criteria (recurrent early miscarriage, fetal death, preeclampsia and placental insufficiency) and the quality of the evidence that treatment(s) provide benefit in terms of avoiding recurrent adverse obstetric outcomes. The association of infertility with aPL and the effectiveness of the treatment of patients with infertility and positive aPL was also investigated. This report presents current knowledge and limitations of published studies regarding pregnancy morbidity, infertility and aPL, identifying areas that need better investigative efforts and proposing how critical flaws could be avoided in future studies, as suggested by participants of the Task Force. Except for fetal death, there are limitations in the quality of the data supporting the association of aPL with obstetric complications included in the current APS classification criteria. Recommended treatments for all pregnancy morbidity associated to APS also lack well-designed studies to confirm its efficacy. APL does not seem to be associated with infertility and treatment does not improve the outcomes in infertile patients with aPL. In another section of the Task Force, Dr. Jane Salmon reviewed complement-mediated inflammation in reproductive failure in APS, considering new therapeutic targets to obstetric APS (Ob APS).

Introduction

The Obstetric Task Force of the 14th International Congress on Antiphospholipid Antibodies met on the 18 September 2013 in Rio de Janeiro, Brazil. The Task Force was charge with reviewing obstetric diagnostics and treatments as they pertain to our current understanding of obstetric antiphospholipid syndrome (Ob APS). In preparation for the meeting, the Task Force chairman, Guilherme R. de Jesus, MD, and associate director, Ware Branch, MD, engaged internationally-known experts in the field to present critical, evidence-based updates on Ob APS. The three current criteria for Ob APS [1] were identified as key components of meeting, and members of the APS international community also felt that a review of the possible association of infertility and antiphospholipid antibodies (aPL) should be included. Drs. de Jesus and Branch also asked Jane Salmon, MD, an expert in the role of complement-mediated inflammation in reproductive failure in antiphospholipid syndrome (APS), to review this topic, especially as findings might point to new therapeutic targets. As a general guideline for each area of Ob APS, presenters and participants were asked to consider the following questions. Drs. de Jesus and Branch stressed a critical, evidence-based analysis of each area.

  • What is our current understanding of association of the clinical feature with antiphospholipid antibodies and antiphospholipid syndrome, and what needs to be done to improve our understanding of the association?

  • What is the current status of the treatment for each clinical feature of Ob APS, and what needs to be done to clarify the evidence for or against currently used treatments?

  • Are there intriguing, new ideas regarding prevention or treatment of Ob APS, and how might these be studied?

Of course, underlying these questions is the larger issue of whether or not the current clinical criteria for Ob APS deserve modification.

The issue of testing for antiphospholipid antibodies came up several times, though it was not the mission of this Task Force to make specific comments or recommendations about such testing. There seems little doubt, however, that crystalizing the relationship between alleged clinical associations and antiphospholipid antibodies fundamentally depends upon improvements in antiphospholipid testing.

Registered attendees were encouraged to offer comments and criticisms during the meeting, though time was somewhat limited, and via email after the meeting. Not surprisingly, several participants voiced their opinions about the current status of the clinical associations with antiphospholipid antibodies and the treatments currently used or recommended. Given the frustrating and emotionally-charged nature of reproductive failure, it came as no surprise that strong opinions emerged. Dr. Nancy Agmon-Levin and her colleagues were enthusiastic participants in this aspect of the Task Force and have offered their unpublished survey results regarding the management of “non-criteria Ob APS” for consideration by the group. We have included an abbreviated version of their observations in the section covering recurrent early miscarriage. Thus, the summary of this Task Force's findings is presented in 5 sections: (1) Recurrent early miscarriage (< 10 weeks gestation), (2) fetal death (≥ 10 weeks gestation), (3) preeclampsia and placental insufficiency, (4) infertility, and (5) complement-mediated inflammation in pathogenesis of APS-related adverse obstetric outcomes.

Section snippets

Association of aPL and REM [summary prepared by Guilherme R. de Jesus, MD, and Cecilia Chighizola, MD, with comments of Nancy Agmon-Levin, MD, and colleagues included]

The main objective of this review was to analyze the association of REM (< 10 weeks gestation) with aPL, as listed in the revised Sapporo criteria [1].

Dr. de Jesus reviewed the rationale for the association of REM and aPL, based on in vitro and animal studies. Besides classical thrombotic mechanism of aPL, these antibodies have been associated to complement activation, reduction of annexin-V, and placental tissue damage, ultimately resulting in abortion [2], [3], [4]. APL also induce trophoblast

Association of aPL and fetal death [summary prepared by Laura Andreoli, MD, and Angela Tincani, MD]

The association between fetal death and aPL has been addressed by a recent article [70]. According to this comprehensive systematic review of the literature, fetal death was shown to be associated with LA in 4 case–control studies and 3 cohort studies, aCL in 7 case–control studies and 5 cohort studies, and aβ2GPI in 2 cohort studies. However, the authors of the systematic review note several limitations that suggest caution. Firstly, many studies included a small number of patients such that

Association of aPL and preeclampsia [summary prepared by Carlos A. Andrade, MD, DSc, and D. Ware Branch, MD]

The objective of this review of the literature was to assess the status of the association between aPL and the obstetric clinical criteria of preeclampsia (PreE) in a two-fold manner. First, the authors assessed previously published systematic reviews or meta-analysis about the mentioned association; then, it was analyzed whether or not an additional meta-analysis should or could be performed.

The authors found two systematic analyses of the association between aPL and PreE that were of credible

Association of aPL and infertility and treatment of patients with infertility and positive aPL [summary prepared by Cecilia Chighizola, MD,and Guilherme R. de Jesus, MD]

The hypothesis that aPL might interfere with the earlier stages of pregnancy was first formulated in the late 80s, when a report suggesting an association between aPL positivity and infertility was published [101]. Since then, based on the assumption that aPL may affect implantation by hindering uterine decidualization, aPL have been investigated as a potential cause of infertility. Even though infertility is not enlisted among obstetrical criteria manifestations of APS [1], many physicians do

The role of complement in pathogenesis of preeclampsia and placental insufficiency in patients with aPL [summary prepared by Jane Salmon, MD]

The complement system protects the host against invading organisms, initiates inflammation and enhances the removal of opsonized and injured cells. It provides an important link between the innate and adaptive immune systems. Experimental observations suggest that increased complement activation causes and/or perpetuates inflammation during pregnancy. Recent studies suggest a link between complement activation and pregnancy loss, growth restriction and preeclampsia. Excessive activation or

Conclusions [prepared by Guilherme R. de Jesus, MD, and D. Ware Branch, MD]

The Obstetric Task Force of the 14th International Congress on Antiphospholipid Antibodies has carefully and critically examined the evidence for both the quality of association of each of the current clinical obstetric criteria for APS and the quality of the evidence that treatment(s) provide benefit in terms of avoiding recurrent adverse obstetric outcomes. The results of our analysis for each clinical obstetric criterion are summarized in the respective sections above. We found that after

Take-home messages

  • High quality studies investigating the association of antiphospholipid antibodies (aPL) with pregnancy morbidity present in current classification criteria are lacking.

  • Treatment of obstetric events related to aPL are not supported by consistent findings from well-designed studies.

  • Patients with infertility should not be investigated or treated for aPL in routine clinical practice.

  • New pathogenic mechanisms of obstetric morbidity related to activation of complement by aPL may lead to different

References (158)

  • A.M. Bahar et al.

    Antibodies to phospholipids and nuclear antigens in non-pregnant women with unexplained spontaneous recurrent abortions

    J Reprod Immunol

    (1993)
  • W.H. Kutteh et al.

    Hypercoagulable state mutation analysis in white patients with early first-trimester recurrent pregnancy loss

    Fertil Steril

    (1999)
  • J.Y. Kwak et al.

    Autoantibodies in women with primary recurrent spontaneous abortion of unknown etiology

    J Reprod Immunol

    (1992)
  • J.E. Ruiz et al.

    Autoantibodies to phospholipids and nuclear antigens in non-pregnant and pregnant Colombian women with recurrent spontaneous abortions

    J Reprod Immunol

    (1995)
  • C. Stern et al.

    Antibodies to beta2 glycoprotein I are associated with in vitro fertilization implantation failure as well as recurrent miscarriage: results of a prevalence study

    Fertil Steril

    (1998)
  • J. Alijotas-Reig et al.

    Anti-beta(2)-glycoprotein-I and anti-phosphatidylserine antibodies in women with spontaneous pregnancy loss

    Fertil Steril

    (2010)
  • N. Mtiraoui et al.

    Lupus anticoagulant and antibodies to beta 2-glycoprotein I, annexin V, and cardiolipin as a cause of recurrent spontaneous abortion

    Fertil Steril

    (2007)
  • M.S. Sater et al.

    Anti-phosphatidylserine, anti-cardiolipin, anti-β2 glycoprotein I and anti-prothrombin antibodies in recurrent miscarriage at 8–12 gestational weeks

    Eur J Obstet Gynecol Reprod Biol

    (2012)
  • R.M. Lee et al.

    Anti-beta2-glycoprotein I antibodies in women with recurrent spontaneous abortion, unexplained fetal death, and antiphospholipid syndrome

    Am J Obstet Gynecol

    (1999)
  • D.L. Yetman et al.

    Antiphospholipid antibody panels and recurrent pregnancy loss: prevalence of anticardiolipin antibodies compared with other antiphospholipid antibodies

    Fertil Steril

    (1996)
  • H. Yamada et al.

    Prevalence of diverse antiphospholipid antibodies in women with recurrent spontaneous abortion

    Fertil Steril

    (2003)
  • V. Pengo et al.

    Correct laboratory approach to APS diagnosis and monitoring

    Autoimmun Rev

    (2013)
  • A. Mekinian et al.

    Outcomes and treatment of obstetrical antiphospholipid syndrome in women with low antiphospholipid antibody levels

    J Reprod Immunol

    (2012)
  • F.S. Cowchock et al.

    Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment

    Am J Obstet Gynecol

    (1992)
  • W.H. Kutteh

    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)
  • N.S. Pattison et al.

    Does aspirin have a role in improving pregnancy outcome for women with the antiphospholipid syndrome? A randomized controlled trial

    Am J Obstet Gynecol

    (2000)
  • R.G. Farquharson et al.

    Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment

    Obstet Gynecol

    (2002)
  • S. Dendrinos et al.

    Low-molecular-weight heparin versus intravenous immunoglobulin for recurrent abortion associated with antiphospholipid antibody syndrome

    Int J Gynaecol Obstet

    (2009)
  • U.M. Fouda et al.

    Enoxaparin versus unfractionated heparin in the management of recurrent abortion secondary to antiphospholipid syndrome

    Int J Gynaecol Obstet

    (2011)
  • K. Abou-Nassar et al.

    The association between antiphospholipid antibodies and placenta mediated complications: a systematic review and meta-analysis

    Thromb Res

    (2011)
  • A. Ruffatti et al.

    Laboratory classification categories and pregnancy outcome in patients with primary antiphospholipid syndrome prescribed antithrombotic therapy

    Thromb Res

    (2009)
  • L.B. Helgadottir et al.

    The association of antiphospholipid antibodies with intrauterine fetal death: a case–control study

    Thromb Res

    (2012)
  • F.J. Korteweg et al.

    Evaluation of 1025 fetal deaths: proposed diagnostic workup

    Am J Obstet Gynecol

    (2012)
  • H. Yamada et al.

    Antiphospholipid antibodies increase the risk of pregnancy-induced hypertension and adverse pregnancy outcomes

    J Reprod Immunol

    (2009)
  • H. Yamada et al.

    Anti-beta2 glycoprotein-I antibody increases the risk of pregnancy-induced hypertension: a case–controlled study

    J Reprod Immunol

    (2010)
  • C. Chauleur 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)
  • D. Faden et al.

    Anti-beta 2 glycoprotein I antibodies in a general obstetric population: preliminary results on the prevalence and correlation with pregnancy outcome. Anti-beta2 glycoprotein I antibodies are associated with some obstetrical complications, mainly preeclampsia-eclampsia

    Eur J Obstet Gynecol Reprod Biol

    (1997)
  • J. Milliez et al.

    The prevalence of autoantibodies during third-trimester pregnancy complicated by hypertension or idiopathic fetal growth retardation

    Am J Obstet Gynecol

    (1991)
  • Z. Alfirevic et al.

    Postnatal screening for thrombophilia in women with severe pregnancy complications

    Obstet Gynecol

    (2001)
  • P.L. Meroni et al.

    Pathogenesis of antiphospholipid syndrome: understanding the antibodies

    Nat Rev Rheumatol

    (2011)
  • L. Opatrny et al.

    Association between antiphospholipid antibodies and recurrent fetal loss in women without autoimmune disease: a metaanalysis

    J Rheumatol

    (2006)
  • L. Andreoli et al.

    The estimated frequency of antiphospholipid antibodies in patients with pregnancy morbidity, stroke, myocardial infarction, and deep vein thrombosis

    Arthritis Care Res (Hoboken)

    (2013)
  • F. Parazzini et al.

    Antiphospholipid antibodies and recurrent abortion

    Obstet Gynecol

    (1991)
  • N.S. Pattison et al.

    Antiphospholipid antibodies in pregnancy: prevalence and clinical associations

    Br J Obstet Gynaecol

    (1993)
  • M. Petri et al.

    Antinuclear antibody, lupus anticoagulant, and anticardiolipin antibody in women with idiopathic habitual abortion. A controlled, prospective study of forty-four women

    Arthritis Rheum

    (1987)
  • D.W. Branch et al.

    Antiphospholipid antibodies other than lupus anticoagulant and anticardiolipin antibodies in women with recurrent pregnancy loss, fertile controls, and antiphospholipid syndrome

    Obstet Gynecol

    (1997)
  • M. Ogasawara et al.

    Anti beta 2glycoprotein I antibodies and lupus anticoagulant in patients with recurrent pregnancy loss: prevalence and clinical significance

    Lupus

    (1996)
  • J.C. Gris et al.

    Case–control study of the frequency of thrombophilic disorders in couples with late foetal loss and no thrombotic antecedent—the Nîmes Obstetricians and Haematologists Study 5 (NOHA5)

    Thromb Haemost

    (1999)
  • I. Das et al.

    Study of lupus anticoagulant in pregnant women with recurrent abortion

    Aust N Z J Obstet Gynaecol

    (1991)
  • HeL Costa et al.

    Prevalence of anti-cardiolipin antibody in habitual aborters

    Gynecol Obstet Invest

    (1993)
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    Dedicated to the memory of Silvia Pierangeli, PhD.

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