14th International Congress on Antiphospholipid Antibodies Task Force report on obstetric antiphospholipid syndrome.

AUTREV-01545; No of Pages 18 Autoimmunity Reviews xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

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Article history: Received 6 February 2014 Accepted 17 February 2014 Available online xxxx

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Keywords: Antiphospholipid syndrome Recurrent early miscarriage Fetal death Preeclampsia Infertility Complement

Department of Obstetrics, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Aviv, Israel Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel d Instituto de Pesquisa Clinica Evandros Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil e Rheumatology and Clinical Immunology, Department of Clinical and Experimental Sciences, Spedali Civili, University of Brescia, Brescia, Italy f Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy g Immunorheumatological Research Laboratory, Istituto Auxologico Italiano, Milan, Italy h Department of Obstetrics and Gynecology, University of UT, Salt Lake City, USA i Intermountain Healthcare, Salt Lake City, USA j Hospital For Special Surgery, Weill Cornell Medical College, NY, USA k Kirkland Center for Lupus Research, NY, USA l Lupus and APS Center of Excellence, NY, USA

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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). © 2014 Elsevier B.V. All rights reserved.

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Guilherme R. de Jesus a,⁎, Nancy Agmon-Levin b,c, Carlos A. Andrade d, Laura Andreoli e, Cecilia B. Chighizola f,g, T. Flint Porter h,i, Jane Salmon j,k,l, Robert M. Silver h, Angela Tincani e, D. Ware Branch h,i

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

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Review

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recurrent early miscarriage (REM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Association of aPL and REM [summary prepared by Guilherme R. de Jesus, MD, and Cecilia Chighizola, MD, with comments of Agmon-Levin, MD, and colleagues included] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Treatment of patients with REM and positive aPL [summary prepared by T. Flint Porter, MD, with observations by Dr. Agmon-Levin, MD, included] 2.3. Summary by the moderators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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☆ Dedicated to the memory of Silvia Pierangeli, PhD. ⁎ Corresponding author at: Departamento de Obstetrícia, Hospital Universitário Pedro Ernesto, Universidade do Estado do Rio de Janeiro, Avenida Professor Manoel de Abreu, 500, 1° andar, 20550-170 Rio de Janeiro, RJ, Brazil. Tel.: +55 21 2868 8646. E-mail address: [email protected] (G.R. de Jesus).

http://dx.doi.org/10.1016/j.autrev.2014.02.003 1568-9972/© 2014 Elsevier B.V. All rights reserved.

Please cite this article as: de Jesus GR, et al, 14th International Congress on Antiphospholipid Antibodies Task Force Report on Obstetric Antiphospholipid Syndrome, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.02.003

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Fetal death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Association of aPL and fetal death [summary prepared by Laura Andreoli, MD and Angela Tincani, MD] . . . . . . . . . . . . . . . . . . 3.2. Treatment of patients with fetal death and positive aPL [summary prepared by Robert M. Silver, MD] . . . . . . . . . . . . . . . . . . . 3.3. Summary by the moderators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Preeclampsia and placental insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Association of aPL and preeclampsia [summary prepared by Carlos A. Andrade, MD, DSc, and D. Ware Branch, MD] . . . . . . . . . . . . . 4.2. Association of aPL and placental insufficiency [summary prepared by D. Ware Branch, MD, and Guilherme R. de Jesus, MD] . . . . . . . . . 4.3. Limitations of studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Summary by the moderators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. 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] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Summary by the moderators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. The role of complement in pathogenesis of preeclampsia and placental insufficiency in patients with aPL [summary prepared by Jane Salmon, MD] . . 6.1. Summary by the moderators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Conclusions [prepared by Guilherme R. de Jesus, MD, and D. Ware Branch, MD] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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• 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?

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2. Recurrent early miscarriage (REM)

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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.

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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 (b10 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.

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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 recommendation 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

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2.1. Association of aPL and REM [summary prepared by Guilherme R. de 134 Jesus, MD, and Cecilia Chighizola, MD, with comments of Agmon-Levin, 135 MD, and colleagues included] 136 The main objective of this review was to analyze the association of REM (b 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 [2–4]. APL also induce trophoblast injury and apoptosis, inhibit syncitia proliferation and formation, decrease production of human chorionic gonadotrophin, and impair trophoblast invasion and adequate secretion of growth factors [5]. Therefore, it seems reasonable, according to basic science studies, that patients with circulating aPL could have a higher frequency of early pregnancy losses. One meta-analysis evaluated the aforementioned association. Opatrny et al. [6] reported a positive association between aCL IgG (OR 3.56, 95% CI 1.48–8.59; low and moderate to high titers included) and recurrent miscarriage occurring at less than 13 weeks' gestational age, but only 2 studies (total of 907 patients) could be included in this analysis. The authors did not find any study examining the association between lupus anticoagulant (LA) and anticardiolipin (aCL) IgM with pregnancy loss before 13 weeks, while the relationship between antiβ2 glycoprotein-I (aβ2GPI) and recurrent abortion before 13 weeks was not statistically significant (OR 2.12, 95% CI 0.69–6.53). Notably, comparison between studies was difficult due to poor standardization


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and/or third trimester losses. Fifteen published studies did not mention the gestational age of the abortion. This disparity of different groups of patients is clearly problematic, as pathogenesis of abortion likely varies considerably over the course of the first 15–20 weeks of gestation, with chromosomal etiologies being far more common in early losses than in later losses. Lastly, most studies did not mention if and how other causes of miscarriage, such as anatomic, hormonal and genetic abnormalities and infectious diseases, were excluded. The use of different thresholds appears to have contributed to the disparate findings. Of the 43 papers that tested for aCL and/or aβ2GPI, 8 used cutoffs lower than 20 units, 9 used cutoffs higher than 20 units, 11 defined a positive test according to standard deviation, 6 considered positive results above the 99th percentile of the population, 1 used the 98th percentile as cutoff and 1 study defined the 95th percentile as cutoff. Seven articles did not mention the cutoff for aCL and/or aβ2GPI. Simply put, the definition of “positive aPL” varied widely [55]. Moreover, Sapporo criteria call for confirmation of positive test results 6 to 12 weeks after the initial positive result. Only 8 out of 46 studies performed this confirmation, increasing the risk of misclassification due transient aPL. In addition to this review of the association of aPL and REM, Dr. Agmon-Levin and colleagues noted that in the last decade a wide array of “non-criteria” obstetric conditions have been proposed by some clinicians as likely being related to APS or aPL, particularly for early miscarriage. They pointed out that some studies conclude that low levels of aPL may be of significance [56–58]. In the study of Mekinian et al. [56] pregnancy outcomes in untreated pregnancy patients with low aPL were as poor as of those with medium-high titer antibodies. In another study by Simchen et al. [57], a better pregnancy outcome was noted in pregnant patients with low titer compare to high titer aPL, 77% vs. 35%, respectively.

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of assays testing for aPL and due to heterogeneity of studies, with different definitions of cases (minimum number of consecutive losses 2 in some studies and 3 in others) and controls (not matched for parity, few studies with appropriate controls). A literature review was carried out by Drs. de Jesus and Chighizola in PubMed to search for studies published through June, 2013, with the intention of complementing a recently published evaluation of the prevalence of aPL among patients with obstetric morbidity and other clinical events [7]. The terms used in this search are mentioned in the Appendix A. As will be discussed further in this text, investigators frequently included preembryonic and embryonic abortion (before 10 weeks of pregnancy) with “late” abortion or fetal loss (at 10 weeks of pregnancy or more). Only studies using first trimester loss as inclusion criteria were considered for this review. Studies clearly addressing only late abortions were excluded. Forty-six original studies investigating the frequency of positive aPL tests in patients with REM were identified and included in the analysis. Of the 46 articles, 27 found a positive association of aPL [8–34] and REM, while 7 did not find an association [35–41]. Twelve papers investigated the prevalence of aPL in patients with REM but did not include healthy control groups, and thus could not report an association [42–53]. Most studies reported a high prevalence of aPL in those patients, with only one article [44] reporting that positive aPL were infrequent in patients with REM. Considering those studies that reported a positive association between aPL and REM, most had a significant number of patients in the study group, with 14 out of 27 including at least 100 patients [9, 14–19,24,25,27,29–31,34]. LA and aCL were the antibodies more frequently studied, with a small number of papers analyzing aβ2GPI. Other non-criteria aPL were evaluated in a small number of studies, with conflicting results [14,17,19,23,26,28–30,37,40,42,48,49,52]. A number of studies found no association between aPL and REM. Parke et al. [35] reported that LA, aCL IgG and aCL IgM were found in a higher frequency in 81 patients with REM than in a general population, but the finding was not statistically significant. Panton et al. described a similar frequency of aCL IgG among 177 women with REM compared to 254 healthy blood donors [36], while Maejima et al., in the same year, also did not find a positive association of aβ2GPI IgG with REM [38]. Another investigation of aβ2GPI IgG and IgM in 141 patients was not able to identify additional patients with REM or fetal death who were initially negative for aCL [39]. Interestingly, the same group later published a different paper showing that aβ2GPI IgA was positively associated with recurrent pregnancy loss [18]. Two large studies [37,40] published in the 2000s found no association between aPL and REM. Mastubayashi et al. tested LA and aCL IgG in 273 patients [37], while Zammiti et al. investigated aβ2GPI IgG and IgM in 172 patients [40], both showing similar frequencies of aPL in patients with REM compared to healthy controls. Hossain et al. reported no significant association between aPL and REM in 52 Pakistani women [41]. The mixed results of the aforementioned studies can be partially explained by different inclusion criteria and different definitions of positive laboratory tests. Most papers (26/46) investigating aPL in patients with REM were published before the first international consensus on aPL [54]. Thus, most of them did not use the criteria currently accepted to classify patients with APS. For example, almost one third of the studies (16/46) included patients with less than 3 abortions, and a great number of the published studies did not mention if patients had consecutive abortions. Only 4 papers [18,29,30,39] strictly followed the pregnancy morbidity criteria for recurrent early abortion described in Sapporo/Sidney consensus (“Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation”). The gestational age of the fetal loss used as inclusion criteria was also heterogeneous among the publications. Seventeen studies included only patients with first trimester abortions, while 14 analyzed patients with first trimester losses in the same group of patients with second

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2.2. Treatment of patients with REM and positive aPL [summary prepared 259 by T. Flint Porter, MD, with observations by Dr. Agmon-Levin, MD, included] 260 Proposed treatments for women with REM who test positive for aPL but without a history of thromboembolism have focused on thromboprophylaxis and immune modulation. These include prednisone, low dose aspirin (LDASA), intravenous immune globulin (IVIG), unfractionated heparin (UFH), low molecular weight heparin (LMWH), and plasmapheresis, either alone or in combination. Only a few, relatively small randomized controlled trials (RCT) have been published and the results are inconsistent. A systematic literature review of the MEDLINE database and Cochrane registry of controlled trials up to August 2013 was conducted. The terms used in this review can be found in the Appendix A. All searches were limited to studies in humans and reviews; expert opinions, and other editorial materials were excluded. Study inclusion criteria were a priori defined to identify RCT that included pregnant women with a history of REM who tested positive for aPL antibodies, stratified to receive treatment with pregnancy outcome as the main outcome measure. Dr. Porter screened the search results, and the following information was retrieved from each relevant article: author, year of publication, type of study design, entry criteria, sample size, therapies, and outcomes stratified according to treatment arm. The initial search returned 16,135 publications, 820 of which were clinical treatment trials. Thirty-eight included women with REM who tested positive for aPL antibodies. Of these 10 were RCTs and thus eligible for inclusion [59–68] (Table 1). Only one of the trials was placebo controlled. The majority compared heparin, either UFH or LMWH, and LDASA to LDASA alone. Two compared LMWH and LDASA to IVIG. Live birth rates in the seven trials which included patients treated with LDASA alone ranged from 42 to 80% (Table 2). The median number of subjects in each study, 25 subjects (range, 19–47), was small, and inclusion criteria were markedly different between studies. Three trials


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Table 1 Randomized controlled trials about recurrent early miscarriage (REM) and antiphospholipid antibodies (aPL) included.

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Year

Authors and reference

Treatment

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1992 1996 1997 2000 2002 2003 2006 2009 2009 2011

Cowchock SF et al. Am J Obstet Gynecol 1992; 166:1318–23. [59] Kutteh W. Obstet Gynecol 1996:174: 584–9 [60] Rai R et al. BMJ 1997; 314:253–7 [61] Pattison R et al. Am J Obstet Gynecol 2000; 183:1008–12 [62] Farquharson R et al. Obstet Gynecol 2002; 100(3): 408–13 [63] Triolo G et al. Arthritis and Rheumatism 48(3), 2003, 728–31 [64] Goel et al. Med Sci Monit, 2006; 12(3): CR132–136 [65] Dendrinos S et al. International Journal of Gynecology and Obstetrics, 2009; 104: 223–225 [66] Laskin C et al. J Rheumatol 2009; 36:279–87 [67] Fouda et al. Int J Gynecol Obstet 2011: 112: 211–15 [68]

Prednisone vs. UFH UFH and LDASA vs LDASA alone UFH and LDASA vs. LDASA alone LDASA vs. placebo LMWH and LDASA vs. LDASA alone LMWH and LDASA vs. IVIG UFH and LDASA vs LDASA alone LMWH and LDASA vs. IVIG LMWH and LDASA vs. IVIG LMWH and LDASA vs. UFH and LDASA

IVIG: intravenous immune globulin. LDASA: low dose aspirin. LMWH: Low molecular weight heparin. UFH: Unfractionated heparin.

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[59,65,67] included subjects with 2 or more miscarriages, none of the trials were limited to patients who meet current laboratory criteria for APS [1], and two of the trials excluded patients who tested for the lupus anticoagulant. Eight trials included groups treated with heparin compounds in combination with LDASA (Table 3). Live birth rates ranged from 71 to 85% and the median number of subjects was small, 29.5. Only one trial was limited to subjects who would meet the current laboratory criteria for APS [66]. A statistically significant improvement in live birth rates is reported in three of five studies comparing treatment with heparin compound and LDASA to LDASA alone [60,61,65] (Table 4). Pooled data also justifies treatment with a combination of a heparin compound and LDASA (Fig. 1A). However, only UFH (in combination with LDASA) has a beneficial effect on live births (Fig. 1B). The data on LMWH and LDASA are inconclusive (Fig. 1C). The two trials comparing LMWH and LDASA to IVIG treatment in women with REM and aPL show conflicting results (Table 5). Pooled data are also inconclusive (Fig. 2). Dr. Porter concluded that the results of treatment trials for otherwise healthy women with REM who test positive for aPL antibodies are conflicting, if not misleading. The most commonly used protocols include either UFH or LMWH, usually in combination with LDASA. These agents have never been subjected to study in a “gold standard,” placebocontrolled trial. Most published trials comparing heparin and LDASA to LDASA alone included subjects who would not meet current criteria for APS. Moreover, the common practice of substituting LMWH for UFH begs the question and appears to be unjustified by currently available evidence. The same is true for using IVIG in women who fail treatment with a heparin compound and or LDASA. Dr. Agmon-Levin and colleagues (Drs. Angela Tincani, Andrea Doria, and Yehuda Shoenfeld) offered their findings of an unpublished survey of how experts in APS manage patients in everyday clinical

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Table 2 Live birth rates in groups with about recurrent early miscarriage (REM) and antiphospholipid antibodies (aPL) treated with low dose aspirin (LDASA) alone.

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1. How do you treat women with a history of obstetric morbidity and low titer criteria aPL? 2. How do you treat women with a single early miscarriage who is found to have aPL according to international non-criteria manifestations (namely 1 early abortion) in the presence of criteria (med-high level) aPL?

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A similar proportion of these experts stated that they recommended the same treatment approach for women with low titer aPL as they do for those with medium-to-high titer aPL. Further, 70% of those surveyed stated that they treated women with a single or two prior early miscarriages and aPL as they do women meeting international clinical criteria.

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2.3. Summary by the moderators

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Though a majority of published studies report a positive association between aPL and REM, they are highly heterogeneous concerning clinical events (number of previous pregnancy losses, gestational age of pregnancy losses, and inclusion of early miscarriage and late fetal death in the same analysis) and laboratory criteria (different cutoffs, inclusion of patients with low titers, and lack of confirmatory testing). In short, only a very few studies meet Sapporo/Sidney criteria and support the association between aPL and REM. Regarding the association of aPL and REM, Table 6 summarizes the limitations of the studies found in our literature review and suggestions to solve these critical issues in future work. We conclude that multicenter studies should be developed using actual international consensus as inclusion criteria in order to establish an evidence-based association between aPL and REM. Standardization of laboratory tests is crucial,

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settings. They surveyed 45 practitioners of rheumatology, hematology, immunology, or obstetrics who stated that they each managed at least 50 APS cases (some claimed to manage as many as 200), asking the following questions of them:

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Author, year

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SAB

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Cowchock, 1992 [59] Kutteh, 1996 [60] Rai, 1997 [61] Pattison, 2000 [62] Farquharson, 2002 [63] Goel, 2006 [65] Laskin, 2009 [67]

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SAB: Spontaneous abortion. LA: lupus anticoagulant.

19 25 45 20 47 39 21

≥2 ≥3 ≥3 ≥3 ≥3 ≥2 ≥2

Anticardiolipin thresholds IgG

IgM

N30 ≥27 N5 ≥5 N9 N18 N15

N11 ≥27 N5 ≥5 N5 No N25

LA

% live births

Yes No Yes Yes Yes No Yes

68.4 44.0 42.2 80.0 72.3 61.5 76.2


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Table 3 Live birth rates in groups with about recurrent early miscarriage (REM) and antiphospholipid antibodies (aPL) treated with heparin and low dose aspirin (LDASA). Author, year

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Anticardiolipin thresholds

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Cowchock, 1992 [59] Kutteh, 1996 [60] Rai, 1997 [61] Farquharson, 2002 [63] Goel, 2006 [65] Laskin, 2009 [67] Dendrinos, 2008 [66] Triolo, 2003 [64]

≥2 ≥3 ≥3 ≥3 ≥2 ≥2 ≥3 ≥3

26 25 45 51 33 22 40 19

IgG

IgM

N30 ≥27 N5 N9 N18 N15 M/H ≥40

N11 ≥27 N5 N5 No N25 M/H No

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Type

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UFH UFH UFH LMWH UFH LMWH LMWH LMWH

73.1 80.0 71.1 78.4 84.8 77.3 72.5 84.2

SAB: Spontaneous abortion. LA: lupus anticoagulant. LMWH: Low molecular weight heparin. UFH: Unfractionated heparin.

355 356

390 391

and independent laboratories, such as APS ACTION network core laboratories, would be helpful in confirming positive tests. The use of core laboratories would also serve to shed light on local and regional differences in laboratory findings. Participants of the Task Force suggested that studies investigating aPL frequency in patients with two consecutive early abortions should be performed, either exclusively with this group of patients or as a subgroup of analysis in a larger study that also included patients with three or more consecutive losses. Considering the treatment of those patients with aPL and REM, current treatment recommendations come from a small number of trials, most of them including women not meeting international consensus for APS. The results were often different when somewhat similar studies were compared, especially when LDASA alone was used. A majority of Task Force members agreed that high quality studies demonstrating consistent results to support treatment of patients with REM and positive aPL are lacking. Task Force members also opined that new RCTs in women with REM and aPL are going to be difficult to implement because they would require assessment of a large number of patients, strict adherence to standard evaluation and central laboratory testing, as well as the problems inherent in randomizing women with an emotional and frustrating clinical condition. Some Task Force members felt that the treatment of “non-criteria Ob APS” cases is justified from the perspective of being eminence-based, while others merely acknowledged the expected variation in clinical practice at the physician– patient level. Certainly, not all Task Force members agreed that treating low-titer cases is justified, pointing out that studies of patients with miscarriage and low titer aPL are inconclusive [56,58,69]. The moderators of the Task Force would stress that while individual practitioners will make their treatment choices based on their local or regional experience and expert advice, those genuinely interested in APS should strive to provide evidence by way of properly designed studies. To this end, Task Force members generally agreed that trials in two subgroups should be considered by the international APS community: (1) treatment of otherwise healthy women with repeatedly low positive immunoassay results, and (2) treatment of otherwise healthy women with repeatedly positive aPL and a single, or perhaps two, early miscarriages (and aPL).

t4:1 t4:2 t4:3

Table 4 Comparison of live birth rates in groups with about recurrent early miscarriage (REM) and antiphospholipid antibodies (aPL) treated with unfractionated heparin (UFH) or low molecular weight heparin (LMWH) plus low dose aspirin (LDASA) and LDASA alone.

371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389

t4:4

Author

Intervention

t4:5 t4:6 t4:7 t4:8 t4:9 t4:10

Kutteh [60] Rai [61] Farqharson [63] Goel [65] Laskin [67]

UFH/LDASA UFH/LDASA LMWH/LDASA UFH/LDASA LMWH/LDASA

O R O

D

P

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 they were considerably underpowered to detect significant associations between aPL and fetal death. Although certainly pertinent from a methodological point of view, this observation should also take into consideration that fetal death is a rare event, much less frequent than early pregnancy loss, and that APS is even a rarer disease. Consequently, case–control studies including no more than 200–300 events of placental mediated complications (including but not limited to fetal deaths) and prospective studies in the general obstetric population could very easily identify only few cases of fetal death. A second limitation noted by the authors was that the timing of fetal deaths being studied varied widely from study to study, ranging from 8 to 24 weeks of gestation. Nevertheless, an association was found between aPL and both stillbirth (N20 weeks of gestation) and fetal death (N10 weeks of gestation), suggesting that antibody mediated damage can similarly affect different pregnancy periods. The third limitation noted was the wide methodological variability in aPL assays, expected perhaps because of the well-known variation in the performance of aPL antibody tests. In the ELISA based papers, the cut-off values applied to the different assays displayed significant variations, and frequently IgG and IgM positive values were merged, making it impossible to evaluate isotypes separately. Finally, only a limited number of papers included all the 3 criteria tests (LA, aCL and aβ2GPI) and performed the longitudinal confirmation of positive results, as recommended by international consensus [1].

E

T

369 370

C

367 368

E

365 366

R

363 364

R

361 362

392

3.1. Association of aPL and fetal death [summary prepared by Laura 393 Andreoli, MD and Angela Tincani, MD] 394

N C O

359 360

3. Fetal death

U

357 358

F

t3:13 t3:14 t3:15 t3:16

Heparin LDASA

LDASA

p value

N

Live births (%)

N

Live births (%)

25 45 51 33 22

80 72 78 85 77

25 45 47 39 21

40 42 72 62 76

b0.05 0.01 NS 0.04 NS


395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426

6


A Study

% RR (95% CI)

Weight

Kutteh (1996)

1.82 (1.12, 2.95)

12.97

Rai (1997)

1.68 (1.14, 2.49)

17.01

Goel (2006)

1.38 (1.03, 1.84)

23.04

Farquharson (2002)

1.08 (0.86, 1.36)

27.28

Laskin (2009)

1.03 (0.73, 1.45)

19.70

Overall (I−squared = 51.8%, p = 0.081)

1.31 (1.06, 1.62)

100.00

O

.25

1

4

B

P

Study

R O

NOTE: Weights are from random effects analysis

D

ID

E

Kutteh (1996)

T

Rai (1997)

%

RR (95% CI)

Weight

1.82 (1.12, 2.95)

18.57

1.68 (1.14, 2.49)

28.68

1.38 (1.03, 1.84)

52.76

1.54 (1.25, 1.89)

100.00

E

C

Goel (2006) Overall (I−squared = 0.0%, p = 0.521)

F

ID

.25

1

4

R

C

R


%

O

Study

C

ID

N

Farquharson (2002)

U

Laskin (2009)


RR (95% CI)

Weight

1.08 (0.86, 1.36)

68.95

1.03 (0.73, 1.45)

31.05

1.07 (0.88, 1.29)

100.00


.25

1

4

Fig. 1. Forest plots of included studies assessing miscarriage patients with antiphospholipid antibodies (aPL) patients treated with heparin compounds. A. The pooled effect of combination treatment justifies the addition of heparin to low-dose aspirin (LDASA). B. The pooled effect of unfractionated heparin combined with low dose aspirin (LDASA) justifies the addition of unfractionated heparin (UFH). C. The pooled effect of substituting low molecular weight heparin (LMWH) for unfractionated heparin (UFH) is uncertain.



438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460

84.2 72.5

21 38

57.1 39.5

– Detailed medical history (previous thrombosis, concomitant SLE or other autoimmune disease, arterial hypertension or other risk factors), including the treatment in the 6 months before conception. – Detailed obstetric and gynecological information (which implies the close collaboration with a dedicated obstetrician). – Complete aPL profile (all 3 criteria tests, repeated at least twice 12 weeks apart). The use of central “core” laboratories to confirm or refute laboratory positivity (the APS ACTION laboratories could serve this purpose).

495 496

O

Recently, a large, multicentric, multiethnic prospective populationbased study was conducted by The Stillbirth Collaborative Research Network (SCRN) in United States and shed light on the association between aPL and stillbirth [71]. By systematically studying 582 cases of fetal death beyond the 20th week of gestation and 1547 controls, this extensive study showed that elevated levels of aCL and aβ2GPI antibodies were associated with a 3- to 5-fold increased odds of stillbirth. Strengths of this study are the inclusion of a significant number of cases and the centralization of aPL testing for homogeneous assessment of positive results. However, the lack of LA testing and the absence of any longitudinal verification of aPL persistence are limitations that do not allow the precise identification of the true positive patients. In order to minimize the interlaboratory variability due to the poor standardization of aPL tests, we analyzed studies that investigated patients for a complete aPL profile. In our review of the literature, we retrieved 10 published studies that performed all the 3 criteria tests in women with fetal death. Many of these papers also stratified the risk for fetal death according to the aPL profile. The information about these studies is summarized in Table 7. Although these studies are not directly comparable due to a high degree of heterogeneity (Table 8), there is agreement on the fact that the aPL profile may be relevant to obstetric APS. Patients with triple aPL positivity more likely have a sound laboratory diagnosis and are more likely to carry the most pathogenic antibodies. Triple aPL positivity was in fact identified as a risk factor for pregnancy failure by several studies [17,69,72–74]. We also sought to determine if the aPL titer (aCL and aβ2GPI) is another important feature in risk stratification. A study from Israel showed a good pregnancy outcome in 77% of low titer pregnancies, while only 35% in high titer pregnancies [57]. Conversely, a French study described that pregnancy outcomes in untreated pregnancies with low aPL are poor and similar to those in patients with medium-high titer [56]. With a different approach (audit of consecutive patients with persistently positive aPL), an English study showed that over 50% of women with pure obstetric APS had low titer aCL and/or anti-beta2GPI in the

F

0.06 0.003

T

436 437

19 40

C

434 435

Live births (%)

E

432 433

N

R

430 431

Live births (%)

R

428 429

p-Value

N C O

427

Triolo, 2003 [64] Dendrinos, 2009 [67]

N

Study

U

t5:7 t5:8

IVIG

R O

t5:6

LMWH/LDASA

461 462

P

Author

absence of LA. Approximately 27% of these patients had clinical features of high-risk APS [69]. Thus, the impression is that in obstetric APS also low titer aPL may play a relevant role. As a matter of fact, low titer aCL were implicated as being clinically relevant for women with purely obstetric APS in a large prospective cohort of European patients [75] as well as in the Stillbirth Collaborative Network study [71]. An alternative interpretation of these findings, though, is that pathologicallyirrelevant, low titer antibodies may be found in women with fetal death. It is also important to recognize that the clinical features associated with aPL confound pregnancy outcomes. Findings from several studies are in agreement that previous thrombosis and the presence of a concomitant systemic lupus erythematosus are strong risk factors for pregnancy failure despite treatment [74,76,77]. Since the last International Congress on aPL held in 2010, no significant progress has been made in terms of clinical trials designed to assess the best treatment of aPL-associated fetal death. The 2010 Obstetric Task Force suggested that women eligible for RCT could be those with a fetal death between 10 and 20 weeks of gestation, while stillbirth was considered such an emotional event that would prevent women to accept a randomization [78]. Although research should aim at the best level of evidence as provided by RCT, most experts recognize that this is difficult, if not impossible, in some clinical settings such as late fetal loss. Drug trials in rare conditions such as aPL-mediated fetal death must necessarily be multicentered and international for adequate sample size, but working with the different IRBs and local regulations would prove daunting, if not impossible. Many Task Force members feel that pregnant patients are particularly unlikely to accept randomization. In light of these problems, Task Force members felt the most feasible approach to collect data about aPL-associated fetal death is via the use of registries of prospectively followed pregnancies from different countries. However, in order to be truly informative, registries should include for each patient:

D

t5:5

Table 5 Trials comparing live birth Rates in women with recurrent early miscarriage (REM) and antiphospholipid antibodies (aPL) treated with low molecular weight heparin (LMWH) and low dose aspirin (LDASA) to those treated with intravenous immune globulin (IVIG).

E

t5:1 t5:2 t5:3 t5:4

7

%

ID

RR (95% CI)

Weight

Dendrinos (2009)

1.84 (1.19, 2.84)

47.77

Triolo (2003)

1.47 (0.97, 2.24)

52.23


1.64 (1.21, 2.22)

100.00


.25

1

4

Fig. 2. Forest plots of included studies assessing miscarriage in patients with antiphospholipid antibodies patients treated with low molecular weight heparin (LMWH) and intravenous immune globulin (IVIG).


463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494

497 498 499 500 501 502 503

8

t6:4 t6:5

Table 6 Significant limitations of existing studies of the association between antiphospholipid antibodies (aPL) and recurrent early miscarriage (REM), fetal death, preeclampsia (PreE) or placental insufficiency (PI). Limitation

Comments

Recommendations regarding future studies

Substantial variability in assays, cut-off values, and reporting of results Inclusion of patients with early abortion, fetal death and stillbirth in the same group of analysis

There are a number of commercial reagents and kits, as well as in-house assays used Pathogenesis of pregnancy losses varies during pregnancy

Most of studies did not mention if and how other causes of pregnancy loss were excluded

Important confounders could be responsible for the pregnancy loss

Heterogeneous inclusion criteria for REM

Majority of studies do not follow pregnancy morbidity criteria for REM described in International Consensus

Heterogeneous definitions of preeclampsia or placental insufficiency Many studies of insufficient sample size

There are at least several sets of practice guidelines.

Local results, including all positives, should be confirmed using APS ACTION network core laboratories. Use well-accepted definitions of pregnancy loss as inclusion criteria. We recommend the use of proposed nomenclature for pregnancy loss (Table 9), presented in this article. Anatomic, hormonal and genetic abnormalities and infectious diseases should be excluded to confirm the real role of aPL in the pregnancy loss. International consensus should be strictly followed as inclusion criteria for REM. Group of patients with exactly two consecutive embryonic deaths could be created to compare with patients that meet international consensus definition. Use well-accepted definitions of hypertensive disease in pregnancy. We recommend those of the ACOG.a Appropriate power analyses are critical.

t6:6

F

t6:7

t6:8

t6:14

A fundamental and critical flaw in many studies.

Lack of repeat testing a

510 511

3.2. Treatment of patients with fetal death and positive aPL [summary prepared by Robert M. Silver, MD]

512

Fetal death was one of the initial clinical problems to be associated with aPL. Although fetal deaths account for fewer than 5% of pregnancy losses, they made up over 50% of a large cohort of losses in women with positive tests for aPL [16]. The perceived association between aPL and fetal death is so strong that even a single fetal death is considered sufficient clinical criteria for APS [1]. However, despite this perception, there have been remarkably few studies focusing on the relationship between fetal death and aPL. In addition, studies have been hampered by a lack of obstetric detail, varied definitions of fetal death, a lack of evaluation for the myriad causes of fetal death other than APS, and virtually no data regarding the efficacy of treatment in appropriately designed clinical trials. Accordingly, considerable knowledge gaps remain regarding fetal death and aPL. Simply stated, there has been no appropriately designed, RCT evaluating treatment for pregnancies complicated by prior fetal death in women with positive tests for aPL. There are two reviews summarizing treatment studies in patients with pregnancy loss and aPL [79,80]. Several issues are worth noting. First, none of the trials included only women with fetal death and fetal death was never sub-analyzed as an inclusion criterion. Second, fetal death is variably defined among studies. Third, all of the trials excluded women with prior thrombosis and finally, most had “low titers” of aPL. Some of the trials analyzed treatment effect on fetal death as an “outcome,” rather than as an “inclusion criterion.” In a meta-analysis by Ziakas and colleagues [80], treatment with heparin and or aspirin had no effect on fetal death as an outcome in five trials. The OR for fetal death in 3 studies using unfractionated heparin was 0.52 (95% CI 0.11, 2.46). In two studies using low molecular weight heparin it was 2.28

519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539

C

E

R

R

O

517 518

C

515 516

N

513 514

U

507 508

(95% CI 0.43, 12.13) and for all five studies combined it was 1.07 (95% CI 0.36, 3.16) [80]. Another meta-analysis noted only 41 patients with fetal death as an outcome in all five studies [81]. Thus, no conclusions can be made regarding efficacy due to insufficient power and sample size. It is important to recognize that none of these trials included women with “bona fide” APS. For example, classic cases with prior thrombosis, positive tests for lupus anticoagulant and recurrent fetal deaths associated with placental insufficiency. Appropriate trials have never been conducted in this type of patient. However, outcomes after treatment with heparins and/or aspirin have been dramatically better in these women compared to historical self-controls [77,82]. Although this type of study design does not permit conclusions regarding efficacy, the outcomes were so markedly improved that treatment is generally accepted as being effective and is almost uniformly recommended in these patients [83]. One recent study was noteworthy because heparin use was not associated with improved obstetric outcomes [76]. In the PROMISSE study, a prospective cohort of pregnancies with aPL, SLE and controls, treatment with heparin was not associated with improved pregnancy outcomes. In general, women testing positive for aPL but negative for LA did well, regardless of treatment. However, women with LA did poorly, regardless of treatment [76]. These data underscore our lack of certainty regarding the efficacy of treatment in patients with aPL and fetal death. A major problem has been a lack of a uniform definition for fetal death. The nomenclature for pregnancy loss is quite outdated and is not reflective of modern understanding of reproductive biology. It is also not clinically useful. Traditionally, all pregnancy losses occurring at less than 20 weeks gestation are grouped together as spontaneous abortions, while those occurring after 20 weeks gestation are termed stillbirths. Even these definitions are not uniformly accepted and there continues to be considerable variation regarding the definition of stillbirth throughout the world. Nomenclature that more accurately reflects our current understanding of developmental biology and that is more aligned with pathophysiology or causes of pregnancy loss as well as the probability of recurrent pregnancy loss has been proposed [84]. These are outlined in Table 9. Another issue has been a failure to consider other potential causes or etiologies for fetal death. Given the numerous causes of fetal death, it is

T

509

505 506

Local results, including all positives, should be confirmed using APS ACTION network core laboratories and operational procedures. Should be included in future studies.

ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. Obstet Gynecol. 2002; 99(1):159–67.

– Complete treatment details (start/stop dates of drugs, changes in dosage). – Information about treatment and events during the 6 months after delivery. – If available, information about neonatal outcome and children's follow-up would be extremely valuable.

504

At a minimum, know confounders should be collected and accounted for using appropriate statistical techniques.

D

t6:12 t6:13

P

Absence of lupus anticoagulant testing in many studies

R O

Heterogeneous study designs limited systematic analyses t6:11

Studies including 200 or more subjects more likely to be statistically significant. Confounders such as parity, BMI, chronic hypertension, and history of prior adverse pregnancy outcomes are not accounted for in many existing studies. Requires properly prepared and stored plasma for LAC testing.

E

t6:9 t6:10

O

t6:1 t6:2 t6:3



540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577

Table 7 Ten studies addressing the association between fetal death and antiphospholipid antibodies (aPL) by analyzing all the 3 criteria aPL tests (lupus anticoagulant, anti-cardiolipin and anti-β2glycoprotein I antibodies).

t7:3

Reference

Study design

t7:4

Gris JC et al. Thromb Haemost 1999; 81:891–99 [17]

Case–control

t7:5

Yamada H et al. Fertility Sterility 2003; 80:1276–8 [52]

Prospective cohort RPL (fetal loss N 14 W)

t7:6

t7:7

t7:8

t7:9

t7:10

t7:11

Outcome

U

Fetal death N22 W

N patient

N patient with fetal death (%)

aPL profile (yes/no)

aPL profile definition

Control group (yes/no)

Treatment

232

232 (100%)

Reported Single pos, LA + aCL but not IgG, triple positive analyzed

Yes (464)

No

15 (13%)

Yes

Different combinations

No

No

No

Yes (100)

Single, double, triple pos (99th perc as cut-off)

No

Different treatments (description available)

Yes (262)

No

N

C

Prospective cohort Pregnancy loss (E = first trimester, L = second + third trimester) Pregnancy failure Ruffatti A et al. Thromb Retrospective despite treatment Res 2009; 123:482–7. study of prospectively [72] followed pregnancies Case–control Fetal death N22 W Helgadottir LB et al. Thromb Res 2012; 130:32–7. [73] Vora S et al. Europ J Obstet Gynecol Reproduc Biol 2008; 137:136–140 [19]

114

O

430

R

R

142 LPL (33%), 126 EPL + LPL (29%)

97 preg in 79 women with PRIMARY APS (12 failures, all fetal deaths)

12 (12.4%) (N10 W)

E

Yes

105

105 (100%)

Yes

C

T

E

LA ± other tests

Take home message

Distribution of aPL in cases and controls: isolated LA 0%/0%, isolated aCL IgG 5.6%/1%, isolated a-beta2GPI IgG 0%/0%, LA + aCL IgG 4.3%/1%, triple pos 3.4%/0.2%. Distribution of aPL in fetal Description of subsquent death N 14 W (n = 15) and pregnancies others (n = 99): LA + aCL 20%/2% (p b 0.5),LA + antibeta2GPI 13.3%/1% (p b 0.05), triple pos + aPS/PT 20%/5.1% (p = ns). No Association between LPL (n = 142) and aCL IgG/M and anti-beta2GPI IgG/M, no association with LA. 12 late fetal deaths despite treatment: 10 in triple positive, 1 in double pos, 1 in single pos for high titer IgG anti-beta2GPI

The association of LA with a history of fetal death (OR 4.3; 95% IC 1.0–18.4) was confined to women positive for other aPL. Being positive for anti-beta2GPI or aCL alone was not significantly associated with a history of fetal death 3 major independent risk Different Single, double, triple Yes (57 factors for pregnancy failure in treatments successful pos (99th perc as pregnancies) (description APS: SLE or other autoimmune cut-off) diseases, a history of both available) thromboembolism and pregnancy morbidity; triple aPL positivity Good outcome in 27/35 (77%) No LDA + High pos more or prophylactic PT pregnancies while only 7/20 equal to 4 times the (35%) in HPT pregnancies LMWH upper limit of normal (not applied to LA)

Comments

–

–

–

–

Women tested 3–18 years after the index pregnancy.

D

Ruffatti A et al. Rheumatology (Oxford) 2011; 50:1684–9. [74]

Case–control

Pregnancy failure despite treatment

57 unsuccessful pregnancies (mixed primary and secondary APS)

25 (43.9%)

Yes

Simchen MJ et al. Acta Obstet Gynecol Scand 2011; 90:1428– 33. [57] Mekinian A et al. J Reproduct Immunol 2012; 94:222–6. [56]

Retrospective study of prospectively followed pregnancies Retrospective study of prospectively followed pregnancies

Composite adverse fetal/ neonatal outcome

55 pregnancies in 51 women (mixed primary and secondary APS)

Not defined

Yes

Pregnancy morbidity (anamnestic pregnancies vs treated pregnancies)

57 pregnancies primary 27 (47%), 11 in Yes APS (25 in medium-high group 1 and 16 titer group — group 1, 32 in group 2) in low titer group— group 2)

P

R O

O

F

Medium-high titer aPL according to Sapporo vs. low titer aPL (40 U as cut-off)

Yes (21)

Different treatments (description available)

Single positivity is associated with good outcome. But still 14 out of 38 failures were in single pos patients



t7:1 t7:2

Good outcome is appropriately grown, live born infant N32 w; maternal complications were also reported

Fetal deaths under treatment: Pregnancy outcomes in untreated pregnancies with low 0 in group 1 and 2 (6%) in aPL are poor and similar to those group 2 in obstetrical patients with confirmed APS (medium-high titer aPL). Conventional APS treatment substantially improved pregnancy and neonatal outcomes in both groups of patients. 9

593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629

There is a positive association between fetal death and aPL according to a small number of studies, including a recent multicenter, prospective, case–control study with more than 500 patients with stillbirths. Nevertheless, the existing studies are highly heterogeneous, and most of them do not follow international criteria calling for detailed information regarding clinical events and for repeat laboratory testing. The participants of the Task Force suggested that future studies should investigate the relationship of fetal death with aPL titer (low vs high titers of aPL) and aPL profile (triple positivity vs double or single positivity). These studies should be multicentric, considering the rarity of the event, and should evaluate other causes of fetal death to rule out confounding factors. Such systematic evaluations, such as the one used in the Stillbirth Collaborative Network [87], are available, though modification might be required. Standardization of the aPL tests between centers is crucial; this would be best done using central, “core” laboratories. Current recommendations to treat patients with history of fetal death and positive aPL are based on studies concerning early recurrent abortions, with all limitations that have been exposed (see item 1.2 — Treatment of patients with REM and positive aPL). There are no welldesigned RCT to support the efficacy of this treatment for fetal death. Although Task Force members agreed that good quality data is lacking, several members commented that RCT involving placebo are unlikely to be done for reasons discussed above. Most Task Force members voiced that they will continue to treat women meeting Sapporo laboratory criteria and having fetal death with such agents as heparin and LDA. Patients with history of fetal death and low titers of aPL, on the other hand, may be prone to randomization as they are not classified as carriers of APS.

633 634

4. Preeclampsia and placental insufficiency

661

T

591 592

C

589 590

E

587 588

R

585 586

R

583 584

O

581 582

C

579 580

imperative that clinicians initiate an appropriate evaluation for potential causes. This has important emotional and medical benefits for families and facilitates counseling and management of subsequent pregnancies. In the context of aPL, it allows us to avoid attributing a stillbirth to positive levels of aPL when it may be due to another etiology such as trisomy. The most useful tests in the evaluation of fetal deaths include perinatal autopsy, placental histology, and fetal karyotype or chromosomal microarray, although others may be helpful in a subset of cases [85,86]. In the previously mentioned study by The Stillbirth Collaborative Research Network (SCRN) [85], in many of the cases of stillbirth with positive tests for aPL it was unclear that APS was the cause of death. The SCRN developed a classification system for stillbirth termed INCODE that accounts for the most likely causes of death [87]. Using this system, only 15% of the stillbirth cases with positive tests for aPL were considered to be due to APS [71]. If we are to improve our understanding of aPL and fetal death, it is critical that subsequent studies include appropriate levels of obstetric detail regarding the gestational age and developmental stage of the pregnancy losses. It is just as important that details are included about any evaluation (or lack of evaluation) for other potential causes of fetal death, as well as details regarding other evidence of placental insufficiency such as fetal growth restriction, abnormal fetal testing and placental histologic abnormalities. It would be ideal, if the APS community can agree on uniform definitions for fetal death, a standard evaluation for fetal death and a classification system (there are over 40) to use when reporting about stillbirths. These goals should be possible to achieve through appropriate communication and collaboration. Solving the issue of the optimal therapy for fetal death is more challenging. In part this is due to the fact that the recurrence risk for fetal death is relatively low and is estimated as 1–5%. It appears to be higher in cases of bona fide APS but the sample size needed to assess efficacy is still considerable due to the high rate of success in controls. In addition, many patients and physicians would be unwilling to consider randomization to a placebo arm in cases of fetal death and positive tests for aPL. This is understandable given the emotional duress of stillbirth and the impressive albeit anecdotal data that are available. Also, patients with prior thrombosis, a group at high risk for adverse perinatal outcomes, require anticoagulant therapy to prevent recurrent thrombosis, regardless of the potential fetal benefits. Nonetheless, there are two populations that may be amenable to appropriately designed trials. The first includes women with fetal death not associated with placental insufficiency and low titers of aPL. It is especially unclear whether these women benefit from standard treatment, and some may be willing to be randomized. The second are women with so called “refractory” APS. This refers to patients with adverse pregnancy outcomes such as fetal death in spite of traditional therapy. Although uncommon, this group is particularly vexing. Better therapies are needed for such cases and it would be feasible to randomize them to traditional therapy compared to traditional therapy plus a novel therapy. Of course such trials would require large collaborative

N

578

Different definitions of positive aPL

U

t8:6 t8:7

632

F

Different outcomes under study


O

t8:5

Case–control studies, cohort studies, etc. From 50 to nearly 400 patients – General obstetric population with fetal death – Primary APS only – Mixed population of primary and SLE-associated APS – Pure obstetric APS vs. Thrombotic APS Not only fetal death (recurrent pregnancy loss, composite indexes of pregnancy outcome, etc.) According to local laboratories

R O

Different study design Different sample size Different patients

P

t8:3 t8:4

efforts due to the relatively small numbers of women meeting these 630 strict criteria. 631

Table 8 Reasons for heterogeneity of the ten studies reported in Table 7.

D

t8:1 t8:2


E

10

635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660

4.1. Association of aPL and preeclampsia [summary prepared by Carlos A. 662 Andrade, MD, DSc, and D. Ware Branch, MD] 663 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 rigor [70,88]. do Prado and colleagues [88] searched PubMed and LILACS through June 2009 to assess the association of aCL with PreE. They sought cohort, case– control, or controlled, cross-sectional studies that (1) included women with no pre-existing autoimmune disease and healthy pregnancy as controls, (2) assessed for IgG aCL, IgM aCL, or both of at least 20 units in ELISA, and (3) had an end-point of PreE (without restriction of definition or severity). The authors identified 64 full-text papers. Based on assessment of study quality [89] and excluding those with substantial scientific deficits, the authors included 12 primary studies, published in 1996–2002, in a meta-analysis. The salient findings of this analysis were that there is an association between aPL and severe, but not mild, PreE in pregnant women without autoimmune disease, but that the existing scientific basis has significant scientific limitations, particularly heterogeneity of study design, study size and, possibly, definition of PreE. Abou-Nassar and colleagues [70] searched MEDLINE, EMBASE, and EBM through May 2009 for cohort, case–control, or controlled, crosssectional studies with at least one positive test for LA, aCL, or aβ2GPI antibodies and one or more primary outcomes that included PreE, late


664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690

G.R. de Jesus et al. / Autoimmunity Reviews xxx (2014) xxx–xxx t9:1 t9:2

11

Table 9 Proposed nomenclature for pregnancy loss. Modified from Silver [81]. Proposed nomenclature

Definition

Old nomenclature

Developmental stage

t9:4

Embryonic death (040–096 weeks of gestation)

Early spontaneous abortion

Embryo

t9:5

Fetal death (100–196 weeks of gestation)

Either 1) death of a conceptus measuring up to 29 mm in CRL or 2) sonographic documentation of a dead conceptus with a crown-rump length (CRL) consistent with a gestational age up to 9 weeks and 6 days gestation (CRL up to 29 mm). The embryo must be identified by ultrasound to rule out anembryonic pregnancy. Either 1) passage of a conceptus measuring at least 30 mm in CRL, 2) sonographic documentation of a dead conceptus with a crown-rump length (CRL) consistent with a gestational age at least 10 weeks gestation (CRL at least 30 mm), or 3) loss of the conceptus after documented fetal cardiac activity at or beyond 10 weeks gestational age. The fetus is dead at the time of delivery with Apgar scores of zero at one and 5 min. Death of a formed fetus alive at birth in the first 28 days of life Fetus at least 20 weeks of gestation that is dead at the time of delivery with Apgar scores of zero at one and 5 min.

Spontaneous abortion

Fetus

Neonatal death Stillbirth

Neonate Fetus

705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739

O

P

R O

The same group, Yamada and colleagues, used samples from their prospective cohort study in a subsequent case–control investigation of anti-β2GP1 only [92]. The assay method was in-house and used the 99th percentile threshold for non-pregnant, healthy controls. Four of 36 (11.1%) PIH cases and 6 of 111 (5.4%) of those without PIH were positive beyond the 99th percentile for anti-β2GP1 IgG, but this difference was not significant. There was no statistical difference between cases and controls regarding IgM results beyond the 99th percentile threshold. Using criteria for severe pregnancy induced hypertension of the Japan Society of Obstetrics and Gynecology, a significant odds ratio for PIH being associated with a positive test for aβ2GPI was found (OR 5.3, 95% CI 1.1–24.3), but the number of cases was very small. Repeat testing was not done. The second case–control study [93] involved 99 Spanish subjects with PreE, defined according to American College of Obstetricians and Gynecologists guidelines, and 83 controls. All were tested for LA, aCL, and aβ2GPI as well as for other non-standardized aPL, and the threshold used for positive was N3 standard deviations from control subjects. Overall, the only significant finding was for aCL IgM, with positive results in 8.08% of PreE cases and 1.2% of controls. Among severe PreE case, significant differences were found for LA, aCL IgM, and aβ2GPI IgM, but the number of cases was small. Repeat testing was not performed. We judged the best of the work published since 2009 to be the prospective, observational, cohort study of Chauleur et al. [94]. The authors studied women having a next pregnancy after suffering a single previous embryonic loss. Women with thrombosis, autoimmune conditions, and other traditional risk factors for adverse pregnancy outcome were excluded. All were tested for LA, aCL, and anti-β2GP1 with the latter two assays being an in-house method and using a threshold at the 99th percentile of 200 healthy women. PreE was defined according to study specific criteria that were reasonable, but not referenced to current guidelines; severe PreE was not defined. One-hundred-forty-two women who repeatedly tested positive and who became pregnant again (after a single prior loss) were matched to a similar number of women who had tested negative. The adjusted OR for PreE in the observed pregnancy was significantly higher in those with aCL or aβ2GPI IgG (3.09, 1.13–8.48 and 4.61, 1.53–13.88, respectively); there was no association with LA. Although it was not the main focus of the Task Force, it was discussed during the meeting that the frequency of aPL among patients with PreE remains unknown, considering all critical issues previously mentioned. Small studies have been published trying to address this relationship with inconsistent results.

D

703 704

T

701 702

C

699 700

E

697 698

R

695 696

R

693 694

fetal loss, IUGR, and placental abruption. Studies with women using thromboprophylaxis, undergoing assisted reproductive treatments or with known autoimmune disease were excluded. The authors were unable to analyze the data for aCL and aβ2GPI results meeting revised Sapporo criteria [1] and so included data with lower thresholds for positive (5 GPL/MPL instead 40 GPL/MPL). Twenty-eight studies met inclusion criteria and were deemed of sufficient quality (using Newcastle–Ottawa Quality Scale [90]). Twenty-nine studies were tested for aCL, only 13 were tested for LA and only 6 were tested for antiβ2GP1. LA was associated with PreE in case–control (OR 2.34, 95% CI 1.18–4.64), but not cohort (OR 5.17, 95% CI 0.60, 44.56) studies. Similarly, any positive aCL (IgG or IgM) were associated with PreE in case– control (OR 1.52, 95% CI 1.05–2.20), but not cohort (OR 1.78, 95% CI 0.39–8.16) studies. In cohort studies, only IgG aCL N 20 GPL was associated with PreE (OR 2.20, 95% CI 1.08–4.49; 3 studies). Any aβ2GPI and IgG aβ2GPI were associated with PreE in cohort studies (respectively, OR 19.14, 95% CI 6.34–57.77 and OR 24.00, 95% CI 5.81–99.13), but not in case–control studies. The authors noted significant flaws in the available data and concluded that most studies are under-powered, with high heterogeneity regarding definitions of PreE and glaring lack of consistency among the observed associations. The authors of this review performed searches of PubMed and LILACS to find case–control, cohort, or controlled cross sectional studies published since 2009 and through May 2013 that involved testing for LA, aCL, or aβ2GPI, included an outcome of PreE and had an appropriate control group of pregnancies in women without known autoimmune disease. The terms used in this search are shown in the Appendix A. Though details of our search are purposefully excluded from this brief report, we identified two case–control and two cohort studies published from 2009 to 2012 that met our criteria for assessment. Yamada and colleagues [91] performed a prospective cohort study in which over 1100 women who underwent LAC and aCL testing, as well as other antibody tests, in the first trimester and were then observed for adverse pregnancy outcomes. The authors used an in-house assay for aCL, and the 99th percentile threshold to determine positive results of immunoassays (derived from 105 women without adverse outcome), as is called for by international guidelines [1]. The authors defined pregnancy induced hypertension (PIH) according to the Japan Society of Obstetrics and Gynecology, with what would be defined as PreE or severe preE in the U.S. included within this definition, but is difficult to sort out with certainty. As expected, only a small number (N = 36) of women developed PIH, and one of these had a prior history compatible with APS. The prevalence of PIH or severe PIH was higher in women who tested positive for LA, and the prevalence of any PIH was higher in those with IgG aCL. Fully a third of the women testing positive for both LA and aCL IgG developed PIH, and all cases were severe in nature. Multivariate analysis proved significant for IgG aCL (OR 11.4, 2.7– 47.6). It is worth noting that the number of cases of PIH was small, and repeat testing was not performed.

N C O

691 692

Neonatal death Stillbirth (at least 20 weeks of gestation)

U

t9:6 t9:7

E

a) Early fetal death (100–156 weeks gestation) b) Late fetal death (160–196 weeks of gestation)

F

t9:3

740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782

4.2. Association of aPL and placental insufficiency [summary prepared by 783 D. Ware Branch, MD, and Guilherme R. de Jesus, MD] 784 This second review in this section of the Task Force was aimed 785 to investigate the association of aPL and placental insufficiency 786


12 t10:1 t10:2


Table 10 Summaries of studies of the association of aPL with intrauterine growth restriction (IUGR). Author, year

Design

Assays and thresholds IUGR⁎ cases or total cohort/ cases of IUGR

Repeat testing?

Definition of IUGR

Milliez J et al., Am J Obstet Gynecol. 1991 Jul; 165(1):51–6. [98]

Case– control

50

LA aCL IgG N15 U

No

EFW b 10th No %tile

No

Polzin WJ et al., Obstet Gynecol. 1991; 78:1108–11. [95]

Case– control

55

LA aCL IgG N 22 U aCL IgM N 10 U

No

EFW b 10th No

Yes, for aCL

Rix P et al., Acta Obstet Gynecol Scand. 1992; 71:605–9. [99]

Cohort

2856/40

LA (via aPTT only) aCL IgG N 34 U aCL IgM N 29 U

No

Not defined

Yes, for aPTT N 35 s (“LA”)

Yasuda M et al., Obstet Gynecol. 1995; 86:555–9. [13]

Cohort

860/22

aCL IgG N 20 GPL U

No

Birth weight No b10th %tile

Katano K et al., Hum Reprod. 1996; 11:509–12.

Cohort

1125/35

aCL IgG N 99th %tile (β2GP1-dependent)

No

Not defined

Cohort

510/11

No

Cohort

1200/22

aCL IgG N 99th %tile aCL IgM N 99th %tile aβ2GP1 IgG N 99th %tile aβ2GP1 IgM N 99th %tile aCL IgG N 2 SD aCL IgM N 2 SD

Case– control

40

t10:11

Faden D et al., Eur J Obstet Gynecol Reprod Biol. 1997; 73:37–42. [97] Matthiesen LS et al., Eur J Obstet Gynecol Reprod Biol. 1999; 83:21–26. Kupferminc MJ et al., N Engl J Med. 1999; 340:9–13. [96]

LA aCL IgG N 15 U aCL IgM N 15 U

Case– control

25

t10:12

Alfirevic Z et al., Obstet Gynecol. 2001; 97:753–9. [100]

Chauleur C et al., J Thromb Haemost. 2010; 8:699–706. [94]

Cohort

284/23

LA aCL IgG, positive acc. to manufactuer aCL IgM, positive acc. to manufactuer LA aCL IgG N 99th %tile aCL IgM N 99th %tile Aβ2GP1 IgG N 99th %tile aβ2GP1 IgM N 99th %tile

t10:3

Adjustment for Statistical confounders? association of aPL and IUGR

Cases identified based on ultrasound estimation of fetal weight. Of 50 cases, 28 had birth weights b10th percentile and 22 had birth weights b3rd percentile. Only one case had LA and none had aCL. Cases identified based on ultrasound estimation of fetal weight. Of 55 cases, 37 had birth weights b10th percentile. Controls were 1458 consecutive obstetric patients, among whom 37 (2.5%) were found positive for aCL. LA was not tested in controls. No subject had LA. Fifteen (27.3%) of 55 cases had aCL (7 IgG, 8 IgM, and 1 both). Non-standard definition of LA. “LA” in 17.5% of IUGR cases and 0.07% of non-IUGR subjects. Two subjects were aCL IgG positive and 54 were aCL IgM positive. Small numbers of positive cases and IUGR in cohort. IUGR in 7 (11.7% of aCL IgG positive subjects vs. 15 (1.9%) of aCL IgG negative subjects. Small numbers of positive cases and IUGR cases in cohort. Three of 8 aβ2GP1-positive cases had IUGR newborns compared to 32 of 1100 aβ2GP1-negatives. Small numbers of positive cases and IUGR cases in cohort. Only 28 women had positive antibody test results. Small numbers of positive cases and IUGR cases in cohort. Thresholds for positive aCL were low (N2 SD).

O

F

t10:4

Comments

t10:5

t10:7

787 788 789 790 791 792 793 794 795 796 797 798 799 800 801

Yes

No

No

Birth weight No b10th %tile

No

Not defined

Not determined independent of other thrombophilias No

E

D Yes

C

E

R

R O

C N

t10:13

No

No Yes, 10 weeks apart

Yes

(PI), in the same fashion as described in previous topic. The specific criteria for PI are referenced in the international criteria, but from a practical standpoint only intrauterine growth restriction (IUGR) has been studied. The systematic review of Abou-Nassar et al. [70] included all of the studies mentioned in Table 10 except those of Polzin et al. [95], Kupferminc et al. [96], and Chauleur et al. [94]. The authors found that associations were found between LA and IUGR (OR 4.65, 95% CI 1.29– 16.71) in case control studies, but not in cohort studies. There was no association of aCL and IUGR in an analysis of case–control or cohort studies. Any aβ2GPI and IgG aβ2GPI were associated with IUGR (respectively, OR 20.03, 95% CI 4.59–87.43 and OR 20.03, 95% CI 4.59–87.43) in cohort studies, but not in case–control studies. A systematic review of the association of aPL with PI was also performed, noting that all studies defined PI via its manifestation in IUGR.

U

t10:10

Yes

No

Not defined

T

t10:8

t10:9

P

t10:6

R O

In some subjects

No

No

Birth weight Yes b10th %tile

Yes, OR 4.64, 95% CI 1.64–13.18

Eleven women had aCL; one of these had LA. There were no positive aCL or LA results among 110 controls.

Ten cases and 3 controls positive for aCL; 9 cases and 0 controls positive for LA.

142 aPL positive cases, but small number of IUGR cases in cohort.

Ten studies were identified, in which the investigators sought to determine the relationship of aPL and PI in women without known autoimmune disease or other confounder and in which an appropriate control group was included. Pertinent details of these studies are summarized in Table 10. Only two studies included testing for aβ2GPI [94, 97] and six [94–96,98–100] included testing for LA. Substantial differences between the studies were noted:

802

• Considerable variation in how testing was done and thresholds used to define positive results. • The lack of repeat testing in all but two studies. • Differing definitions of IUGR, or the absence of description of definition. • Lack of adjustment for confounders in statistical analyses in all but one study.

809


803 804 805 806 807 808

810 811 812 813 814 815


859

As found by do Prado et al. and Abou-Nassar et al., our updated systematic review found a number of limitations or flaws that made a true meta-analysis for either PreE or PI unrealistic. The major limitations are presented in Table 6. We viewed the most critical of these as being in the general areas of variability of assay methods and definition of assay positivity, heterogeneous definitions of PreE and PI, small sample size, and lack of repeat testing. Recommendations regarding how these limitations may be overcome in future studies also are shown in Table 6. After careful analysis, we would view studies that did not address each of these as unacceptable for our current understanding of aPL associations. We suggest that the availability of core laboratories through the APS ACTION network represents a great stride forward. Though studies to determine if there is an association between any degree of aPL and PreE or PI at any gestational age are important, investigators should carefully delineate whether or not aPL are associated with the stated international clinical criterion: One or more premature births of a morphologically normal neonate before 34 weeks gestation because of preeclampsia, eclampsia, or features of placental insufficiency. In particular, the suggested definition of PI includes abnormal or non-reassuring fetal surveillance test(s), e.g. a non-reactive non-stress test, suggestive of fetal hypoxemia, abnormal Doppler flow velocimetry waveform analysis suggestive of fetal hypoxemia, e.g. absent end-diastolic flow in the umbilical artery, oligohydramnios, e.g. an amniotic fluid index of 5 cm or less, or a postnatal birth weight less than the 10th percentile for the gestational age. In addition, international guidelines call for classification of patients in studies into one of the following categories: I, more than one laboratory criteria present (any combination); IIa, LA present alone; IIb, aCL antibody present alone; IIc, anti-β2 glycoprotein-I antibody present alone.

860


861

This updated systematic analysis suggests that there may be an association between aPL and PreE or PI. Considering PreE, a majority of studies, particularly case–control studies, found positive associations, while for PI, a majority of cohort studies described such relationship. It should be mentioned, however, the significant concern about the lack of consistency among the observed associations. True meta-analyses using existing studies are unrealistic due to differences in clinical definitions and laboratory methodology, therefore could not be performed. The limitations of existing studies are substantial (Table 6) and should be addressed by studies of better design and statistical power. In future studies, investigators are strongly encouraged to 1) use APS ACTION core laboratories for confirmation of test results and to assure testing using standardized methodology, 2) describe whether or not the current international clinical criterion, i.e., “one or more premature births of a morphologically normal neonate before 34 weeks gestation because of preeclampsia, eclampsia, or features of placental insufficiency”

839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858

862 863 864 865 866 867 868 869 870 871 872 873 874 875 876

C

837 838

E

835 836

R

833 834

R

828 829

N C O

826 827

U

824 825

5. Infertility

886

879 880 881 882 883 884 885

5.1. Association of aPL and infertility and treatment of patients with 887 infertility and positive aPL [summary prepared by Cecilia Chighizola, MD, 888 and Guilherme R. de Jesus, MD] 889

F

832

822 823

O

4.3. Limitations of studies

821

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 currently screen infertile women for aPL. Similarly, in many centers it is common clinical practice to treat infertile but otherwise asymptomatic aPL positive women undergoing in vitro fertilization (IVF), despite the lack of supporting evidence-based recommendations. Given this low grade of agreement in the scientific community, a systematic review of literature was performed to accurately evaluate the available evidence about aPL and infertility. In particular, three research items have been assessed, namely: i) the potential differences in aPL positivity rates between infertile women and control subjects, ii) the association between aPL and IVF outcome and iii) the effects of medical treatments on IVF outcome of aPL positive women. A search on PubMed using as keywords the terms “aPL”, “infertility”, “IVF” and “treatment” was conducted. Moreover, cross-checking of references was performed in order to include all available studies. Our search was restricted to full-text manuscripts written in English published between 1988 and September 2013. A wide disparity across retrieved studies was observed, limiting the comparability of studies and preventing the conduction of a metaanalysis. In particular, an extreme heterogeneity was reported in i) the selection criteria of both study and control populations, ii) the aPL tests performed, iii) the definition of outcome, iv) the evaluated medical treatment and v) the study design (Table 11). Twenty-nine studies assessing aPL frequency among both infertile women and control populations were identified [28,102–128]. Two main subpopulations of infertile women were identified: women with unexplained infertility and those candidate to a first IVF cycle, and women with IVF failure. Of the 29 relevant studies, 13 (44.8%) reported a significant difference of aPL frequency between infertile women and controls [28,102–105,108–111,119,122,125,129]. These 13 studies were impinged by several limitations. Indeed, two studies only (15.4%) evaluated all three criteria tests [125,130], while most of them assessed non-criteria aPL tests. In particular, the aCL assay was performed in all the 13 studies (100%), followed by non-criteria aPL tests in 7 (53.8% [28,103,108,109,111,119,125]) and LA in 5 [28,104,109, 110,125], while only 2 studies (15.4%) evaluated aβ2GPI antibodies [125,130]. A medium-high titer aCL cut-off conforming to international guidelines was used in one study (15.4% [125]), and only two 2 studies (15.4%) confirmed aPL positivity 6 to 12 weeks apart [103,125]. Of the 14 studies addressing the relationship between aPL and IVF outcome [101,113,114,118,125,126,128,129,131–136], only two reported a detrimental effect of these autoantibodies [135,136]. The PubMed search lead to the identification of 10 relevant studies assessing the effects of medical treatment on IVF outcome [104,112,

R O

831

819 820

P

830

Five studies concluded that aPL were statistically associated with IUGR, four of which were cohort studies. These 5 studies included 175 cases of IUGR. Five studies, including two cohort studies and a total of 108 cases of IUGR, concluded that aPL were not statistically associated with IUGR. None of the studies used core laboratory confirmation of positive tests. After careful analysis of the existing studies, we conclude that a meta-analysis using these studies is unrealistic due differences in clinical definitions and laboratory methodology. As with PreE, the prospective, observational, cohort study of Chauler et al. [94] was judged the best. Defining IUGR as b 10th percentile birth weight, the authors found that the adjusted OR for IUGR in the observed pregnancy aPL versus non-aPL pregnancy was 4.64 (95% CI 1.64–13.18). The strongest association for IUGR was with LAC positive status.

877 878

D

818

is associated with aPL, and 3) classify subjects according to aPL profile as suggested by international clinical criterion. It was proposed during the Task Force that multicenter prevalence study should be performed for better understanding the association between aPL and PreE. Although the same question occurs about aPL and PI, the participants of the Task Force agreed that studies addressing this specific topic are more difficult to be developed considering the great number of causes of IUGR that would have to be excluded and confounding by PreE.

E

• Small numbers of IUGR cases including in most studies. • Small numbers of aPL positive cases in all but one study.

T

816 817

13


890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939

Critical issues

All

Study population – – – – –

Infertility diagnostic work-up IVF failure Age Parity Associated autoimmune conditions

Control population Ongoing pregnancy Age Parity Fertility (tubal/ovulatory infertility)

aPL tests – Criteria/non criteria tests – Number of aPL criteria tests performed (one/two/three) – aPL cut offs (low titer, medium/high titer) – aPL positivity confirmation t11:5

– Implantation rate/live birth rate Lower likelihood of embryo implantation in IVF cycle compared to physiological pregnancy aPL interference with pregnancy progression Poor comparibility between groups Positivity for other autoantibodies Different treatment regimen

t11:6

aPL, IVF outcome and medical treatment

Available evidence does not support a role for aPL as potential mediators of infertility. A positive association was described mainly with non-criteria aPL, autoantibodies that do not have well-established clinical implications. The studies are highly heterogeneous, especially considering laboratory tests, inclusion criteria and definition of control groups, leading to mixed results. Either way, IVF outcome does not seem to be affected by aPL positivity, and no treatment was able to consistently improve these outcomes in patients with positive aPL. The participants of the Task Force agreed that there are no data to support the inclusion of infertility as criteria for APS and investigation of aPL in patients with infertility should not be done in routine clinical practice, being reserved only for research purposes. Also, there are no well-designed studies to show that patients with infertility and positive aPL require treatment (e.g., with heparin compounds) to improve IVF outcome per se.

979 980

949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971

C

E

R

R

947 948

O

945 946

C

943 944

128–130,137–141]. Three studies evaluated a regimen comprising heparin 5000 U twice daily plus low-dose aspirin, but none of them reported a positive effect on IVF outcome [128–130]. A single study evaluated steroids as the only medical therapy, describing a higher clinical pregnancy rate per cycle in the treatment group [112]. The combination of prednisone and aspirin was evaluated in 4 studies [104,133, 137,139]. One study published in 2012 giving methylprednisolone plus aspirin for three months before IVF reported an increased efficacy on IVF outcome [139], while the three others either did not consider a control group or observed no effects. The addition of intravenous immunoglobulin to heparin–aspirin combo therapy in two studies did not improve IVF outcome [138,140]. As a whole, some of available studies observed a higher frequency of positive aPL among infertile women as compared to control women. To note, a rather low prevalence of LA, the aPL test regarded as the strongest risk-factor for aPL-associated pregnancy complications, was reported in both groups, while most of supportive evidence comes from studies assessing non-criteria aPL tests. However, the clinical significance of non-criteria aPL tests is highly controversial. Moreover, it should be noted that association does not necessarily imply causation. Indeed, the high frequency of aPL among women undergoing IVF cycles might be a mere epiphenomenon due to hormonal treatment. Similarly, all studies but two assessing the effect of aPL positivity on IVF outcome reported no significant effects. This is consistent with a metanalysis published in 2000, where the odds ratios for both clinical pregnancy and live birth in aPL positive women undergoing IVF compared to those negative for aPL were estimated to be around one, suggesting that aPL positivity is not associated with a reduced IVF success [142]. The American Society for Reproductive Medicine also presented similar data in a critical review published in 2008 [143]. Accordingly, available data do not support the efficacy of medical treatment of women candidate to IVF with aPL positivity.

N

941 942

U

940

974 975 976 977

981 982 983 984 985 986 987 988 989 990 991 992 993

6. The role of complement in pathogenesis of preeclampsia and 994 placental insufficiency in patients with aPL [summary prepared by 995 Jane Salmon, MD] 996 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 insufficient regulation of complement recruits leukocytes and unleashes potent inflammatory and antiangiogenic mediators associated with PI and, in some cases, maternal endothelial dysfunction characteristic of PreE. APL have been shown to induce a proinflammatory, proadhesive and procoagulant phenotype in the vasculature. Complement activation initiates and amplifies the cellular features characteristic of APS: endothelial cell activation, monocyte tissue factor expression and platelet aggregation. In a similar manner, pregnancy complications in APS are triggered by inflammation at the maternal–fetal interface where complement activation plays an essential role. Mouse models of aPL antibody-induced pregnancy loss and growth restriction show that classical and alternative pathway components (C4, factor B, C3, C5, and C5aR) are required for placental injury [145]. Passive transfer of IgG from women with recurrent pregnancy loss and high titer APL antibodies into mice results in increased fetal resorptions compared to mice treated with IgG from healthy individuals, and reduction in average weight of surviving fetuses [146]. Inhibition of complement prevents these complications [145,146]. Using mice deficient in complement elements and inhibitors of complement activation in this model of APS, C5, and particularly its cleavage product C5a, was identified as a key mediator of fetal injury [145,146]. Based on the results of these mouse studies, a mechanism for pregnancy complications associated with aPL antibodies was proposed: aPL antibodies preferentially target placental tissue and activate complement via the classical (Fc- and C4-dependent) pathway, leading to generation of potent anaphylatoxins (C3a and C5a), as well as the release of proinflammatory (TNF-α and tissue factor) [145,147,148] and anti-angiogenic factors (sFlt-1) [149]. The result is an influx of inflammatory cells into the placenta leading to intrauterine fetal demise or intrauterine growth

T

t11:7

978

P

Study design (prospectic/non-prospectic) IVF outcome

aPL and IVF outcome


F

– – – –

972 973

O

Study item

Some Task Force members felt it important to note that women with APS or repeatedly positive aPL who are undergoing ovulation induction (controlled ovarian hyperstimulation) are candidates for thromboprophylaxis based on the known elevation of 17β-estradiol in this setting. Reviews of this clinical circumstance, with expert recommendation, are available [144].

R O

t11:4

Table 11 Critical issues limiting the comparability of available studies about antiphospholipid antibodies (aPL) and infertility.

D

t11:1 t11:2 t11:3


E

14


997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033


1055 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073

1079 1080 1081 1082 1083 1084 Q5 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096

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1049 1050

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New mechanisms of obstetric morbidity related to aPL have been described in the last years, with special attention to complement system. The activation of complement by aPL, both classical and alternative pathways, results in fetal loss, IUGR, and PreE in animal models. Interestingly, those complications could be prevented or reversed by complement inhibition in mice. Task Force members noted that we don't currently have a proven treatment to prevent or treat PreE or PI in the setting of APS and what those findings are. However, human data about safety and efficacy of complement inhibitors during pregnancy are still lacking and the use of these medications during pregnancy cannot be recommended until further, much needed studies are done. The moderators propose that women who have failed to have successful obstetric outcomes with currently used treatments (heparin compounds and low-dose aspirin) and who will undertake another pregnancy be considered for an international trial of an immunomodulatory treatment that targets recently defined pathogenic mechanisms. These have been termed “refractory APS” by Dr. Silver (see item 2.2 Treatment of patients with fetal death and positive aPL). Such a trial would have to be thoughtfully constructed and would require the willing participation of multiple centers and the pharmaceutical industry.

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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 nearly 30 years of recognizing APS as a syndrome and nearly 15 years of “consensus” clinical and laboratory criteria, uncertainties abound. We believe that it is incumbent upon the international APS community to organize well-designed studies to address the existing uncertainties and to make concrete suggestions as to how these might be best performed. We also noted considerable enthusiasm among the Task Force participants for diagnosing APS and treating as yet unrecognized obstetric morbidities in the setting of positive aPL results. However well-intended this enthusiasm might be, we are concerned that it will further obscure our search for genuine associations and proven treatments. Of particular concern to the moderators is the call by some for liberalizing diagnostic criteria in the absence of critical studies of association or treatment benefit. Again, we believe it should be the role the international APS community to organize well-designed studies before proposing the introduction of additional criteria and their attendant uncertainties. Task Force members identified clinical subsets for study such as multicenter trials of women with one miscarriage and repeatedly positive moderate titer aPL or two miscarriages and repeatedly positive low titer of aPL. Lastly, our critical analyses uncovered shortcomings in the area of proven treatments that are in dire need of proper investigation. Newly identified therapeutic targets, such as complement inhibition, appear to hold promise [3,158]. The next international congress on antiphospholipid antibodies will be in 2016, only a mere 2 years away. We hope that this next gathering will be filled with reports of solid scientific evidence in the realm of Ob APS, or at least with reports of well-designed work in progress.

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7. Conclusions [prepared by Guilherme R. de Jesus, MD, and D. Ware 1097 Branch, MD] 1098

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restriction. The model is supported by studies of human placenta from patients with APS in which complement deposition has been identified [150]. Furthermore, patients with APL antibodies, with or without clinical manifestation of APS, show elevated circulating levels of cleavage fragment factors Bb and C3a suggesting that dysregulation of the alternative pathway which may decrease the threshold for autoantibodymediated injury [151]. Dr. Salmon and others have suggested a relationship between activation of the complement system and angiogenic factor imbalance linked to placental dysfunction [149,152–154]. In normal pregnancy, excessive complement activation is prevented by complement regulatory proteins (MCP, decay accelerating factor, and CD59) which are highly expressed on trophoblast membranes and circulating complement regulatory proteins (FH, FI and C4b binding protein). In preeclampsia, complement activation products, notably the terminal complement complex (C5b-9), have been confirmed on villous trophoblasts and are associated with injury [155]. In mouse models, complement deposition and neutrophil infiltrates in placenta are associated with abnormal placental development, miscarriage and glomerular fibrin deposition. Inhibition of complement at the maternal–fetal interface rescues pregnancies, restores angiogenic balance and prevents preeclampsia in mice, suggesting that complement triggers a feed-forward cycle of placental damage, anti-angiogenic factor production and maternal vascular damage [145,149]. These studies, taken together, suggest the use of complement inhibitor therapies to prevent or treat preeclampsia in patients at risk. The importance of alternative pathway activation in human pregnancy complications is underscored by three recent findings: (1) the presence of elevated levels of the complement activation fragments C3a and Bb in blood during the first 20 weeks of pregnancy in nonautoimmune patients who develop PE later in pregnancy [153,156], (2) mutations in complement regulatory proteins (MCP, factor H and factor I) preeclampsia in patients with preeclampsia who have SLE and/or APL antibodies and (3) similar mutations in the HELLP syndrome in non-autoimmune patients [157]. Variants in these same genes are involved in atypical hemolytic syndrome, another microthrombotic angiopathy, with features like those seen in catastrophic antiphospholipid syndrome (CAPS) and preeclampsia. The presence of risk variants in complement regulatory proteins in patients with SLE and/or APL antibodies who develop pregnancy complication links complement activation to disease pathogenesis and suggests new targets for prevention and treatment.

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1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 Q6 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124 1125 1126 1127 1128 1129 1130 1131

Take-home messages

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• 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 therapeutic targets. • We strongly encourage and would look forward to better quality scientific evidence regarding obstetric antiphospholipid syndrome to be presented at the next International Congress that will be held in September 2016 in Istanbul, Turkey.

1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147

Appendix A

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Terms used for search considering antiphospholipid antibodies: “antiphospholipid syndrome”, “antiphospholipid antibodies”, “antiphospholipid”, “lupus anticoagulant”, “anticardiolipin antibodies” or “anti-β2-glycoprotein-I antibodies”. Terms used for search of antiphospholipid antibodies were associated with terms for each specific clinical event. Terms used for search considering recurrent early miscarriage: “pregnancy loss”, “miscarriage”, “abortion”, “fetal death”, “recurrent abortion”, “recurrent miscarriage”, and “abortion, habitual”.

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[1] Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4(2):295–306. [2] Galarza-Maldonado C, Kourilovitch MR, Pérez-Fernández OM, Gaybor M, Cordero C, Cabrera S, et al. Obstetric antiphospholipid syndrome. Autoimmun Rev 2012;11(4):288–95. [3] Comarmond C, Cacoub P. Antiphospholipid syndrome: from pathogenesis to novel immunomodulatory therapies. Autoimmun Rev 2013;12(7):752–7. [4] Khattri S, Zandman-Goddard G, Peeva E. B-cell directed therapies in antiphospholipid antibody syndrome—new directions based on murine and human data. Autoimmun Rev 2012;11(10):717–22. [5] Meroni PL, Borghi MO, Raschi E, Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol 2011;7(6):330–9. [6] Opatrny L, David M, Kahn SR, Shrier I, Rey E. Association between antiphospholipid antibodies and recurrent fetal loss in women without autoimmune disease: a metaanalysis. J Rheumatol 2006;33(11):2214–21. [7] Andreoli L, Chighizola CB, Banzato A, Pons-Estel GJ, de Jesus GR, Erkan D, 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. [8] Barbui T, Cortelazzo S, Galli M, Parazzini F, Radici E, Rossi E, et al. Antiphospholipid antibodies in early repeated abortions: a case–controlled study. Fertil Steril 1988;50(4):589–92. [9] Parazzini F, Acaia B, Faden D, Lovotti M, Marelli G, Cortelazzo S. Antiphospholipid antibodies and recurrent abortion. Obstet Gynecol 1991;77(6):854–8. [10] Pattison NS, Chamley LW, McKay EJ, Liggins GC, Butler WS. Antiphospholipid antibodies in pregnancy: prevalence and clinical associations. Br J Obstet Gynaecol 1993;100(10):909–13. 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Anti beta 2glycoprotein I antibodies and lupus anticoagulant in patients with recurrent pregnancy loss: prevalence and clinical significance. Lupus 1996;5(6):587–92. [16] Oshiro BT, Silver RM, Scott JR, Yu H, Branch DW. Antiphospholipid antibodies and fetal death. Obstet Gynecol 1996;87(4):489–93. [17] Gris JC, Quéré I, Monpeyroux F, Mercier E, Ripart-Neveu S, Tailland ML, 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;81(6):891–9. [18] Lee RM, Branch DW, Silver RM. Immunoglobulin A anti-beta2-glycoprotein antibodies in women who experience unexplained recurrent spontaneous abortion and unexplained fetal death. Am J Obstet Gynecol 2001;185(3):748–53. [19] Vora S, Shetty S, Salvi V, Satoskar P, Ghosh K. A comprehensive screening analysis of antiphospholipid antibodies in Indian women with fetal loss. Eur J Obstet Gynecol Reprod Biol 2008;137(2):136–40. [20] Bahar AM, Kwak JY, Beer AE, Kim JH, Nelson LA, Beaman KD, et al. Antibodies to phospholipids and nuclear antigens in non-pregnant women with unexplained spontaneous recurrent abortions. J Reprod Immunol 1993;24(3):213–22. [21] Das I, Vasishta K, Dash S. Study of lupus anticoagulant in pregnant women with recurrent abortion. Aust N Z J Obstet Gynaecol 1991;31(4):323–6. [22] Costa HeL, de Moura MD, Ferriani RA, Anceschi MI, Barbosa JE. Prevalence of anticardiolipin antibody in habitual aborters. Gynecol Obstet Invest 1993;36(4):221–5. [23] Kutteh WH, Park VM, Deitcher SR. Hypercoagulable state mutation analysis in white patients with early first-trimester recurrent pregnancy loss. Fertil Steril 1999;71(6):1048–53. [24] De Carolis S, Caruso A, Ferrazzani S, Carducci B, De Santis L, Mancuso S. Poor pregnancy outcome and anticardiolipin antibodies. Fetal Diagn Ther 1994;9(5):296–9. [25] Kwak JY, Gilman-Sachs A, Beaman KD, Beer AE. Autoantibodies in women with primary recurrent spontaneous abortion of unknown etiology. J Reprod Immunol 1992;22(1):15–31. [26] Ruiz JE, Cubillos J, Mendoza JC, Espinel FJ, Kwak JY, Beer AE. Autoantibodies to phospholipids and nuclear antigens in non-pregnant and pregnant Colombian women with recurrent spontaneous abortions. J Reprod Immunol 1995;28(1):41–51. [27] Saha SP, Bhattacharjee N, Ganguli RP, Sil S, Patra KK, Sengupta M, et al. Prevalence and significance of antiphospholipid antibodies in selected at-risk obstetrics cases: a comparative prospective study. J Obstet Gynaecol 2009;29(7):614–8.

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Terms used for search considering preeclampsia: “preeclampsia”, and “pre-eclampsia”. 1160 Terms used for search considering infertility: “infertility”, “in vitro 1161 fertilization”, and “treatment”. 1158 1159

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Autoantibodies and antisperm antibodies in sera and follicular fluids of infertile patients; relation to reproductive outcome after in-vitro fertilization. Hum Reprod 1995;10(10):2564–9. [115] Ruiz AM, Kwak JY, Kwak FM, Beer AE. Impact of age on reproductive outcome in women with recurrent spontaneous abortions and infertility of immune etiology. Am J Reprod Immunol 1996;35(4):408–14. [116] Azem F, Geva E, Amit A, Lerner-Geva L, Shwartz T, Ben-Yosef D, et al. High levels of anticardiolipin antibodies in patients with abnormal embryo morphology

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[58] Andreoli L, Tincani A. Beyond the “syndrome”: antiphospholipid antibodies as risk factors. Arthritis Rheum 2012;64(2):342–5. [59] Cowchock FS, Reece EA, Balaban D, Branch DW, Plouffe L. Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am J Obstet Gynecol 1992;166(5):1318–23. [60] 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(5):1584–9. [61] Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997;314(7076):253–7. [62] Pattison NS, Chamley LW, Birdsall M, Zanderigo AM, Liddell HS, McDougall J. 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14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends.

14th International Congress on Antiphospholipid Antibodies: task force report on antiphospholipid syndrome treatment trends.

14th International Congress on Antiphospholipid Antibodies Task Force Report on Catastrophic Antiphospholipid Syndrome.

Catastrophic antiphospholipid syndrome: task force report summary.

APS. 30 years on, what have we learnt? Opening talk at the 14th International Congress on antiphospholipid antibodies Rio de Janiero, October 2013.

Determination of clinically significant tests for antiphospholipid antibodies and cutoff levels for obstetric antiphospholipid syndrome.

Budd-Chiari syndrome, obstetric complications, and antiphospholipid antibodies.

Antiphospholipid syndrome and antibodies.

Multiple antiphospholipid antibodies positivity and antiphospholipid syndrome criteria re-evaluation.

Antiphospholipid syndrome, antiphospholipid antibodies and solid organ transplantation.

Cutaneous pseudovasculitis, antiphospholipid syndrome and obstetric misadventure.

[Antiphospholipid syndrome].

A prospective, controlled multicenter study on the obstetric risks of pregnant women with antiphospholipid antibodies.

Antiphospholipid antibodies in stillbirth.

Antiphospholipid antibodies in pregnancy.

Antiphospholipid antibodies: neuropsychiatric presentations.

Antiphospholipid syndrome.

The European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS): A survey of 247 consecutive cases.

Primary antiphospholipid syndrome presenting as antiphospholipid syndrome nephropathy: a case report.

Bridging therapy in antiphospholipid syndrome and antiphospholipid antibodies carriers: case series and review of the literature.

Antiphospholipid antibodies in neonates with stroke--a unique entity or variant of antiphospholipid syndrome?

Antiphospholipid antibodies and infertility.

Primary Antiphospholipid Antibody Syndrome: A Case Report.

Antiphospholipid syndrome.