Controversies Concerning the Antiphospholipid Syndrome in Obstetrics

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The classification criteria of Sapporo and Sidney consider intermediate or high antibody titers, but not low or negative values; it is essential that we do not underestimate the diagnosis of APS in patients with obstetric complications, as an intervention can improve the implicated perinatal outcomes and, thus, it is important to analyze concepts of obstetric antiphospholipid antibody syndrome (O-APS) and seronegative antiphospholipid syndrome (SN-APS).<a class="elsevierStyleCrossRefs" href="#bib0230">3–5</a>The objective of this study is to provide a review of the controversies that surround the diagnosis of APS and its relationship to obstetrics and adverse perinatal outcomes, as well as the current recommendations for its management. We performed an analytical search of the available literature up to December 2015 in the major electronic databases, PubMed (MEDLINE), EMBASE (Elsevier), Cochrane, EBSCO (Dynamed) and Ovid, to retrieve the best available evidence (meta-analyses, systematic reviews, randomized clinical trials and observational studies). The languages used were English and Spanish, and we utilized a combination of the following terms: “antiphospholipid syndrome”, “international consensus criteria”, “antiphospholipid antibodies”, “obstetric APS”, “low titer aPL”, “antiphospholipid antibodies” and “seronegative obstetric antiphospholipid syndrome”, using the Boolean operators “AND” and “OR”.BackgroundAntiphospholipid syndrome is an autoimmune disease that is characterized by arterial or venous thromboembolisms and/or certain obstetric complications in association with antiphospholipid antibodies (APA).<a class="elsevierStyleCrossRefs" href="#bib0245">6–9</a>These antibodies react with phospholipid-binding plasma proteins (mainly anti-β2 glycoprotein-I [aβ2GP-I], prothrombin, protein C, protein S, annexin V, annexin II and low-density lipoproteins), protein/phospholipid complexes and anionic phospholipids.<a class="elsevierStyleCrossRefs" href="#bib0230">3,4,10</a>Expert consensus had been called on to establish the clinical and laboratory criteria to enable the classification of patients, in 1999 in Sapporo, Japan, and later, in 2006, in Sidney, Australia. The criteria for classification were updated and aβ2GP-I isotypes IgG and/or IgM were added, and the interval between assessing the presence of antibodies was increased from 6 to 12 weeks between 1 measurement and the next.<a class="elsevierStyleCrossRef" href="#bib0270">11</a>In 2013, in Rio de Janeiro, Brazil, a new consensus was established and the proposal was to separate as 2 different entities thrombotic APS and that associated with obstetric morbidity (APS-O), with suggestions for novel clinical criteria concerning the latter, such as early recurrent pregnancy loss (RPL [embryonic and preembryonic]), early fetal death, placental insufficiency, infertility and changes in laboratory criteria.<a class="elsevierStyleCrossRef" href="#bib0275">12</a>There may be a substantial clinical correlation between aPL levels in patients with a related obstetric history, and still with low titers and against only one antibody, which could represent a reduced immune function when compared with patients with thrombotic aPL.<a class="elsevierStyleCrossRef" href="#bib0280">13</a>The diagnostic criteria considered have implications in clinical practice, with novel antigen targets, cut-off points, laboratory techniques and the intervals for their measurement, as well as their correlation with the clinical manifestations.Pathophysiological Mechanisms of Obstetric ComplicationsFetal well-being depends critically on the role of the uteroplacental circulation, which joins the mother and the fetus. A normal pregnancy is associated with homeostatic changes, including an increase in the concentration of coagulation factors, and a decrease in natural anticoagulants and the fibrinolytic activity; these pregnancy-related physiological changes predispose the mother to thromboses and to vascular complications, which are related to an increase in the adverse perinatal outcomes in patients with APS.The pathophysiological mechanisms related to the obstetric complications of aPL have yet to be completely clarified, and initially would involve extensive infarctions and placental microthrombi<a class="elsevierStyleCrossRef" href="#bib0285">14</a> and, although these phenomenon are more frequent in patients with who are positive for aPL, they are not the primary origin of the obstetric complications. Placental infarctions are caused by the incapacity of the uteroplacental blood flow, which is secondary to the occlusion of the spiral arteries by an intraluminal thrombus, which can cause ischemic injury in the intervillous space, affecting the placental villosity; however, these lesions are present in only one sixth of the cases and, thus, we must consider that there are multiple pathophysiological processes occurring in patients with APS.<a class="elsevierStyleCrossRef" href="#bib0290">15</a>Considering that aPL are a heterogeneous group of antibodies, with different mechanisms of action, it is not very likely that the obstetric morbidity be caused by a single mechanism like infarction and/or thrombosis. Antiphospholipid antibodies can induce changes in spiral artery remodeling, decidual inflammation and decrease the vasculosyncytial membrane, secondary to other immunological phenomena, such as inflammation, complement activation,<a class="elsevierStyleCrossRefs" href="#bib0290">15–17</a> overexpression of tissue factor in neutrophils and monocytes and imbalance between angiogenic factors, even in the absence of thrombosis.<a class="elsevierStyleCrossRef" href="#bib0280">13</a>Inflammatory manifestations related to aPL are mainly mediated by complement and, secondarily, by the activation of the coagulation cascade,<a class="elsevierStyleCrossRefs" href="#bib0295">16,18</a> as well as a reduction in annexin vand placental tissue damage.<a class="elsevierStyleCrossRef" href="#bib0290">15</a>Other mechanisms are indirect damage to the trophoblast through apoptosis, inhibition of proliferation and syncytiotrophoblast formation, a decrease in chorionic gonadotropin hormone production, and damage to trophoblastic invasion and growth factor secretion, which result in pregnancy loss or placental dysfunction.<a class="elsevierStyleCrossRefs" href="#bib0290">15,19</a>The extravillous trophoblast is the target of inflammatory injury, even for placental infarctions associated with the presence of aPL secondary to the occlusion of the spiral arteries.<a class="elsevierStyleCrossRef" href="#bib0290">15</a>Uncontrolled complement activation<a class="elsevierStyleCrossRef" href="#bib0315">20</a> plays a critical role in the pathogenesis of placental damage induced by aPL; hypocomplementemia is found in up to half of the patients with APS and pregnancy, and is related to adverse perinatal outcomes such as prematurity, low birth weight, death, preterm delivery and preeclampsia (PE).<a class="elsevierStyleCrossRefs" href="#bib0295">16,17,21</a> Fetal loss can be explained by histopathological inflammatory signs secondary to the overexpression of tissue factor in neutrophils and monocytes, or to an imbalance in the angiogenic factors, there being evidence of biochemical markers.<a class="elsevierStyleCrossRef" href="#bib0300">17</a>Obstetric antiphospholipid antibody syndromeAntiphospholipid syndrome is considered a thromboembolic disease; however, in the group with associated obstetric complications, only a small percentage will have thrombotic events (either systemic or uteroplacental). In a prospective, multicenter study of 1000 patients, Cervera et al. studied patients with APS for 5 years, and found that the group with a related obstetric disease had no thrombosis or other manifestations of APS, and less than 5% progressed to a demonstrated thrombosis or systemic lupus erythematosus,<a class="elsevierStyleCrossRef" href="#bib0325">22</a> a fact that suggests that the concept of O-APS involves pathophysiological mechanisms other than the aPL, in comparison with thrombotic APS, in which thrombosis and progression to systemic lupus erythematosus are less frequent than in classical APS.The concept of O-APS as being different from the thrombotic disorder involves both nonconventional clinical and laboratory criteria (<a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1 and 2</a>), as prospective and retrospective have shown that this group of patients has a higher risk of placental dysfunction (PE, intrauterine growth restriction [IUGR]) and prematurity, as well as a long-term increase in the risk of thrombotic events.<a class="elsevierStyleCrossRef" href="#bib0330">23</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>In 2012, Mekinian et al. compared perinatal outcomes in patients with a confirmed diagnosis of APS, using the Sapporo criteria, and patients with an obstetric background and low aPL titers, and found that the perinatal outcomes were similar in the two groups and, even more notable, they observed a significant reduction in adverse perinatal outcomes in both groups with the implementation of standard management (low-molecular weight heparin and acetyl salicylic acid [LMWH+ASA]); however, the limitation to this study was the fact that it was retrospective.<a class="elsevierStyleCrossRef" href="#bib0280">13</a> Nevertheless, these findings support the premise that patients with a diagnosis of O-APS could benefit with a standard treatment and, thus, have live newborns, with few maternal complications.<a class="elsevierStyleCrossRefs" href="#bib0290">15,24–26</a>At the 9th meeting of the European Forum on Antiphospholipid Antibodies, it was proposed that O-APS should be distinguished from the thrombotic syndrome as a distinct entity since, in the absence of thrombosis, there is histological and biochemical evidence of the action of aPL, aside from the improvement in the perinatal outcomes with conventional treatment. At that forum, the classical notions were joined by additional clinical criteria, such as 2 consecutive pregnancy losses or 3 non-consecutive losses, late PE, abruptio placentae, late preterm birth and 2 or more unexplained unsuccessful in vitro fertilizations.<a class="elsevierStyleCrossRef" href="#bib0305">18</a>The O-APS concept also covers biochemical aspects, proposing novel situations such as the presence of nonstandardized antibodies like antiannexin v, antiphosphatidylserine, and even low titers of anticardiolipin antibodies (aCL), detected at some time, during the pregnancy, since it has been demonstrated that with therapeutic management the perinatal outcomes are better.<a class="elsevierStyleCrossRef" href="#bib0300">17</a>Up to 50% of the patients with related obstetric morbidity have low titers of aCL and/or aβ2GP-I, with perinatal outcomes similar to those of individuals with high or intermediate titers, if they do not receive treatment.<a class="elsevierStyleCrossRefs" href="#bib0280">13,27</a>Like triple positivity of aPL, which is related to a higher rate of loss during pregnancy, just one positivity (lupus anticoagulant [LA] or aβ2GP-I, more than LA) has been reported more frequently in O-APS.In all, 15% of the patients with a history of rRPL, embryonic and preembryonic, have persistent aPL positivity, and, if they do not receive treatment, up to 90% will have another pregnancy loss<a class="elsevierStyleCrossRef" href="#bib0335">24</a>; the combination of low-dose LMWH+ASA promotes embryo implantation during the early stages of pregnancy and additionally protects against thrombosis of the uteroplacental vasculature after a successful placentation, with a low rate of complications.<a class="elsevierStyleCrossRefs" href="#bib0335">24–26,28</a>Seronegative Antiphospholipid Antibody SyndromeThere is a group of patients that has a clinical history, including the obstetric background, strongly related to repetitive adverse perinatal outcomes (RPL, history of disease related to placental insufficiency), persistently negative in laboratory tests, that could be classified as SN-APS. This concept was introduced for the first time in 2003 by Hughes and Khamashta, who described patients with clinical manifestations highly indicative of APS, in individuals who rapidly developed the classical accelerated and progressive multiorgan damage of patients with catastrophic APS, but with persistently negative aPL tests.<a class="elsevierStyleCrossRef" href="#bib0240">5</a>In this group of patients it is important to consider the following clinical and biochemical aspects:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">•Antiphospholipid antibodies may be consumed over time, meaning that at the time of measuring them, we obtain a positive laboratory test that later becomes negative.<a class="elsevierStyleCrossRef" href="#bib0355">28</a></li><li class="elsevierStyleListItem" id="lsti0010">•The aPL titers can decrease notably during treatment with corticosteroids and nonsteroidal anti-inflammatory drugs used frequently during pregnancy (ASA, inducers of lung maturity): in these cases, a future titration should be requested (for 3–6 months later).<a class="elsevierStyleCrossRef" href="#bib0360">29</a></li><li class="elsevierStyleListItem" id="lsti0015">•If the patient has a thrombotic event during pregnancy, aPL can be consumed and are reduced. Thus, their determination can never be considered definitive. The cases in which this situation has occurred are referred to as transient SN-APS, since the follow-up of serial measurements of aPL reveals a positive seroconversion after the resolution of the thrombotic event.<a class="elsevierStyleCrossRefs" href="#bib0365">30,31</a></li><li class="elsevierStyleListItem" id="lsti0020">•We should consider whether the patient has nephrotic syndrome, as there would be a reduction in aPL levels, attributed to urinary excretion of IgG, decreased synthesis and/or increased catabolism.<a class="elsevierStyleCrossRefs" href="#bib0370">31,32</a></li><li class="elsevierStyleListItem" id="lsti0025">•Analyze whether the laboratory techniques employed in detection comply with internationally standardized guidelines.<a class="elsevierStyleCrossRefs" href="#bib0230">3–5</a></li><li class="elsevierStyleListItem" id="lsti0030">•Lupus anticoagulant quantification can be undetected if the antibody is weak because the sample is not completely free of platelets, producing an erroneous result. Therefore, LA determination should be performed with ultracentrifugation and plasma filtration.<a class="elsevierStyleCrossRef" href="#bib0355">28</a></li><li class="elsevierStyleListItem" id="lsti0035">•A small proportion of patients who are negative for aCL or aβ2GP-I IgG and IgM, may be positive for the IgA isotope of these antibodies, which is not generally investigated by conventional laboratories.<a class="elsevierStyleCrossRef" href="#bib0375">32</a> In a retrospective study involving 170 patients with kidney disease, who had been classified as SN-APS, who were tested for IgA aβ2GP-I. This isotype was positive in 66% of the patients and 91% had persistently positive titers.<a class="elsevierStyleCrossRefs" href="#bib0380">33,34</a></li></ul>However, the most convincing explanation for the existence of a group of seronegative patients could be that the series of tests is insufficient, either because of the limitations of standard techniques or because of the existence of different antigenic targets.Antiphospholipid antibodies are directed against phospholipids, but also against protein/phospholipid complexes and cofactors. In recent years there have been new lines of research, focused on finding other antigenic targets, as well as on improving present techniques and proposing novel methodologies, that detect not only antibodies against phospholipids, but against protein/phospholipid complexes and cofactors.<a class="elsevierStyleCrossRef" href="#bib0315">20</a>In a series of cases, Conti et al. studied 24 patients with a diagnosis of SN-APS, using a thin-layer chromatography immunostaining technique, which is able to detect the reactivity of phospholipid molecules other than those identified by enzyme-linked immunosorbent assay (ELISA), and found that 54.2% were positive to aCL, 45.8% to anti-vimentin/cardiolipin, 12.5% to antiprothrombin and 4.2% to antiannexin V<a class="elsevierStyleCrossRef" href="#bib0265">10</a>; this proposes other lines of research related to the search for nonclassical antibodies, like those directed against proteins of the coagulation cascade, domains other than β2GP-I, platelets, glycoproteins, mitochondrial antigens and other surface molecules.<a class="elsevierStyleCrossRefs" href="#bib0265">10,20</a>Antiphospholipid antibodies can also be directed against other phospholipids, like lysophosphatidic acid and phosphatidylethanolamine or proteins like vimentin and protein C components. On occasion, these patients are positive to zwitterionic phospholipid antibodies (such as phosphatidylethanolamine), to several protein/phospholipid complexes, or to phospholipids other than those studied conventionally.<a class="elsevierStyleCrossRef" href="#bib0330">23</a>Clinical research of other aPL targets, the implementation and development of other novel laboratory techniques could improve our capacity to detect APS. Nevertheless, the availability of laboratory tests for antibodies of this type is limited in routine practice, and is done only for investigative purposes.<a class="elsevierStyleCrossRefs" href="#bib0355">28,34</a> There is debate as to whether to demand costly additional tests in the attempt to identify those novel aPL, or to establish the diagnosis of SN-APS and introduce a treatment, given the potential risk of thrombosis and adverse perinatal outcomes,<a class="elsevierStyleCrossRefs" href="#bib0390">35,36</a> on the part of those who would possibly benefit from the treatment. However, to date, there is no quality evidence that can demonstrate the key.Rodríguez-García et al. compared 87 patients with APS and 67 with SN-APS, and found no significant differences with respect to thrombotic events and obstetric morbidity, early spontaneous miscarriage (67.1 vs 52.1%), death (62.5% vs 59.4%), prematurity (28.1% vs 21.7%) or PE (28.1% vs 23.1%); however, the retrospective design is a limitation to this study.<a class="elsevierStyleCrossRef" href="#bib0400">37</a>The existence of SN-APS continues to be controversial. Nonetheless, it is important that this entity be considered, since the prognosis of the pregnancy may benefit from a proper management. However, there is still not enough evidence to establish a standard for attending to these patients, which should be personalized and multidisplinary.<a class="elsevierStyleCrossRefs" href="#bib0395">36,38</a> Nevertheless, the diagnosis of SN-APS could increase the rate of false positives, leading to the implementation of unnecessary pharmacological management, which would imply elevated economical and emotional resources.Management of Patients With Antiphospholipid Syndrome in ObstetricsWe used the grade, recommendation, assessment, development and evaluation (GRADE) system to describe the available evidence on patients with APS (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Owing to the close relationship, when there are serious medical problems for the mother and child, management should begin prior to conception. In patients with a related obstetric history, the complete panel of aPL should be requested (level of evidence 1b).<a class="elsevierStyleCrossRef" href="#bib0410">39</a>If the patient has confirmed or a suspicion of APS, O-APS or SN-APS, the approach is multidisciplinary, involving specialties like rheumatology, hematology, fetal medicine, neonatology and psychology.In those cases in which the patient is receiving prenatal care and is taking a vitamin K antagonist, this anticoagulant could be changed for therapeutic doses of LMWH in combination with ASA, especially during the first trimester, because of the relationship to serious structural defects, especially during organogenesis.Current recommendations consider that patients with a diagnosis of APS, whether primipara or with previous term pregnancies without related complications, close monitoring of the dyad with surveillance of fetal growth, maternal blood pressure, weight gain of mother and infant, and management of low-dose ASA, as prophylaxis for placental dysfunction (PE and/or IUGR); however, this decision will be made according to the common sense of the attending physician (level of evidence 2B).<a class="elsevierStyleCrossRef" href="#bib0405">38</a>In a meta-analysis, Mak et al. included 5 clinical trials that involved 334 patients who were positive for aPL, with RPL, and found that the patients who received LMWH+ASA in comparison with those who received only ASA had a significantly higher rate of live newborns (relative risk [RR] 1.3, 95% confidence interval [CI] 1.04–1.6), demonstrating that the combination of LMWH+ASA is superior, with a number needed to treat of 5.6 with a reduction of 72% in PE in that group of patients and, thus, in preterm births associated with RPL.<a class="elsevierStyleCrossRef" href="#bib0415">40</a>When a patient has a diagnosis of APS, with a history of RPL, even without a history of thrombosis, LMWH is recommended at a prophylactic or intermediate dose, together with ASA (level of evidence 1B),<a class="elsevierStyleCrossRef" href="#bib0410">39</a> and if the history includes thrombosis, therapeutic doses of LMWH should be considered (level of evidence 1B).<a class="elsevierStyleCrossRef" href="#bib0405">38</a>In patients with documented APS, the use of fractionated heparin+ASA vs ASA and a history of RPL has demonstrated a decrease in pregnancy loss with a RR 0.44 and 95% CI 0.33–0.66 (level of evidence 1B); however, there was no significant difference in the development of complications related to placental dysfunction (IUGR: RR 1.71, 95% CI 0.48–6.17; PE: RR 0.43, 95% CI 0.09–2.08) (level of evidence 1C) in randomized clinical trials, although they had a low methodological quality, with inaccuracies and biases.With respect to the management in the puerperium of patients with a diagnosis of APS, who did not receive thromboprophylaxis and had no risk factors for thrombosis, it is recommended that only LMWH be used 7 days postpartum; in those who have risk factors for thrombosis or were being treated with LMWH during the pregnancy, the treatment could be extended for 6 more weeks (level of evidence 2C).<a class="elsevierStyleCrossRef" href="#bib0405">38</a>However, the controversy revolves around the management of the group of patients with O-APS more than around the diagnosis, as the mainstay of treatment in this group of patients is LMWH+ASA (which helps to limit vascular, thrombotic and inflammatory events, as well as complement activation and the coagulation cascade), which potentially improves the prognosis for the dyad, reducing adverse perinatal outcomes; then again, at the present time, there is no evidence demonstrating that the usual management has a significant beneficial effect. There are no well-designed, randomized clinical trials and, thus, the recommendation for treatment should be based on expert opinion, and be discussed with the patient (level of evidence 2B).<a class="elsevierStyleCrossRef" href="#bib0405">38</a>In women with a history of RPL, who do not meet the clinical and/or diagnostic criteria for APS, there is still not enough evidence to maintain that there is an improvement in perinatal outcomes with the utilization of low-dose LMWH+ASA. Moreover, it could even increase the risk of bleeding during the resolution of the pregnancy (level of evidence 2B).<a class="elsevierStyleCrossRefs" href="#bib0415">40,41</a>In the pathophysiology of PE, endothelial and platelet dysfunction is the main hypothesis for the utilization of antiplatelet agents that prevent or delay platelet dysfunction (low-dose ASA), which is associated with a decrease in the relative risk of PE. A Cochrane systematic review evaluated 43 clinical trials with 32,590 patients with risk factors for platelet dysfunction. The finding was a significant reduction in the risk of PE (RR 0.83, 95% CI 0.77–0.89), with a number needed to treat (NNT) of 28 high-risk patients (level of evidence 1B). Some have recommended anticoagulant therapy with LMWH or fractionated heparin in patients with a very high risk of PE. This is biologically valid, not only because of the decrease in thrombus formation, but also due to the antiapoptotic effects of LMWH in the trophoblast, which is a potential trigger of PE.In a randomized clinical trial, Mello et al. included 80 patients without documented thrombophilia, with an increased risk of PE based on their medical records and underlying angiotensin-converting enzyme polymorphisms or its deletion. Using LMWH (dalteparin 5000IU/day), they found that patients with this treatment had a lower incidence of adverse perinatal outcomes, with a decrease of 74.1% in PE (RR 0.26, 95% CI 0.08–0.86) and of 77.5% in IUGR (RR 0.14, 95% CI 0.03–0.56); however, it is limited because it only deals with patients who have this polymorphism (homozygotes for angiotensin-converting enzyme polymorphisms).<a class="elsevierStyleCrossRef" href="#bib0425">42</a> A later pilot study with 110 patients in whom it was not possible to identify thrombophilia, and with a history of severe PE, IUGR, abruptio placentae or fetal death, were randomized to receive prophylactic dalteparin doses or no dalteparin. The authors reported that the group that was treated with LMWH had lower rates of PE, IUGR and abruptio placentae (adjusted odds ratio 0.15, 95% CI 0.03–0.70)<a class="elsevierStyleCrossRef" href="#bib0430">43</a>; however, this study was not double-blinded and was terminated before completing the sample size because of an exaggerated effect of the benefit. This could be attributed to the use of LMWH and, thus, is considered only a preliminary study, with no validity for use in routine practice. The results of these studies must be interpreted with caution, as it is not clear whether the positive effects of LMWH for the prevention of PE can be generalized.In patients with a history of death, PE or IUGR, in whom APS has not been documented, low-dose ASA should be used, although there is no evidence of the benefit of utilizing prophylactic or therapeutic doses of unfractionated heparin or prophylactic doses of LMWH (level of evidence 1B).<a class="elsevierStyleCrossRefs" href="#bib0405">38,39</a>In patients diagnosed with SN-APS, the management should be the same as in those with diagnosed APS; however, there are no randomized studies with a suitable design to demonstrate the benefits (level of evidence 2C).<a class="elsevierStyleCrossRefs" href="#bib0345">26,38</a>It is important, both in patients with definite APS and with O-APS and SN-APS, to maintain close monitoring, during the pregnancy, of maternal blood pressure, weight gain of both mother and infant, and periodical laboratory studies including platelets, complement and antibody titers (aCL, LA and aβ2GP-I). Likewise, fetal surveillance will require structural studies in both the first and second trimesters; the focus during the third trimester will be on fetal growth, in the search for evidence of early and late placental insufficiency; uterine artery Doppler has a major role, as it is correlated with the prediction of placental dysfunction (PE and/or IUGR).ConclusionsAntiphospholipid syndrome in women of reproductive age can initially become apparent with fertility problems, in early stages of pregnancy (embryonic and preembryonic), as well as in relation to placental insufficiency and even fetal death, increasing the maternal and fetal rates of morbidity and mortality.Obstetric complications are due to multiple immunological processes related to the heterogeneity of aPL and their diverse mechanisms of action (inflammatory phenomena, complement activation, the coagulation cascade, in some cases, infarction and thrombosis), not exclusively with a primary thrombotic event, which is the reason for proposing to differentiate this group of patients from thrombotic APS.Obstetric manifestations related to APS are clinically relevant and warrant research areas especially concerning the therapeutic approach since, apparently, they are associated with a higher risk of disease related to placental insufficiency (PE, IUGR) and neonatal death; however, the clinical application of these observations has yet to be determined, since the evidence we have is still insufficient. The emergence of this group also obliges us to undertake a rational analysis of the clinical and technical conditions of taking samples for antibodies, as well as the possibility of the presence of other nonstandardized antibodies since, aside from the risk of morbidity related to pregnancy, both O-APS and SN-APS have the potential risk of generating thrombotic events and will require treatment during the pregnancy, the puerperium and, probably, over a long period of time.Approaching the patient during pregnancy should be multidisciplinary, preferentially prior to conception, and should be done with close surveillance of the dyad from the moment of gestation, in order to reduce the associated maternofetal morbidity and mortality, as well as sequelae that could subsequently develop.The management of APS is often uncertain and, in the absence of scientific clairvoyance, clinical common sense and experience are necessary for improving the perinatal outcomes; the behavior and nature of APS during pregnancy is a matter of debate, and should be confirmed by well-designed experimental studies that involve a large number of patients, to enhance the quality of care.Ethical DisclosuresProtection of human and animal subjectsThe authors declare that no experiments were performed on humans or animals for this study.Confidentiality of dataThe authors declare that no patient data appear in this article.Right to privacy and informed consentThe authors declare that no patient data appear in this article.Conflicts of InterestThe authors declare they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres798094" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec796067" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres798093" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec796068" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Background" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Pathophysiological Mechanisms of Obstetric Complications" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Obstetric antiphospholipid antibody syndrome" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Seronegative Antiphospholipid Antibody Syndrome" ] ] ] 6 => array:2 [ "identificador" => "sec0065" "titulo" => "Management of Patients With Antiphospholipid Syndrome in Obstetrics" ] 7 => array:2 [ "identificador" => "sec0035" "titulo" => "Conclusions" ] 8 => array:3 [ "identificador" => "sec0040" "titulo" => "Ethical Disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Right to privacy and informed consent" ] ] ] 9 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflicts of Interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-03-09" "fechaAceptado" => "2016-04-28" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec796067" "palabras" => array:5 [ 0 => "Antiphospholipid antibody syndrome" 1 => "Obstetric antiphospholipid syndrome" 2 => "Seronegative antiphospholipid syndrome" 3 => "Antiphospholipid antibodies" 4 => "Adverse perinatal outcome" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec796068" "palabras" => array:5 [ 0 => "Síndrome de anticuerpos antifosfolipídicos" 1 => "Síndrome de anticuerpos antifosfolipídicos obstétrico" 2 => "Síndrome de anticuerpos antifosfolipídicos seronegativo" 3 => "Anticuerpos antifosfilipídicos" 4 => "Resultados perinatales adversos" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Antiphospholipid antibody syndrome is a non-inflammatory autoimmune disease characterized by recurrent thrombotic events and/or obstetric complications associated with the presence of circulating antiphospholipid antibodies (anticardiolipin antibodies, anti-β2 glycoprotein-I antibodies, and/or lupus anticoagulant).Antiphospholipid antibodies are a heterogeneous group of autoantibodies associated with recurrent miscarriage, stillbirth, fetal growth restriction and premature birth. The diversity of the features of the proposed placental antiphospholipid antibodies fingerprint suggests that several disease processes may occur in the placentae of women with antiphospholipid antibody syndrome in the form of immune responses: inflammatory events, complement activation, angiogenic imbalance and, less commonly, thrombosis and infarction. Because of the disparity between clinical and laboratory criteria, and the impact on perinatal outcome in patients starting treatment, we reviewed the aspects of antiphospholipid antibody syndrome related to obstetric complications and seronegative antiphospholipid antibody syndrome, and their treatment in obstetrics." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "El síndrome de anticuerpos antifosfolipídicos es una enfermedad autoinmune no inflamatoria, caracterizada por eventos trombóticos recurrentes y/o complicaciones obstétricas, asociados a la presencia de anticuerpos antifosfolipídicos circulantes: anticuerpos anticardiolipina, anti-β2 glucoproteína-i y/o anticoagulante lúpico.Los anticuerpos antifosfolipídicos son un grupo heterogéneo de autoanticuerpos asociados con morbilidad obstétrica, como pérdida gestacional recurrente, muerte fetal, parto pretérmino asociado a insuficiencia placentaria como enfermedad hipertensiva del embarazo y/o restricción del crecimiento intrauterino. Los procesos fisiopatológicos relacionados con la morbilidad obstétrica no se han comprendido del todo, involucrándose múltiples eventos inmunológicos, entre ellos los inflamatorios, la activación del complemento, el desbalance de los factores angiogénicos y, en alguna proporción de los casos, se ha demostrado trombosis e infarto. Debido a la controversia en los criterios clínicos y de laboratorio, así como a la repercusión en la mejora de los resultados perinatales en pacientes que inician tratamiento, decidimos llevar a cabo esta revisión sobre los conceptos de síndrome de anticuerpos antifosfolipídico relacionado con complicaciones obstétricas y síndrome de anticuerpos antifosfolipídico seronegativo, así como su manejo en obstetricia." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Camarena Cabrera DMA, Rodriguez-Jaimes C, Acevedo-Gallegos S, Gallardo-Gaona JM, Velazquez-Torres B, Ramírez-Calvo JA. Controversias del síndrome de anticuerpos antifosfolipídicos en obstetricia. Reumatol Clin. 2017;13:30–36." ] ] "multimedia" => array:3 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "aCL, anticardiolipin antibodies; gw, gestational week; LA, lupus anticoagulant; 99p, percentile; PE, preeclampsia.O-APS is diagnosed with at least 1 clinical criteria and 1 laboratory criteria." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical criteria \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Laboratory criteria \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">One or more unexplainable deaths of a morphologically normal fetus or after 10gw \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LA in plasma on 2 or more occasions at intervals of 12 weeks \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">One or more preterm births in a morphologically normal newborn prior to 34gw due to eclampsia or severe PE or other manifestations of placental insufficiency \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Intermediate or high titers of aCL IgG and/or IgM in plasma/serum (>40GPL, or >99p) on 2 or more occasions at intervals of 12 weeks \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Three or more spontaneous inexplicable miscarriages prior to 10gw, with exclusion of an anatomic or hormonal maternal cause and maternal and fetal chromosomal causes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">aβ2GP-I IgG and/or IgM in plasma/serum (>99p) on 2 occasions at an interval of 12 weeks \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1338597.png" ] ] ] ] "descripcion" => array:1 [ "en" => "International Consensus (Sapporo Revisited) for the Diagnosis of Antiphospholipid Antibody Syndrome Associated With Obstetric Morbidity." ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "aβ2GP-I, anti-β2 glycoprotein-I; aCL, anticardiolipin antibodies; aPL, antiphospholipid antibodies; APS, antiphospholipid syndrome; IVF-ET, in vitro fertilization-embryo transfer; 95p, percentile; PE, preeclampsia.A diagnosis of nonconventional or classical criteria for antiphospholipid antibody syndrome is considered if the patient has a combination of nonconventional clinical manifestations with laboratory criteria in accordance with the international consensus, or international clinical criteria with nonconventional laboratory criteria." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Clinical criteria \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Laboratory criteria \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Two or more unexplainable consecutive miscarriages Three or more unexplainable nonconsecutive miscarriages Late PE Abruptio placentae, late preterm birth Two or more unexplained failed IVF-ET \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low positivity for aCL or aβ2GP-I between 95p and 99p Intermittent presence of aPL in patients with classical clinical manifestations of obstetric APS \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1338598.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Nonconventional and Classical Criteria for the Diagnosis of Antiphospholipid Antibody Syndrome Associated With Obstetric Morbidity." ] ] 2 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "GRADE, grade, recommendation, assessment, development and evaluation; RCT, randomized clinical trials." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Grade of recommendation \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk/benefit \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Methodological quality of the evidence \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Implications \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1A/strong recommendation, quality of the evidence high \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The benefits clearly surpass the risks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RCT without important limits, high quality observational \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recommendation to apply the recommendation is clear \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1B/strong recommendation, quality of evidence moderate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Clear benefits that surpass the risks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RCT with important limitations (inconsistent results, methodological flaws or inaccuracies) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recommendation that can be applied in the majority of the patients \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1C/strong recommendation, quality of the evidence low or very low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The benefits surpass the risks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Observational studies or case series \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The recommendations can change when there is evidence of greater quality \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2A/weak recommendation, quality of the evidence high \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The benefits are nearly on the par with the risks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RCT with important limitations or overwhelming evidence from observational studies \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Weak recommendation, the best intervention can vary depending on the circumstances of the patients or social values \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2B/weak recommendation, quality of the evidence moderate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RCT with important limitations (inconsistent results, methodological flaws or inaccuracies) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Weak recommendation, the best intervention can vary depending on the circumstances of the patients or social values \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2C/weak recommendation, quality of the evidence low or very low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">There is nothing certain regarding the benefits, risks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Observational studies or case series \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Very weak recommendation, there are other alternatives that are just as reasonable \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1338596.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Grades of Recommendation and Level of Evidence (GRADE)." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:43 [ 0 => array:3 [ "identificador" => "bib0220" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Placentation, antiphospholipid syndrome and pregnancy outcome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "S. 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Review Article

Controversies Concerning the Antiphospholipid Syndrome in Obstetrics

Controversias del síndrome de anticuerpos antifosfolipídicos en obstetricia

Dulce María Albertina Camarena Cabrera

Corresponding author

dulce.camarena@inper.mx

Corresponding author.

, Claudia Rodriguez-Jaimes, Sandra Acevedo-Gallegos, Juan Manuel Gallardo-Gaona, Berenice Velazquez-Torres, José Antonio Ramírez-Calvo

Servicio de Medicina Materno Fetal, Instituto Nacional de Perinatología, Mexico City, Mexico

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Since the bases for proposing antiphospholipid antibody syndrome &#40;APS&#41; were suggested&#44; the pathophysiology of that disease has not been completely understood&#44; and questions have been raised as to whether the current criteria are sufficient to establish the diagnosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">1&#44;2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In clinical practice&#44; we identify pregnant patients who have thrombotic events and those who have obstetric complications related to APS&#44; but rarely both disorders&#59; in individuals with APS&#44; antibody levels can vary&#44; or even be undetectable&#46; The classification criteria of Sapporo and Sidney consider intermediate or high antibody titers&#44; but not low or negative values&#59; it is essential that we do not underestimate the diagnosis of APS in patients with obstetric complications&#44; as an intervention can improve the implicated perinatal outcomes and&#44; thus&#44; it is important to analyze concepts of obstetric antiphospholipid antibody syndrome &#40;O-APS&#41; and seronegative antiphospholipid syndrome &#40;SN-APS&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">3&#8211;5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The objective of this study is to provide a review of the controversies that surround the diagnosis of APS and its relationship to obstetrics and adverse perinatal outcomes&#44; as well as the current recommendations for its management&#46; We performed an analytical search of the available literature up to December 2015 in the major electronic databases&#44; PubMed &#40;MEDLINE&#41;&#44; EMBASE &#40;Elsevier&#41;&#44; Cochrane&#44; EBSCO &#40;Dynamed&#41; and Ovid&#44; to retrieve the best available evidence &#40;meta-analyses&#44; systematic reviews&#44; randomized clinical trials and observational studies&#41;&#46; The languages used were English and Spanish&#44; and we utilized a combination of the following terms&#58; &#8220;antiphospholipid syndrome&#8221;&#44; &#8220;international consensus criteria&#8221;&#44; &#8220;antiphospholipid antibodies&#8221;&#44; &#8220;obstetric APS&#8221;&#44; &#8220;low titer aPL&#8221;&#44; &#8220;antiphospholipid antibodies&#8221; and &#8220;seronegative obstetric antiphospholipid syndrome&#8221;&#44; using the Boolean operators &#8220;AND&#8221; and &#8220;OR&#8221;&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Background</span><p id="par0020" class="elsevierStylePara elsevierViewall">Antiphospholipid syndrome is an autoimmune disease that is characterized by arterial or venous thromboembolisms and&#47;or certain obstetric complications in association with antiphospholipid antibodies &#40;APA&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">6&#8211;9</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">These antibodies react with phospholipid-binding plasma proteins &#40;mainly anti-&#946;<span class="elsevierStyleInf">2</span> glycoprotein-I &#91;a&#946;<span class="elsevierStyleInf">2</span>GP-I<span class="elsevierStyleSmallCaps">&#93;</span>&#44; prothrombin&#44; protein C&#44; protein S&#44; annexin V&#44; annexin II and low-density lipoproteins&#41;&#44; protein&#47;phospholipid complexes and anionic phospholipids&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">3&#44;4&#44;10</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Expert consensus had been called on to establish the clinical and laboratory criteria to enable the classification of patients&#44; in 1999 in Sapporo&#44; Japan&#44; and later&#44; in 2006&#44; in Sidney&#44; Australia&#46; The criteria for classification were updated and a&#946;<span class="elsevierStyleInf">2</span>GP-I isotypes IgG and&#47;or IgM were added&#44; and the interval between assessing the presence of antibodies was increased from 6 to 12 weeks between 1 measurement and the next&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">11</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">In 2013&#44; in Rio de Janeiro&#44; Brazil&#44; a new consensus was established and the proposal was to separate as 2 different entities thrombotic APS and that associated with obstetric morbidity &#40;APS-O&#41;&#44; with suggestions for novel clinical criteria concerning the latter&#44; such as early recurrent pregnancy loss &#40;RPL &#91;embryonic and preembryonic&#93;&#41;&#44; early fetal death&#44; placental insufficiency&#44; infertility and changes in laboratory criteria&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">12</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">There may be a substantial clinical correlation between aPL levels in patients with a related obstetric history&#44; and still with low titers and against only one antibody&#44; which could represent a reduced immune function when compared with patients with thrombotic aPL&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">13</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The diagnostic criteria considered have implications in clinical practice&#44; with novel antigen targets&#44; cut-off points&#44; laboratory techniques and the intervals for their measurement&#44; as well as their correlation with the clinical manifestations&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Pathophysiological Mechanisms of Obstetric Complications</span><p id="par0050" class="elsevierStylePara elsevierViewall">Fetal well-being depends critically on the role of the uteroplacental circulation&#44; which joins the mother and the fetus&#46; A normal pregnancy is associated with homeostatic changes&#44; including an increase in the concentration of coagulation factors&#44; and a decrease in natural anticoagulants and the fibrinolytic activity&#59; these pregnancy-related physiological changes predispose the mother to thromboses and to vascular complications&#44; which are related to an increase in the adverse perinatal outcomes in patients with APS&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The pathophysiological mechanisms related to the obstetric complications of aPL have yet to be completely clarified&#44; and initially would involve extensive infarctions and placental microthrombi<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">14</span></a> and&#44; although these phenomenon are more frequent in patients with who are positive for aPL&#44; they are not the primary origin of the obstetric complications&#46; Placental infarctions are caused by the incapacity of the uteroplacental blood flow&#44; which is secondary to the occlusion of the spiral arteries by an intraluminal thrombus&#44; which can cause ischemic injury in the intervillous space&#44; affecting the placental villosity&#59; however&#44; these lesions are present in only one sixth of the cases and&#44; thus&#44; we must consider that there are multiple pathophysiological processes occurring in patients with APS&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">15</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Considering that aPL are a heterogeneous group of antibodies&#44; with different mechanisms of action&#44; it is not very likely that the obstetric morbidity be caused by a single mechanism like infarction and&#47;or thrombosis&#46; Antiphospholipid antibodies can induce changes in spiral artery remodeling&#44; decidual inflammation and decrease the vasculosyncytial membrane&#44; secondary to other immunological phenomena&#44; such as inflammation&#44; complement activation&#44;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">15&#8211;17</span></a> overexpression of tissue factor in neutrophils and monocytes and imbalance between angiogenic factors&#44; even in the absence of thrombosis&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">13</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Inflammatory manifestations related to aPL are mainly mediated by complement and&#44; secondarily&#44; by the activation of the coagulation cascade&#44;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">16&#44;18</span></a> as well as a reduction in annexin <span class="elsevierStyleSmallCaps">v</span>and placental tissue damage&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">15</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Other mechanisms are indirect damage to the trophoblast through apoptosis&#44; inhibition of proliferation and syncytiotrophoblast formation&#44; a decrease in chorionic gonadotropin hormone production&#44; and damage to trophoblastic invasion and growth factor secretion&#44; which result in pregnancy loss or placental dysfunction&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">15&#44;19</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">The extravillous trophoblast is the target of inflammatory injury&#44; even for placental infarctions associated with the presence of aPL secondary to the occlusion of the spiral arteries&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">15</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Uncontrolled complement activation<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">20</span></a> plays a critical role in the pathogenesis of placental damage induced by aPL&#59; hypocomplementemia is found in up to half of the patients with APS and pregnancy&#44; and is related to adverse perinatal outcomes such as prematurity&#44; low birth weight&#44; death&#44; preterm delivery and preeclampsia &#40;PE&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">16&#44;17&#44;21</span></a> Fetal loss can be explained by histopathological inflammatory signs secondary to the overexpression of tissue factor in neutrophils and monocytes&#44; or to an imbalance in the angiogenic factors&#44; there being evidence of biochemical markers&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">17</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Obstetric antiphospholipid antibody syndrome</span><p id="par0085" class="elsevierStylePara elsevierViewall">Antiphospholipid syndrome is considered a thromboembolic disease&#59; however&#44; in the group with associated obstetric complications&#44; only a small percentage will have thrombotic events &#40;either systemic or uteroplacental&#41;&#46; In a prospective&#44; multicenter study of 1000 patients&#44; Cervera et al&#46; studied patients with APS for 5 years&#44; and found that the group with a related obstetric disease had no thrombosis or other manifestations of APS&#44; and less than 5&#37; progressed to a demonstrated thrombosis or systemic lupus erythematosus&#44;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">22</span></a> a fact that suggests that the concept of O-APS involves pathophysiological mechanisms other than the aPL&#44; in comparison with thrombotic APS&#44; in which thrombosis and progression to systemic lupus erythematosus are less frequent than in classical APS&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The concept of O-APS as being different from the thrombotic disorder involves both nonconventional clinical and laboratory criteria &#40;<a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1 and 2</a>&#41;&#44; as prospective and retrospective have shown that this group of patients has a higher risk of placental dysfunction &#40;PE&#44; intrauterine growth restriction &#91;IUGR&#93;&#41; and prematurity&#44; as well as a long-term increase in the risk of thrombotic events&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">23</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">In 2012&#44; Mekinian et al&#46; compared perinatal outcomes in patients with a confirmed diagnosis of APS&#44; using the Sapporo criteria&#44; and patients with an obstetric background and low aPL titers&#44; and found that the perinatal outcomes were similar in the two groups and&#44; even more notable&#44; they observed a significant reduction in adverse perinatal outcomes in both groups with the implementation of standard management &#40;low-molecular weight heparin and acetyl salicylic acid &#91;LMWH<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ASA&#93;&#41;&#59; however&#44; the limitation to this study was the fact that it was retrospective&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">13</span></a> Nevertheless&#44; these findings support the premise that patients with a diagnosis of O-APS could benefit with a standard treatment and&#44; thus&#44; have live newborns&#44; with few maternal complications&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">15&#44;24&#8211;26</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">At the 9th meeting of the European Forum on Antiphospholipid Antibodies&#44; it was proposed that O-APS should be distinguished from the thrombotic syndrome as a distinct entity since&#44; in the absence of thrombosis&#44; there is histological and biochemical evidence of the action of aPL&#44; aside from the improvement in the perinatal outcomes with conventional treatment&#46; At that forum&#44; the classical notions were joined by additional clinical criteria&#44; such as 2 consecutive pregnancy losses or 3 non-consecutive losses&#44; late PE&#44; <span class="elsevierStyleItalic">abruptio placentae</span>&#44; late preterm birth and 2 or more unexplained unsuccessful in vitro fertilizations&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">18</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">The O-APS concept also covers biochemical aspects&#44; proposing novel situations such as the presence of nonstandardized antibodies like antiannexin <span class="elsevierStyleSmallCaps">v</span>&#44; antiphosphatidylserine&#44; and even low titers of anticardiolipin antibodies &#40;aCL&#41;&#44; detected at some time&#44; during the pregnancy&#44; since it has been demonstrated that with therapeutic management the perinatal outcomes are better&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">17</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Up to 50&#37; of the patients with related obstetric morbidity have low titers of aCL and&#47;or a&#946;<span class="elsevierStyleInf">2</span>GP-I&#44; with perinatal outcomes similar to those of individuals with high or intermediate titers&#44; if they do not receive treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">13&#44;27</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Like triple positivity of aPL&#44; which is related to a higher rate of loss during pregnancy&#44; just one positivity &#40;lupus anticoagulant &#91;LA&#93; or a&#946;<span class="elsevierStyleInf">2</span>GP-I&#44; more than LA&#41; has been reported more frequently in O-APS&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">In all&#44; 15&#37; of the patients with a history of rRPL&#44; embryonic and preembryonic&#44; have persistent aPL positivity&#44; and&#44; if they do not receive treatment&#44; up to 90&#37; will have another pregnancy loss<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">24</span></a>&#59; the combination of low-dose LMWH<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ASA promotes embryo implantation during the early stages of pregnancy and additionally protects against thrombosis of the uteroplacental vasculature after a successful placentation&#44; with a low rate of complications&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">24&#8211;26&#44;28</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Seronegative Antiphospholipid Antibody Syndrome</span><p id="par0125" class="elsevierStylePara elsevierViewall">There is a group of patients that has a clinical history&#44; including the obstetric background&#44; strongly related to repetitive adverse perinatal outcomes &#40;RPL&#44; history of disease related to placental insufficiency&#41;&#44; persistently negative in laboratory tests&#44; that could be classified as SN-APS&#46; This concept was introduced for the first time in 2003 by Hughes and Khamashta&#44; who described patients with clinical manifestations highly indicative of APS&#44; in individuals who rapidly developed the classical accelerated and progressive multiorgan damage of patients with catastrophic APS&#44; but with persistently negative aPL tests&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">5</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">In this group of patients it is important to consider the following clinical and biochemical aspects&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0135" class="elsevierStylePara elsevierViewall">Antiphospholipid antibodies may be consumed over time&#44; meaning that at the time of measuring them&#44; we obtain a positive laboratory test that later becomes negative&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">28</span></a></p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0140" class="elsevierStylePara elsevierViewall">The aPL titers can decrease notably during treatment with corticosteroids and nonsteroidal anti-inflammatory drugs used frequently during pregnancy &#40;ASA&#44; inducers of lung maturity&#41;&#58; in these cases&#44; a future titration should be requested &#40;for 3&#8211;6 months later&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">29</span></a></p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0145" class="elsevierStylePara elsevierViewall">If the patient has a thrombotic event during pregnancy&#44; aPL can be consumed and are reduced&#46; Thus&#44; their determination can never be considered definitive&#46; The cases in which this situation has occurred are referred to as transient SN-APS&#44; since the follow-up of serial measurements of aPL reveals a positive seroconversion after the resolution of the thrombotic event&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">30&#44;31</span></a></p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8226;</span><p id="par0150" class="elsevierStylePara elsevierViewall">We should consider whether the patient has nephrotic syndrome&#44; as there would be a reduction in aPL levels&#44; attributed to urinary excretion of IgG&#44; decreased synthesis and&#47;or increased catabolism&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">31&#44;32</span></a></p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8226;</span><p id="par0155" class="elsevierStylePara elsevierViewall">Analyze whether the laboratory techniques employed in detection comply with internationally standardized guidelines&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">3&#8211;5</span></a></p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8226;</span><p id="par0160" class="elsevierStylePara elsevierViewall">Lupus anticoagulant quantification can be undetected if the antibody is weak because the sample is not completely free of platelets&#44; producing an erroneous result&#46; Therefore&#44; LA determination should be performed with ultracentrifugation and plasma filtration&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">28</span></a></p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8226;</span><p id="par0165" class="elsevierStylePara elsevierViewall">A small proportion of patients who are negative for aCL or a&#946;<span class="elsevierStyleInf">2</span>GP-I IgG and IgM&#44; may be positive for the IgA isotope of these antibodies&#44; which is not generally investigated by conventional laboratories&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">32</span></a> In a retrospective study involving 170 patients with kidney disease&#44; who had been classified as SN-APS&#44; who were tested for IgA a&#946;<span class="elsevierStyleInf">2</span>GP-I&#46; This isotype was positive in 66&#37; of the patients and 91&#37; had persistently positive titers&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">33&#44;34</span></a></p></li></ul></p><p id="par0170" class="elsevierStylePara elsevierViewall">However&#44; the most convincing explanation for the existence of a group of seronegative patients could be that the series of tests is insufficient&#44; either because of the limitations of standard techniques or because of the existence of different antigenic targets&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Antiphospholipid antibodies are directed against phospholipids&#44; but also against protein&#47;phospholipid complexes and cofactors&#46; In recent years there have been new lines of research&#44; focused on finding other antigenic targets&#44; as well as on improving present techniques and proposing novel methodologies&#44; that detect not only antibodies against phospholipids&#44; but against protein&#47;phospholipid complexes and cofactors&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">20</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">In a series of cases&#44; Conti et al&#46; studied 24 patients with a diagnosis of SN-APS&#44; using a thin-layer chromatography immunostaining technique&#44; which is able to detect the reactivity of phospholipid molecules other than those identified by enzyme-linked immunosorbent assay &#40;ELISA&#41;&#44; and found that 54&#46;2&#37; were positive to aCL&#44; 45&#46;8&#37; to anti-vimentin&#47;cardiolipin&#44; 12&#46;5&#37; to antiprothrombin and 4&#46;2&#37; to antiannexin V<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">10</span></a>&#59; this proposes other lines of research related to the search for nonclassical antibodies&#44; like those directed against proteins of the coagulation cascade&#44; domains other than &#946;<span class="elsevierStyleInf">2</span>GP-I&#44; platelets&#44; glycoproteins&#44; mitochondrial antigens and other surface molecules&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">10&#44;20</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Antiphospholipid antibodies can also be directed against other phospholipids&#44; like lysophosphatidic acid and phosphatidylethanolamine or proteins like vimentin and protein C components&#46; On occasion&#44; these patients are positive to zwitterionic phospholipid antibodies &#40;such as phosphatidylethanolamine&#41;&#44; to several protein&#47;phospholipid complexes&#44; or to phospholipids other than those studied conventionally&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">23</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Clinical research of other aPL targets&#44; the implementation and development of other novel laboratory techniques could improve our capacity to detect APS&#46; Nevertheless&#44; the availability of laboratory tests for antibodies of this type is limited in routine practice&#44; and is done only for investigative purposes&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">28&#44;34</span></a> There is debate as to whether to demand costly additional tests in the attempt to identify those novel aPL&#44; or to establish the diagnosis of SN-APS and introduce a treatment&#44; given the potential risk of thrombosis and adverse perinatal outcomes&#44;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">35&#44;36</span></a> on the part of those who would possibly benefit from the treatment&#46; However&#44; to date&#44; there is no quality evidence that can demonstrate the key&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Rodr&#237;guez-Garc&#237;a et al&#46; compared 87 patients with APS and 67 with SN-APS&#44; and found no significant differences with respect to thrombotic events and obstetric morbidity&#44; early spontaneous miscarriage &#40;67&#46;1 vs 52&#46;1&#37;&#41;&#44; death &#40;62&#46;5&#37; vs 59&#46;4&#37;&#41;&#44; prematurity &#40;28&#46;1&#37; vs 21&#46;7&#37;&#41; or PE &#40;28&#46;1&#37; vs 23&#46;1&#37;&#41;&#59; however&#44; the retrospective design is a limitation to this study&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">37</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">The existence of SN-APS continues to be controversial&#46; Nonetheless&#44; it is important that this entity be considered&#44; since the prognosis of the pregnancy may benefit from a proper management&#46; However&#44; there is still not enough evidence to establish a standard for attending to these patients&#44; which should be personalized and multidisplinary&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">36&#44;38</span></a> Nevertheless&#44; the diagnosis of SN-APS could increase the rate of false positives&#44; leading to the implementation of unnecessary pharmacological management&#44; which would imply elevated economical and emotional resources&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Management of Patients With Antiphospholipid Syndrome in Obstetrics</span><p id="par0205" class="elsevierStylePara elsevierViewall">We used the grade&#44; recommendation&#44; assessment&#44; development and evaluation &#40;GRADE&#41; system to describe the available evidence on patients with APS &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0210" class="elsevierStylePara elsevierViewall">Owing to the close relationship&#44; when there are serious medical problems for the mother and child&#44; management should begin prior to conception&#46; In patients with a related obstetric history&#44; the complete panel of aPL should be requested &#40;level of evidence 1b&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">39</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">If the patient has confirmed or a suspicion of APS&#44; O-APS or SN-APS&#44; the approach is multidisciplinary&#44; involving specialties like rheumatology&#44; hematology&#44; fetal medicine&#44; neonatology and psychology&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">In those cases in which the patient is receiving prenatal care and is taking a vitamin K antagonist&#44; this anticoagulant could be changed for therapeutic doses of LMWH in combination with ASA&#44; especially during the first trimester&#44; because of the relationship to serious structural defects&#44; especially during organogenesis&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Current recommendations consider that patients with a diagnosis of APS&#44; whether primipara or with previous term pregnancies without related complications&#44; close monitoring of the dyad with surveillance of fetal growth&#44; maternal blood pressure&#44; weight gain of mother and infant&#44; and management of low-dose ASA&#44; as prophylaxis for placental dysfunction &#40;PE and&#47;or IUGR&#41;&#59; however&#44; this decision will be made according to the common sense of the attending physician &#40;level of evidence 2B&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">38</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">In a meta-analysis&#44; Mak et al&#46; included 5 clinical trials that involved 334 patients who were positive for aPL&#44; with RPL&#44; and found that the patients who received LMWH<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ASA in comparison with those who received only ASA had a significantly higher rate of live newborns &#40;relative risk &#91;RR&#93; 1&#46;3&#44; 95&#37; confidence interval &#91;CI&#93; 1&#46;04&#8211;1&#46;6&#41;&#44; demonstrating that the combination of LMWH<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ASA is superior&#44; with a number needed to treat of 5&#46;6 with a reduction of 72&#37; in PE in that group of patients and&#44; thus&#44; in preterm births associated with RPL&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">40</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">When a patient has a diagnosis of APS&#44; with a history of RPL&#44; even without a history of thrombosis&#44; LMWH is recommended at a prophylactic or intermediate dose&#44; together with ASA &#40;level of evidence 1B&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">39</span></a> and if the history includes thrombosis&#44; therapeutic doses of LMWH should be considered &#40;level of evidence 1B&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">38</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">In patients with documented APS&#44; the use of fractionated heparin<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ASA vs ASA and a history of RPL has demonstrated a decrease in pregnancy loss with a RR 0&#46;44 and 95&#37; CI 0&#46;33&#8211;0&#46;66 &#40;level of evidence 1B&#41;&#59; however&#44; there was no significant difference in the development of complications related to placental dysfunction &#40;IUGR&#58; RR 1&#46;71&#44; 95&#37; CI 0&#46;48&#8211;6&#46;17&#59; PE&#58; RR 0&#46;43&#44; 95&#37; CI 0&#46;09&#8211;2&#46;08&#41; &#40;level of evidence 1C&#41; in randomized clinical trials&#44; although they had a low methodological quality&#44; with inaccuracies and biases&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">With respect to the management in the puerperium of patients with a diagnosis of APS&#44; who did not receive thromboprophylaxis and had no risk factors for thrombosis&#44; it is recommended that only LMWH be used 7 days postpartum&#59; in those who have risk factors for thrombosis or were being treated with LMWH during the pregnancy&#44; the treatment could be extended for 6 more weeks &#40;level of evidence 2C&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">38</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">However&#44; the controversy revolves around the management of the group of patients with O-APS more than around the diagnosis&#44; as the mainstay of treatment in this group of patients is LMWH<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ASA &#40;which helps to limit vascular&#44; thrombotic and inflammatory events&#44; as well as complement activation and the coagulation cascade&#41;&#44; which potentially improves the prognosis for the dyad&#44; reducing adverse perinatal outcomes&#59; then again&#44; at the present time&#44; there is no evidence demonstrating that the usual management has a significant beneficial effect&#46; There are no well-designed&#44; randomized clinical trials and&#44; thus&#44; the recommendation for treatment should be based on expert opinion&#44; and be discussed with the patient &#40;level of evidence 2B&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">38</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">In women with a history of RPL&#44; who do not meet the clinical and&#47;or diagnostic criteria for APS&#44; there is still not enough evidence to maintain that there is an improvement in perinatal outcomes with the utilization of low-dose LMWH<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ASA&#46; Moreover&#44; it could even increase the risk of bleeding during the resolution of the pregnancy &#40;level of evidence 2B&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">40&#44;41</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">In the pathophysiology of PE&#44; endothelial and platelet dysfunction is the main hypothesis for the utilization of antiplatelet agents that prevent or delay platelet dysfunction &#40;low-dose ASA&#41;&#44; which is associated with a decrease in the relative risk of PE&#46; A Cochrane systematic review evaluated 43 clinical trials with 32&#44;590 patients with risk factors for platelet dysfunction&#46; The finding was a significant reduction in the risk of PE &#40;RR 0&#46;83&#44; 95&#37; CI 0&#46;77&#8211;0&#46;89&#41;&#44; with a number needed to treat &#40;NNT&#41; of 28 high-risk patients &#40;level of evidence 1B&#41;&#46; Some have recommended anticoagulant therapy with LMWH or fractionated heparin in patients with a very high risk of PE&#46; This is biologically valid&#44; not only because of the decrease in thrombus formation&#44; but also due to the antiapoptotic effects of LMWH in the trophoblast&#44; which is a potential trigger of PE&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">In a randomized clinical trial&#44; Mello et al&#46; included 80 patients without documented thrombophilia&#44; with an increased risk of PE based on their medical records and underlying angiotensin-converting enzyme polymorphisms or its deletion&#46; Using LMWH &#40;dalteparin 5000<span class="elsevierStyleHsp" style=""></span>IU&#47;day&#41;&#44; they found that patients with this treatment had a lower incidence of adverse perinatal outcomes&#44; with a decrease of 74&#46;1&#37; in PE &#40;RR 0&#46;26&#44; 95&#37; CI 0&#46;08&#8211;0&#46;86&#41; and of 77&#46;5&#37; in IUGR &#40;RR 0&#46;14&#44; 95&#37; CI 0&#46;03&#8211;0&#46;56&#41;&#59; however&#44; it is limited because it only deals with patients who have this polymorphism &#40;homozygotes for angiotensin-converting enzyme polymorphisms&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">42</span></a> A later pilot study with 110 patients in whom it was not possible to identify thrombophilia&#44; and with a history of severe PE&#44; IUGR&#44; <span class="elsevierStyleItalic">abruptio placentae</span> or fetal death&#44; were randomized to receive prophylactic dalteparin doses or no dalteparin&#46; The authors reported that the group that was treated with LMWH had lower rates of PE&#44; IUGR and <span class="elsevierStyleItalic">abruptio placentae</span> &#40;adjusted odds ratio 0&#46;15&#44; 95&#37; CI 0&#46;03&#8211;0&#46;70&#41;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">43</span></a>&#59; however&#44; this study was not double-blinded and was terminated before completing the sample size because of an exaggerated effect of the benefit&#46; This could be attributed to the use of LMWH and&#44; thus&#44; is considered only a preliminary study&#44; with no validity for use in routine practice&#46; The results of these studies must be interpreted with caution&#44; as it is not clear whether the positive effects of LMWH for the prevention of PE can be generalized&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">In patients with a history of death&#44; PE or IUGR&#44; in whom APS has not been documented&#44; low-dose ASA should be used&#44; although there is no evidence of the benefit of utilizing prophylactic or therapeutic doses of unfractionated heparin or prophylactic doses of LMWH &#40;level of evidence 1B&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">38&#44;39</span></a></p><p id="par0275" class="elsevierStylePara elsevierViewall">In patients diagnosed with SN-APS&#44; the management should be the same as in those with diagnosed APS&#59; however&#44; there are no randomized studies with a suitable design to demonstrate the benefits &#40;level of evidence 2C&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">26&#44;38</span></a></p><p id="par0280" class="elsevierStylePara elsevierViewall">It is important&#44; both in patients with definite APS and with O-APS and SN-APS&#44; to maintain close monitoring&#44; during the pregnancy&#44; of maternal blood pressure&#44; weight gain of both mother and infant&#44; and periodical laboratory studies including platelets&#44; complement and antibody titers &#40;aCL&#44; LA and a&#946;<span class="elsevierStyleInf">2</span>GP-I&#41;&#46; Likewise&#44; fetal surveillance will require structural studies in both the first and second trimesters&#59; the focus during the third trimester will be on fetal growth&#44; in the search for evidence of early and late placental insufficiency&#59; uterine artery Doppler has a major role&#44; as it is correlated with the prediction of placental dysfunction &#40;PE and&#47;or IUGR&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusions</span><p id="par0285" class="elsevierStylePara elsevierViewall">Antiphospholipid syndrome in women of reproductive age can initially become apparent with fertility problems&#44; in early stages of pregnancy &#40;embryonic and preembryonic&#41;&#44; as well as in relation to placental insufficiency and even fetal death&#44; increasing the maternal and fetal rates of morbidity and mortality&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall">Obstetric complications are due to multiple immunological processes related to the heterogeneity of aPL and their diverse mechanisms of action &#40;inflammatory phenomena&#44; complement activation&#44; the coagulation cascade&#44; in some cases&#44; infarction and thrombosis&#41;&#44; not exclusively with a primary thrombotic event&#44; which is the reason for proposing to differentiate this group of patients from thrombotic APS&#46;</p><p id="par0295" class="elsevierStylePara elsevierViewall">Obstetric manifestations related to APS are clinically relevant and warrant research areas especially concerning the therapeutic approach since&#44; apparently&#44; they are associated with a higher risk of disease related to placental insufficiency &#40;PE&#44; IUGR&#41; and neonatal death&#59; however&#44; the clinical application of these observations has yet to be determined&#44; since the evidence we have is still insufficient&#46; The emergence of this group also obliges us to undertake a rational analysis of the clinical and technical conditions of taking samples for antibodies&#44; as well as the possibility of the presence of other nonstandardized antibodies since&#44; aside from the risk of morbidity related to pregnancy&#44; both O-APS and SN-APS have the potential risk of generating thrombotic events and will require treatment during the pregnancy&#44; the puerperium and&#44; probably&#44; over a long period of time&#46;</p><p id="par0300" class="elsevierStylePara elsevierViewall">Approaching the patient during pregnancy should be multidisciplinary&#44; preferentially prior to conception&#44; and should be done with close surveillance of the dyad from the moment of gestation&#44; in order to reduce the associated maternofetal morbidity and mortality&#44; as well as sequelae that could subsequently develop&#46;</p><p id="par0305" class="elsevierStylePara elsevierViewall">The management of APS is often uncertain and&#44; in the absence of scientific clairvoyance&#44; clinical common sense and experience are necessary for improving the perinatal outcomes&#59; the behavior and nature of APS during pregnancy is a matter of debate&#44; and should be confirmed by well-designed experimental studies that involve a large number of patients&#44; to enhance the quality of care&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Ethical Disclosures</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Protection of human and animal subjects</span><p id="par0315" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Confidentiality of data</span><p id="par0320" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Right to privacy and informed consent</span><p id="par0325" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conflicts of Interest</span><p id="par0330" class="elsevierStylePara elsevierViewall">The authors declare they have no conflicts of interest&#46;</p></span></span>"
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          "titulo" => "Keywords"
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          "identificador" => "xpalclavsec796068"
          "titulo" => "Palabras clave"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
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          "identificador" => "sec0010"
          "titulo" => "Background"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Pathophysiological Mechanisms of Obstetric Complications"
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            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Obstetric antiphospholipid antibody syndrome"
            ]
            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Seronegative Antiphospholipid Antibody Syndrome"
            ]
          ]
        ]
        6 => array:2 [
          "identificador" => "sec0065"
          "titulo" => "Management of Patients With Antiphospholipid Syndrome in Obstetrics"
        ]
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          "identificador" => "sec0035"
          "titulo" => "Conclusions"
        ]
        8 => array:3 [
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          "titulo" => "Ethical Disclosures"
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            0 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Protection of human and animal subjects"
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              "identificador" => "sec0050"
              "titulo" => "Confidentiality of data"
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            2 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Right to privacy and informed consent"
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          "identificador" => "sec0060"
          "titulo" => "Conflicts of Interest"
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          "titulo" => "References"
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    "fechaRecibido" => "2015-03-09"
    "fechaAceptado" => "2016-04-28"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec796067"
          "palabras" => array:5 [
            0 => "Antiphospholipid antibody syndrome"
            1 => "Obstetric antiphospholipid syndrome"
            2 => "Seronegative antiphospholipid syndrome"
            3 => "Antiphospholipid antibodies"
            4 => "Adverse perinatal outcome"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec796068"
          "palabras" => array:5 [
            0 => "S&#237;ndrome de anticuerpos antifosfolip&#237;dicos"
            1 => "S&#237;ndrome de anticuerpos antifosfolip&#237;dicos obst&#233;trico"
            2 => "S&#237;ndrome de anticuerpos antifosfolip&#237;dicos seronegativo"
            3 => "Anticuerpos antifosfilip&#237;dicos"
            4 => "Resultados perinatales adversos"
          ]
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    "resumen" => array:2 [
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Antiphospholipid antibody syndrome is a non-inflammatory autoimmune disease characterized by recurrent thrombotic events and&#47;or obstetric complications associated with the presence of circulating antiphospholipid antibodies &#40;anticardiolipin antibodies&#44; anti-&#946;<span class="elsevierStyleInf">2</span> glycoprotein-I antibodies&#44; and&#47;or lupus anticoagulant&#41;&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Antiphospholipid antibodies are a heterogeneous group of autoantibodies associated with recurrent miscarriage&#44; stillbirth&#44; fetal growth restriction and premature birth&#46; The diversity of the features of the proposed placental antiphospholipid antibodies fingerprint suggests that several disease processes may occur in the placentae of women with antiphospholipid antibody syndrome in the form of immune responses&#58; inflammatory events&#44; complement activation&#44; angiogenic imbalance and&#44; less commonly&#44; thrombosis and infarction&#46; Because of the disparity between clinical and laboratory criteria&#44; and the impact on perinatal outcome in patients starting treatment&#44; we reviewed the aspects of antiphospholipid antibody syndrome related to obstetric complications and seronegative antiphospholipid antibody syndrome&#44; and their treatment in obstetrics&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">El s&#237;ndrome de anticuerpos antifosfolip&#237;dicos es una enfermedad autoinmune no inflamatoria&#44; caracterizada por eventos tromb&#243;ticos recurrentes y&#47;o complicaciones obst&#233;tricas&#44; asociados a la presencia de anticuerpos antifosfolip&#237;dicos circulantes&#58; anticuerpos anticardiolipina&#44; anti-&#946;<span class="elsevierStyleInf">2</span> glucoprote&#237;na-<span class="elsevierStyleSmallCaps">i</span> y&#47;o anticoagulante l&#250;pico&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Los anticuerpos antifosfolip&#237;dicos son un grupo heterog&#233;neo de autoanticuerpos asociados con morbilidad obst&#233;trica&#44; como p&#233;rdida gestacional recurrente&#44; muerte fetal&#44; parto pret&#233;rmino asociado a insuficiencia placentaria como enfermedad hipertensiva del embarazo y&#47;o restricci&#243;n del crecimiento intrauterino&#46; Los procesos fisiopatol&#243;gicos relacionados con la morbilidad obst&#233;trica no se han comprendido del todo&#44; involucr&#225;ndose m&#250;ltiples eventos inmunol&#243;gicos&#44; entre ellos los inflamatorios&#44; la activaci&#243;n del complemento&#44; el desbalance de los factores angiog&#233;nicos y&#44; en alguna proporci&#243;n de los casos&#44; se ha demostrado trombosis e infarto&#46; Debido a la controversia en los criterios cl&#237;nicos y de laboratorio&#44; as&#237; como a la repercusi&#243;n en la mejora de los resultados perinatales en pacientes que inician tratamiento&#44; decidimos llevar a cabo esta revisi&#243;n sobre los conceptos de s&#237;ndrome de anticuerpos antifosfolip&#237;dico relacionado con complicaciones obst&#233;tricas y s&#237;ndrome de anticuerpos antifosfolip&#237;dico seronegativo&#44; as&#237; como su manejo en obstetricia&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Camarena Cabrera DMA&#44; Rodriguez-Jaimes C&#44; Acevedo-Gallegos S&#44; Gallardo-Gaona JM&#44; Velazquez-Torres B&#44; Ram&#237;rez-Calvo JA&#46; Controversias del s&#237;ndrome de anticuerpos antifosfolip&#237;dicos en obstetricia&#46; Reumatol Clin&#46; 2017&#59;13&#58;30&#8211;36&#46;</p>"
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          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">aCL&#44; anticardiolipin antibodies&#59; gw&#44; gestational week&#59; LA&#44; lupus anticoagulant&#59; 99p&#44; percentile&#59; PE&#44; preeclampsia&#46;</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">O-APS is diagnosed with at least 1 clinical criteria and 1 laboratory criteria&#46;</p>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Laboratory criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">One or more unexplainable deaths of a morphologically normal fetus or after 10<span class="elsevierStyleHsp" style=""></span>gw&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">LA in plasma on 2 or more occasions at intervals of 12 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">One or more preterm births in a morphologically normal newborn prior to 34<span class="elsevierStyleHsp" style=""></span>gw due to eclampsia or severe PE or other manifestations of placental insufficiency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Intermediate or high titers of aCL IgG and&#47;or IgM in plasma&#47;serum &#40;&#62;40<span class="elsevierStyleHsp" style=""></span>GPL&#44; or &#62;99p&#41; on 2 or more occasions at intervals of 12 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Three or more spontaneous inexplicable miscarriages prior to 10<span class="elsevierStyleHsp" style=""></span>gw&#44; with exclusion of an anatomic or hormonal maternal cause and maternal and fetal chromosomal causes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">a&#946;<span class="elsevierStyleInf">2</span>GP-I IgG and&#47;or IgM in plasma&#47;serum &#40;&#62;99p&#41; on 2 occasions at an interval of 12 weeks&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">International Consensus &#40;Sapporo Revisited&#41; for the Diagnosis of Antiphospholipid Antibody Syndrome Associated With Obstetric Morbidity&#46;</p>"
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        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">a&#946;<span class="elsevierStyleInf">2</span>GP-I&#44; anti-&#946;<span class="elsevierStyleInf">2</span> glycoprotein-<span class="elsevierStyleSmallCaps">I&#59;</span> aCL&#44; anticardiolipin antibodies&#59; aPL&#44; antiphospholipid antibodies&#59; APS&#44; antiphospholipid syndrome&#59; IVF-ET&#44; in vitro fertilization-embryo transfer&#59; 95p&#44; percentile&#59; PE&#44; preeclampsia&#46;</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">A diagnosis of nonconventional or classical criteria for antiphospholipid antibody syndrome is considered if the patient has a combination of nonconventional clinical manifestations with laboratory criteria in accordance with the international consensus&#44; or international clinical criteria with nonconventional laboratory criteria&#46;</p>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Clinical criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Laboratory criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Two or more unexplainable consecutive miscarriages<br>Three or more unexplainable nonconsecutive miscarriages<br>Late PE<br><span class="elsevierStyleItalic">Abruptio placentae</span>&#44; late preterm birth<br>Two or more unexplained failed IVF-ET&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Low positivity for aCL or a&#946;<span class="elsevierStyleInf">2</span>GP-I between 95p and 99p<br>Intermittent presence of aPL in patients with classical clinical manifestations of obstetric APS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">GRADE&#44; grade&#44; recommendation&#44; assessment&#44; development and evaluation&#59; RCT&#44; randomized clinical trials&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Grade of recommendation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk&#47;benefit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Methodological quality of the evidence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Implications&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1A&#47;strong recommendation&#44; quality of the evidence high&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">The benefits clearly surpass the risks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RCT without important limits&#44; high quality observational&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Recommendation to apply the recommendation is clear&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1B&#47;strong recommendation&#44; quality of evidence moderate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Clear benefits that surpass the risks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RCT with important limitations &#40;inconsistent results&#44; methodological flaws or inaccuracies&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Recommendation that can be applied in the majority of the patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1C&#47;strong recommendation&#44; quality of the evidence low or very low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">The benefits surpass the risks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational studies or case series&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">The recommendations can change when there is evidence of greater quality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2A&#47;weak recommendation&#44; quality of the evidence high&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">The benefits are nearly on the par with the risks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RCT with important limitations or overwhelming evidence from observational studies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Weak recommendation&#44; the best intervention can vary depending on the circumstances of the patients or social values&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2B&#47;weak recommendation&#44; quality of the evidence moderate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RCT with important limitations &#40;inconsistent results&#44; methodological flaws or inaccuracies&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Weak recommendation&#44; the best intervention can vary depending on the circumstances of the patients or social values&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2C&#47;weak recommendation&#44; quality of the evidence low or very low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">There is nothing certain regarding the benefits&#44; risks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational studies or case series&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Very weak recommendation&#44; there are other alternatives that are just as reasonable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Grades of Recommendation and Level of Evidence &#40;GRADE&#41;&#46;</p>"
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Article information

ISSN: 21735743
Original language: English

DOI:10.1016/j.reumae.2016.04.005

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Year/Month	Html	Pdf	Total

2024 November	17	16	33
2024 October	109	32	141
2024 September	100	35	135
2024 August	71	43	114
2024 July	84	46	130
2024 June	80	48	128
2024 May	90	49	139
2024 April	78	19	97
2024 March	63	28	91
2024 February	61	20	81
2024 January	69	31	100
2023 December	58	32	90
2023 November	58	29	87
2023 October	75	44	119
2023 September	122	40	162
2023 August	48	15	63
2023 July	83	51	134
2023 June	73	29	102
2023 May	70	34	104
2023 April	35	11	46
2023 March	79	37	116
2023 February	83	31	114
2023 January	66	26	92
2022 December	117	60	177
2022 November	105	30	135
2022 October	79	47	126
2022 September	63	57	120
2022 August	36	72	108
2022 July	43	81	124
2022 June	50	42	92
2022 May	61	47	108
2022 April	67	71	138
2022 March	61	55	116
2022 February	62	39	101
2022 January	62	46	108
2021 December	33	35	68
2021 November	43	50	93
2021 October	63	63	126
2021 September	48	45	93
2021 August	35	63	98
2021 July	40	25	65
2021 June	44	52	96
2021 May	48	53	101
2021 April	110	134	244
2021 March	89	51	140
2021 February	59	32	91
2021 January	51	31	82
2020 December	38	39	77
2020 November	56	24	80
2020 October	40	22	62
2020 September	63	36	99
2020 August	53	22	75
2020 July	31	30	61
2020 June	57	25	82
2020 May	55	45	100
2020 April	65	22	87
2020 March	22	4	26
2018 May	6	1	7
2018 April	64	22	86
2018 March	45	13	58
2018 February	34	12	46
2018 January	20	17	37
2017 December	34	28	62
2017 November	28	12	40
2017 October	36	17	53
2017 September	28	18	46
2017 August	25	22	47
2017 July	41	12	53
2017 June	37	23	60
2017 May	63	26	89
2017 April	39	42	81
2017 March	65	59	124
2017 February	35	42	77
2017 January	4	19	23
2016 December	3	6	9

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