Obstetric antiphospholipid syndrome | Revista Clínica Española

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Esteve-Valverde, R. Ferrer-Oliveras, J. Alijotas-Reig" "autores" => array:3 [ 0 => array:3 [ "nombre" => "E." "apellidos" => "Esteve-Valverde" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 1 => array:3 [ "nombre" => "R." "apellidos" => "Ferrer-Oliveras" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:4 [ "nombre" => "J." "apellidos" => "Alijotas-Reig" "email" => array:2 [ 0 => "jalijotas@vhebron.net" 1 => "16297jar@comb.cat" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Servicio de Medicina Interna, Althaia, Xarxa Assistencial de Manresa, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Obstetricia y Ginecología, Hospital Universitari Vall d’Hebron, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Unidad de Enfermedades Autoinmunes Sistémicas, Servicio de Medicina Interna, Hospital Universitari Vall d’Hebrón, Universitat Autònoma, Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Síndrome antifosfolipídico obstétrico" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 2460 "Ancho" => 3451 "Tamanyo" => 897898 ] ] "descripcion" => array:1 [ "en" => "Various scenarios in terms of aFL, SAF and SAFO. Abbreviations: aPL: antiphospholipid antibodies; APS: antiphospholipid syndrome; OAPS: obstetric antiphospholipid syndrome." ] ] ] "textoCompleto" => "BackgroundObstetric antiphospholipid syndrome (OAPS) is a variant of the classical antiphospholipid syndrome (APS). APS is characterized by the presence of arterial and/or venous thrombosis and/or obstetric morbidity, along with the recurring presence of antiphospholipid antibodies (aPLs), according to 2006 Sydney classification criteria.<a class="elsevierStyleCrossRef" href="#bib0410">1</a> The clinical manifestations of APS have classically been related to the ability of aPLs to trigger the coagulation pathway, which is considered the most common form of acquired thrombophilia in our community. However, aPLs can induce a primary inflammatory response that is occasionally accompanied by a second prothrombotic response. This appears to be especially the case for OAPS.According to the current definitions, OAPS includes recurrent spontaneous miscarriages before the 10th week of pregnancy that are not explained by other causes, as well as fetal losses, prematurity, fetal growth delay and early onset preeclampsia.<a class="elsevierStyleCrossRef" href="#bib0410">1</a> We consider OAPS to comprise those cases that meet the obstetric APS criteria and that have not previously presented thrombotic episodes according to the Sydney criteria.<a class="elsevierStyleCrossRef" href="#bib0410">1</a>Some patients have obstetric problems, such as recurrent implantation failure, up to 2 consecutive miscarriages, late or puerperal preeclampsia, premature rupture of the membranes and retroplacental hematoma and yet do not meet the clinical or laboratory criteria for OAPS.<a class="elsevierStyleCrossRef" href="#bib0410">1</a> This situation is known as incomplete OAPS or, following the nomenclature of the European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS Project), obstetric morbidity related to antiphospholipid antibodies (OMAPS).<a class="elsevierStyleCrossRef" href="#bib0415">2</a> The paramount importance of recognizing OAPS lies in the fact that this is one of the few treatable causes of obstetric complications. The proper management of OAPS can also prevent the maternal thromboembolic complications associated with aPL during pregnancy and postpartum. Nevertheless, due to the fact that the prevalence of aPL in the healthy population reaches 5%,<a class="elsevierStyleCrossRef" href="#bib0420">3</a> its routine measurement in previously healthy pregnant patients is not recommended.<a class="elsevierStyleCrossRef" href="#bib0425">4</a> In this clinical review, we aim to address all of these issues.Brief historical backgroundAlthough there have been references to similar clinical–biological conditions since the 1950s<a class="elsevierStyleCrossRef" href="#bib0430">5</a> (and especially in the 1970s<a class="elsevierStyleCrossRef" href="#bib0435">6</a>), the “modern” APS appeared in the 1980s (1983–1986), described by the medical team at the Rayne Institute St Thomas’ Hospital of London, led by professor Graham RV Hughes.<a class="elsevierStyleCrossRefs" href="#bib0440">7,8</a> Laurell and Nilson<a class="elsevierStyleCrossRef" href="#bib0430">5</a> had previously reported the correlation between a syphilis false positive on one hand and the coagulation disorder and recurrent miscarriage on the other. Reaginic tests (e.g., rapid plasma regain and the venereal disease research laboratory test) for lues, which are known to be in reality a type of aPL.<a class="elsevierStyleCrossRefs" href="#bib0450">9,10</a> From this, we base the concept of patients with a false positive syphilis serology.<a class="elsevierStyleCrossRef" href="#bib0460">11</a>In 1980, Firkin et al.<a class="elsevierStyleCrossRef" href="#bib0465">12</a> suggested the relationship between recurrent miscarriage and lupus anticoagulant (LA). In 1981, Carreras et al.<a class="elsevierStyleCrossRef" href="#bib0470">13</a> described the presence of an antibody that interferes with the formation of prostacyclins and related it to arterial thrombosis and intrauterine fetal death. In 1983, Lubbe et al.<a class="elsevierStyleCrossRef" href="#bib0475">14</a> established for the first time the use of low-dose corticosteroids as treatment for patients with APS, with the aim of preventing fetal death by inhibiting the effects of these antibodies. Later, Harris et al.<a class="elsevierStyleCrossRef" href="#bib0480">15</a> standardized the technique for measuring anticardiolipin antibodies (aCL), thereby better delimiting its role in APS. In 1987, a group of experts met in Sapporo (Japan) to define the first ever classification criteria for APS.<a class="elsevierStyleCrossRef" href="#bib0485">16</a> At the beginning of the 1990s, the associations between aPL and gestational morbidity were described and strengthened.<a class="elsevierStyleCrossRef" href="#bib0490">17</a> In 1990, it was shown that β2-glycoprotein I is the main aPL cofactor.<a class="elsevierStyleCrossRef" href="#bib0495">18</a> The classification criteria and treatment strategies have since been revised.EpidemiologyThe prevalence of APS in the general population is unknown, although it has been estimated at 0.5–1%.<a class="elsevierStyleCrossRef" href="#bib0500">19</a> APLs can be detected in 1–5% of healthy women of reproductive age.<a class="elsevierStyleCrossRef" href="#bib0505">20</a> Approximately 40% of women with systemic lupus erythematosus have aPL, and it is estimated that less than 40% of women ultimately present thrombotic events.<a class="elsevierStyleCrossRef" href="#bib0510">21</a> Between 10% and 25% of recurrent miscarriages are due to aPL. The prevalence of aPL in women with obstetric morbidity varies widely from 5% to 50%. The prevalence of LA varies between 0% and 14%, but for women with fetal losses after week 20, the rate increases up to 30%.<a class="elsevierStyleCrossRef" href="#bib0515">22</a> The differences in these results can be explained by the diversity of the study groups, the different inclusion criteria and the lack of standardization of many of the aPL detection methods.<a class="elsevierStyleCrossRef" href="#bib0520">23</a>In a cohort of 590 pregnant women belonging to the Euro-Phospholipid Project, which included 1000 patients with APS, Cervera et al.<a class="elsevierStyleCrossRef" href="#bib0525">24</a> observed that the prevalence of preeclampsia, eclampsia and abruptio placentae was 9.5%, 4.4% and 2%, respectively. The authors also observed that the prevalence of early and late fetal losses in 1580 pregnancies was 35.4% and 16.9%, respectively, with a 48% rate of live births. Alijotas-Reig et al.<a class="elsevierStyleCrossRefs" href="#bib0415">2,25</a> reported the preliminary data from the EUROAPS study, which included 211 women and 530 pregnancies. The prevalence of recurrent miscarriages was 43.3%, and the rate of late fetal losses was 32.4%, while the rate of live births reached 80% in the treated women and was only 20% in those who were not treated. The unpublished data from a second EUROAPS study on the same group, which this time included 338 women with OAPS, showed that the most common complications were prematurity (47%), early preeclampsia (25.6%), fetal losses (22.5%) and recurrent miscarriages (16.5%).The prevalence of aPL in preeclampsia/eclampsia is not well established. In a recent study, the prevalence of aPL in women with preeclampsia was 14% and 28% in hemolysis, raised liver enzyme and thrombocytopenia syndrome,<a class="elsevierStyleCrossRef" href="#bib0530">25</a> a syndrome that complicates 0.01–0.2% of pregnancies in healthy pregnant women and in up to 10–12% of patients with OAPS.<a class="elsevierStyleCrossRef" href="#bib0535">26</a>Catastrophic APS is a severe and life-threatening form of APS. The condition represents only 1% of APS cases; however, 5–6% of catastrophic APS cases occur during pregnancy or the postpartum.<a class="elsevierStyleCrossRef" href="#bib0540">27</a>Antiphospholipid antibodiesAPLs are autoantibodies that mainly target anionic phospholipids (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). As a practical manner, aPLs can be divided into those capable of extending the basic coagulation tests in vitro, mainly the cephalin test or dilute tissue thromboplastin time (LA activity), and those targeted at molecules similar to cardiolipin.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>It was initially thought that aPLs react directly with the negatively charged phospholipids. However, it has been shown that aPLs target epitopes of certain proteins called cofactors, including proteins C and S,<a class="elsevierStyleCrossRef" href="#bib0545">28</a> annexin A2 and A5 and high-molecular-weight kininogen.<a class="elsevierStyleCrossRef" href="#bib0550">29</a> Nevertheless, the 2 cofactors most related to aPL pathogenicity are beta2-glycoprotein I (β2GPI) and prothrombin.<a class="elsevierStyleCrossRef" href="#bib0555">30</a> The aPLs directed against β2GPI and against prothrombin (aPT) are the ones most often related to laboratory test positivity and clinical manifestations.<a class="elsevierStyleCrossRefs" href="#bib0560">31–33</a> β2GPI consists of 5 domains (DI–DV), with DV the one touching the cell receptor and DI the one that binds to aPL, specifically through certain oxidized thiol groups in the -Gly40-Arg43- position.<a class="elsevierStyleCrossRef" href="#bib0575">34</a> It is interesting that the β2GPI molecule is in circular form in plasma and that to exert its pathogenic properties it must dimerize on the cell membrane surface, at which point it can be immunogenetic.<a class="elsevierStyleCrossRef" href="#bib0580">35</a>In 2003, 2 systematic reviews confirmed that LA activity better correlates with the risk of thrombosis and probably with the risk of experiencing obstetric complications. The revisions also confirmed that AL-β2GPI is a more powerful risk marker than AL-aPT.<a class="elsevierStyleCrossRef" href="#bib0585">36</a>EtiopathogenesisThe activation of endothelial cells, monocytes and platelets is boosted by aPL, with a subsequent increase in cell adhesion molecules (ICAM,<a class="elsevierStyleCrossRef" href="#bib0590">37</a> VCAM and tissue factor) and coagulation pathway activation. However, pathology observations in animal models and in humans have led to the conclusion that this thrombotic model is not unique. Therefore, there are 2 mechanisms, prothrombotic and proinflammatory, which can explain the aPL-related pathogenesis, especially during gestation.It has been reported that β2GPI-dependent aPLs are the most relevant in the pathogenic effect on implantation and this is believed to be due to placental overexpression of β2GPI.<a class="elsevierStyleCrossRef" href="#bib0595">38</a> At the same time, the formation of β2GPI-antiβ2GPI complexes activates the complement system by the classical pathway, inducing local inflammatory damage.<a class="elsevierStyleCrossRef" href="#bib0600">39</a> Out et al.,<a class="elsevierStyleCrossRef" href="#bib0605">40</a> Girardi et al.<a class="elsevierStyleCrossRef" href="#bib0610">41</a> and Holers et al.<a class="elsevierStyleCrossRef" href="#bib0615">42</a> analyzed placentas from women with recurrent miscarriages due to OAPS and demonstrated that thrombotic phenomena were missing in more than half of the cases, although there were inflammatory signs. This hypothesis has been validated by the Girardi et al. group,<a class="elsevierStyleCrossRef" href="#bib0620">43</a> suggesting that local activation of the complement would be a lesional mechanism for trophoblasts and the vascular endothelium. Therefore, inflammatory changes have been observed in many cases without evidence of placental thrombosis,<a class="elsevierStyleCrossRef" href="#bib0625">44</a> which is probably due to complement activation<a class="elsevierStyleCrossRef" href="#bib0630">45</a> and/or a negative balance of angiogenic factors.<a class="elsevierStyleCrossRef" href="#bib0635">46</a>It has been reported that the increase in CD16+CD56dim natural killer (NK) cells and the decrease in CD16−CD56bright NK cells in the endometrium are risk factors for recurrent miscarriages.<a class="elsevierStyleCrossRef" href="#bib0640">47</a> It has been shown that aPLs interfere with implantation and subsequent placentation by increasing trophoblastic apoptosis, with a consequent reduction in human chorionic gonadotropin levels and perhaps progesterone levels. This hormonal reduction could change the activity of NK cells.<a class="elsevierStyleCrossRef" href="#bib0645">48</a> Carp and Shoenfeld<a class="elsevierStyleCrossRef" href="#bib0650">49</a> and Perricone et al.<a class="elsevierStyleCrossRef" href="#bib0655">50</a> observed that women with APS and recurrent miscarriages had higher levels of NK cells than those with APS but without miscarriages. Berman et al.<a class="elsevierStyleCrossRef" href="#bib0660">51</a> observed that tumor necrosis factor alpha is a significant effector of placental injury. Recent studies on animal models have demonstrated a direct effect of aPLs on trophoblastic cells.<a class="elsevierStyleCrossRef" href="#bib0665">52</a> Di Simone et al.<a class="elsevierStyleCrossRef" href="#bib0670">53</a> have demonstrated the capacity of aPL to harm the maternal side of the placenta, by directly acting on the human endometrial endothelial cells. We can conclude that aPLs act on trophoblastic cells, endothelial cells, platelets and placental bed, ultimately reducing the trophoblastic invasion, weakening the differentiation of human endometrial endothelial cells and interfering with proper placentation. We should emphasize the correlation between aPLs and the direct lesional effect of the membrane attack complex (C5b-9), the activation of innate immune cells by C3a and especially C5a, with the consequent increase in the production of free radicals and antiangiogenic cytokines, which, as a whole, cause irreversible lesions. A prothrombotic condition is then produced, given that aPLs, in addition to increasing tissue factor synthesis and release, have the ability to trigger endothelial cells through nuclear factor κB and protein kinase p38.<a class="elsevierStyleCrossRef" href="#bib0675">54</a> All of this contributes to the increases in the already increased prothrombotic state during gestational and puerperal periods (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Clinical signs and symptomsGeneral obstetric signs and symptomsThe typical clinical complications of OAPS are those that determine obstetric morbidity, according to the Sydney criteria (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). We are referring to recurrent miscarriages that occur before week 10 of pregnancy with no other known causes that could explain them; fetal losses starting from week 10; preeclampsia/eclampsia/hemolysis, raised liver enzyme and thrombocytopenia syndrome (<34 weeks of gestation); and delayed fetal growth (<10th percentile). It is not uncommon for patients to experience more than one episode of preeclampsia before being diagnosed with OAPS. Early onset preeclampsia and prematurity are believed to be related to placental vascular insufficiency. The experts who drafted the Sydney criteria defined in more detail the concept of placental insufficiency, namely. (1) abnormal or uncertain fetal survival test results (e.g., lack of reactivity in the fetal heart rate monitoring test, suggestive of fetal hypoxia); (2) abnormal results from Doppler flow velocity waveform analyses, suggestive of fetal hypoxemia (e.g., absent end diastolic flow in the umbilical artery); (3) oligohydramnios (e.g., amniotic fluid index ≤5cm); or (4), postnatal weight less than the 10th percentile for the gestational age.<a class="elsevierStyleCrossRef" href="#bib0680">55</a> These disorders complicate 15–30% of cases in most series. Although a number of studies have suggested that fetal losses are the most common obstetric complication of APS,<a class="elsevierStyleCrossRef" href="#bib0685">56</a> other authors have found that recurrent miscarriages are the most common.<a class="elsevierStyleCrossRef" href="#bib0690">57</a> Although it is classically accepted that these patients have miscarriages without previous living children, it is not uncommon to find women with a living child (occasionally premature or low weight) and who subsequently have multiple miscarriages or recurrent fetal losses.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Additionally, there is another series of obstetric complications related to aPLs that is worth considering: subchorionic or retroplacental hematoma, abruptio placentae, premature membrane rupture, late onset preeclampsia and puerperal preeclampsia. The relationship between aPLs and recurrent implantation failure syndrome is also the subject of debate.<a class="elsevierStyleCrossRef" href="#bib0695">58</a> Lastly, the following clinical–biological disorders can accompany or precede obstetric complications and can suggest the possible presence of aPLs: associated autoimmune disease, livedo reticularis, ulcers in the lower limbs, recent onset migraine, chorea, thrombocytopenia, hemolytic anemia and false positive luetic serology.Effects of antiphospholipid antibodies and antiphospholipid syndrome on gestation and vice versaWomen with untreated aPL/OAPS are at much higher risk than the general pregnant population of experiencing gestational losses at any point in the pregnancy. Various studies have shown a clear association between preeclampsia (especially early preeclampsia) and APS. In the Spanish population, the association between preeclampsia and the presence of LA and/or IgM aCL has been demonstrated.<a class="elsevierStyleCrossRef" href="#bib0530">25</a> Preeclampsia and severe preeclampsia (especially early onset) have been reported in up to 50% and 25% of pregnant women with APS, respectively.APL/OAPS has also been associated with the new assisted reproduction techniques.<a class="elsevierStyleCrossRef" href="#bib0695">58</a> For a number of authors, pre-embryonic miscarriage is the equivalent of implantation failure in cases in which in vitro fertilization or intracytoplasmic sperm injection was employed as the pathway.<a class="elsevierStyleCrossRef" href="#bib0695">58</a> Lastly, aPLs further increase the already higher risk of thrombosis in pregnant women. Thrombosis can appear at any time during pregnancy, with more venous thrombosis than arterial.<a class="elsevierStyleCrossRef" href="#bib0415">2</a> Occasionally, the onset of thrombotic phenomena can coincide with the interruption of prophylactic treatment with aspirin and heparin. Venous thrombosis tends to affect the usual territories, followed by the veins in the upper extremities, the portal system and cerebral venous sinuses. The most common arterial thrombotic complications are those that affect the intracranial vessels, in the form of stroke.<a class="elsevierStyleCrossRefs" href="#bib0700">59,60</a> Thrombocytopenia can be difficult to assess, because it is sometimes multifactorial or due to some other cause (e.g., gestational, autoimmune but not related to aPL or to a pharmaceutical).Classification criteriaOAPS is defined by the persistent presence of aPLs in patients with obstetric morbidity. The classification criteria, which in daily clinical practice have become synonymous with the diagnostic criteria, were reviewed in Sydney in 2005. At least one laboratory criterion and one clinical criterion are needed to establish a diagnosis of classical APS.<a class="elsevierStyleCrossRef" href="#bib0410">1</a> By extrapolating, a diagnosis of OAPS requires that the clinical criterion of obstetric morbidity be met, along with a laboratory criterion. Patients with OAPS can be classified into 3 major clinical groups (a, b and c), depending on the gestational period during which the clinical event occurred (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).Given the fact that aPLs can be temporarily positivized, the diagnosis should be established with at least a positive result in 2 different measurements, separated by at least 12 weeks. This underscores the importance of persistent positivity, which, if accompanied by an appropriate clinical manifestation, gives the diagnosis a high degree of certainty. The Sydney meeting recommended subclassifying aPLs into 4 laboratory categories, according to the predominant type and isotype: I, IIa, IIb and IIc (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). These categories are dynamic and can vary among pregnancies.<elsevierMultimedia ident="fig0015"></elsevierMultimedia>The current criteria, envisaged more for research purposes, can result in false negative diagnoses, given their restrictive character. Alijotas-Reig<a class="elsevierStyleCrossRef" href="#bib0555">30</a> established the need to modify these criteria to encapsulate all patients with aPL and obstetric complications not included in the current criteria (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>). Various prospective studies have been designed for this reason, including the EUROAPS study, which reported on 338 consecutive patients with complete or incomplete OAPS and a total of 1253 recorded pregnancies.<a class="elsevierStyleCrossRefs" href="#bib0415">2,61</a> It is worth emphasizing that all laboratory categories have been related to obstetric morbidity,<a class="elsevierStyleCrossRefs" href="#bib0415">2,60</a> although a number of authors believe that aCLs could have a residual role, given that the wells in ELISA detection kits include not only cardiolipin but also β2GPI.<a class="elsevierStyleCrossRef" href="#bib0710">61</a> Nevertheless, there are patients who only have aCL as the only aPL. There are cases yet to be clarified and classified that do not meet the current Sydney criteria (partial forms), which are known as obstetric morbidity related to antiphospholipid antibodies (see <a id="intr0010" class="elsevierStyleInterRef" href="http://www.euroaps.wordpress.com/">www.euroaps.wordpress.com</a>).<elsevierMultimedia ident="fig0020"></elsevierMultimedia>Preconception recommendations and gestational managementPatients should be informed about the fetal and maternal risk, with and without treatment. Although the diagnosis of OAPS has already been established, we recommend a new aPL reading to determine the potential variations in the antibody type and concentration. The importance of aspirin treatment before starting a pregnancy should be explained.<a class="elsevierStyleCrossRef" href="#bib0715">62</a> Treatment with low-molecular-weight heparins (LMWHs) should be started as soon as possible, given that, in the authors’ experience, their effectiveness is likely more related to the starting time than to the administered dose.Patients with OAPS should be monitored by specialized multidisciplinary units. Periodic ultrasound checkups, with Doppler studies if possible, are recommended. Starting on week 20–24, Doppler velocimetry studies are mandatory, with an initial periodicity of 2–4 weeks, every 2 weeks starting on week 32, and weekly starting on week 37. If the results of the ultrasound checkup are normal, the pregnancy will be completed according to the obstetrician criterion. If complications such as preeclampsia and intrauterine growth restriction occur, specific protocols should be applied for each condition.TreatmentWith appropriate treatment, more than 70% of pregnant women with OAPS will give birth to a living child.<a class="elsevierStyleCrossRef" href="#bib0720">63</a> Aspirin in combination with heparin (preferentially LMWHs) are the gold standard for treatment of OAPS. Aspirin was the first drug that showed a change in the prognosis of patients with primary APS.<a class="elsevierStyleCrossRef" href="#bib0725">64</a> Aspirin's mechanism of action is based on inhibiting platelet cyclooxygenase (reduced thromboxane A production) and reducing the proinflammatory and pro-oxidant state, also promoting implantation through an increase in IL-3.<a class="elsevierStyleCrossRef" href="#bib0730">65</a>Heparin, both fractionated and unfractionated, has shown benefits in both monotherapy and when combined with low-dose aspirin. This result is due not only to its anticoagulant effect but also to its anti-inflammatory and immunomodulatory properties. Heparin is able to prevent aPLs from binding to trophoblastic membrane cells, reduce complement system activation and decrease TNF-α levels.<a class="elsevierStyleCrossRef" href="#bib0735">66</a>Prednisone was the first treatment for preventing fetal death linked to OAPS, combining it with aspirin.<a class="elsevierStyleCrossRefs" href="#bib0475">14,67</a> Prednisone's adverse effects on pregnancy (hypertension and gestational diabetes, increased rate of asymptomatic infections and prematurity) were later demonstrated. Nevertheless, prednisone is indicated for controlling the symptoms of systemic lupus erythematosus and for autoimmune thrombocytopenia. There are studies that suggest its use at low doses, combining it with aspirin and heparin, for women who are refractory to conventional treatment.<a class="elsevierStyleCrossRef" href="#bib0745">68</a>Antimalarial agents, mainly hydroxychloroquine, are widely studied in the treatment of systemic autoimmune diseases, as is its safety during pregnancy and breastfeeding. Hydroxychloroquine is able to dissociate the aPL immune complexes, reduce the binding of aPL to syncytium and restore the expression of annexin A5 on cell membranes.<a class="elsevierStyleCrossRef" href="#bib0750">69</a> The addition of hydroxychloroquine to treatment with LMWHs and aspirin could improve the pregnancy's progression.<a class="elsevierStyleCrossRef" href="#bib0755">70</a>Intravenous immunoglobulins can be used in selected cases in which the combination of heparin, aspirin and hydroxychloroquine has failed. A meta-analysis confirmed the benefit of IVIGs in patients with other associated autoimmune diseases (e.g., autoimmune thrombocytopenia, Evans syndrome) and recurrent implantation failure.<a class="elsevierStyleCrossRef" href="#bib0760">71</a> The mechanism of action of intravenous immunoglobulins is not known but appears to suppress the production of antibodies by B lymphocytes and acts on the circulating immunoglobulins by binding to the Fc-IgG-idiotype-anti-idiotype.<a class="elsevierStyleCrossRef" href="#bib0765">72</a>Thus, the currently recommended treatment for OAPS<a class="elsevierStyleCrossRef" href="#bib0770">73</a> is<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">(a)Low-dose aspirin (100mg/day) combined with unfractionated heparin (5000–7500IU/12h subcutaneously) or LMWHs (enoxaparin 40mg/24h subcutaneously or equivalent dosage of tinzaparin, bemiparin or dalteparin). Puerperal thromboprophylaxis with LMWHs should be extended for a minimum of 6 weeks, and the use of aspirin at prophylactic dosages should be continued. The duration of prophylaxis with aspirin has not been determined, although we recommend maintaining the prophylaxis until 2 consecutive years of aPL negativity have been documented.</li><li class="elsevierStyleListItem" id="lsti0010">(b)For pregnant women who have a thrombotic event during pregnancy, the recommended regimen is low-dose aspirin combined with LMWHs at anticoagulant dosages (e.g., enoxaparin 1mg/kg/12h).</li><li class="elsevierStyleListItem" id="lsti0015">(c)It is important to start treatment as soon as possible, even prior to conception. For patients with OAPS who weigh more than 80kg or those who weigh 130kg and require thromboprophylaxis with LMWHs, the enoxaparin dosage should be increased to 60mg and 80mg daily, respectively.</li><li class="elsevierStyleListItem" id="lsti0020">(d)For cases of OAPS refractory (15–20%) to conventional treatment, other drugs may be tried,<a class="elsevierStyleCrossRef" href="#bib0775">74</a> although, with the exception of antimalarial drugs, there are no verified data on their efficacy. Alijotas-Reig<a class="elsevierStyleCrossRef" href="#bib0745">68</a> recently suggested a new therapeutic algorithm for these cases (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>).<elsevierMultimedia ident="fig0025"></elsevierMultimedia></li></ul>Progesterone supplements may be added at any of the previous steps, due to their immunomodulatory effect.<a class="elsevierStyleCrossRef" href="#bib0780">75</a>Puerperium monitoring and subsequent follow-upA checkup during the first days of the postpartum and another at 6 weeks is recommended to check for normalization of laboratory and clinical parameters. It is also recommended that aPL levels be again measured at 6–12 months to determine their progression.The progression of OAPS to other autoimmune diseases, particularly systemic lupus erythematosus and autoimmune thrombocytopenic purpura, is much lower than that found in cases of classical APS.<a class="elsevierStyleCrossRef" href="#bib0785">76</a> With regard to the subsequent onset of thrombotic phenomena in women, the prevalence is also much lower than in cases of classical APS.<a class="elsevierStyleCrossRef" href="#bib0790">77</a> The aPLs negativize in a small percentage of women, although they frequently return to positivity in a new pregnancy.<a class="elsevierStyleCrossRef" href="#bib0795">78</a>There is a European registry of newborns of mothers with OAPS that has shown, as has the EUROAPS study, a high percentage of prematurity compared with the general population and a lower than expected gestational age (up to 17% lower), despite many of these cases undergoing treatment.<a class="elsevierStyleCrossRef" href="#bib0800">79</a> It has been reported that the premature babies of women with OAPS might have an increased probability of neurocognitive development disorders the (autism, learning difficulties) at 2 years of follow-up.<a class="elsevierStyleCrossRef" href="#bib0805">80</a> Nevertheless, further studies are needed to establish a causal relationship.<a class="elsevierStyleCrossRef" href="#bib0810">81</a>FundingThis manuscript was created within the framework of the Gestation-related Autoimmune Disorders project (Trastornos autoinmunitarios relacionados con la gestación, VHIR-2009/298) and was partially funded by ONAGRUP España.Conflicts of interestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:17 [ 0 => array:3 [ "identificador" => "xres624510" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec637913" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres624509" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec637912" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Brief historical background" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Epidemiology" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Antiphospholipid antibodies" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Etiopathogenesis" ] 9 => array:3 [ "identificador" => "sec0030" "titulo" => "Clinical signs and symptoms" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "General obstetric signs and symptoms" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Effects of antiphospholipid antibodies and antiphospholipid syndrome on gestation and vice versa" ] ] ] 10 => array:2 [ "identificador" => "sec0045" "titulo" => "Classification criteria" ] 11 => array:2 [ "identificador" => "sec0050" "titulo" => "Preconception recommendations and gestational management" ] 12 => array:2 [ "identificador" => "sec0055" "titulo" => "Treatment" ] 13 => array:2 [ "identificador" => "sec0060" "titulo" => "Puerperium monitoring and subsequent follow-up" ] 14 => array:2 [ "identificador" => "sec0065" "titulo" => "Funding" ] 15 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflicts of interest" ] 16 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-07-13" "fechaAceptado" => "2015-09-09" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec637913" "palabras" => array:6 [ 0 => "Recurrent miscarriages" 1 => "Antiphospholipid antibodies" 2 => "Pregnancy" 3 => "Fetal loss" 4 => "Preeclampsia" 5 => "Obstetric antiphospholipid syndrome" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec637912" "palabras" => array:6 [ 0 => "Abortos recurrentes" 1 => "Anticuerpos antifosfolipídicos" 2 => "Embarazo" 3 => "Pérdidas fetales" 4 => "Preeclampsia" 5 => "Síndrome antifosfolipídico obstétrico" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Obstetric antiphospholipid syndrome is an acquired autoimmune disorder that is associated with various obstetric complications and, in the absence of prior history of thrombosis, with the presence of antiphospholipid antibodies directed against other phospholipids, proteins called cofactors or PL-cofactor complexes. Although the obstetric complications have been related to the procoagulant properties of antiphospholipid antibodies, pathological studies of human placenta have shown the proinflammatory capacity of antiphospholipid antibodies via the complement system and proinflammatory cytokines. There is no general agreement on which antiphospholipid antibodies profile (laboratory) confers the greatest obstetric risk, but the best candidates are categories I and IIa. Combined treatment with low doses of aspirin and heparin achieves good obstetric and maternal outcomes. In this study, we also review the therapeutic possibilities in refractory cases, although the likelihood of progressing to other autoimmune diseases is low. We briefly comment on incomplete obstetric antiphospholipid syndrome, also known as antiphospholipid antibody-mediated pregnancy morbidity syndrome." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "El síndrome antifosfolipídico obstétrico es una alteración autoinmune adquirida que asocia diversas complicaciones obstétricas, en ausencia de historia trombótica previa, junto con la existencia de anticuerpos antifosfolipídicos dirigidos contra fosfolípidos, proteínas denominadas cofactores o contra complejos fosfolípidos-cofactor. Aunque las complicaciones obstétricas se han relacionado con sus propiedades procoagulantes, estudios anatomopatológicos en placentas humanas han demostrado su capacidad proinflamatoria vía sistema del complemento-citocinas proinflamatorias. No hay acuerdo general sobre cuál es el perfil de anticuerpos antifosfolipídicos (categoría de laboratorio) que confiere más riesgo obstétrico, aunque las denominadas categorías I y IIa son las mejores candidatas. El tratamiento combinado con dosis bajas de aspirina y heparina consigue buenos resultados obstétricos y maternos. Se revisan también las posibilidades terapéuticas en los casos refractarios. La evolución a otras enfermedades autoinmunes es baja. Se comenta brevemente el denominado síndrome antifosfolipídico obstétrico incompleto, también conocido como síndrome de morbilidad obstétrica asociada a anticuerpos antifosfolipídicos." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Esteve-Valverde E, Ferrer-Oliveras R, Alijotas-Reig J. Síndrome antifosfolipídico obstétrico. Rev Clin Esp. 2016;216:135–145." ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1245 "Ancho" => 1658 "Tamanyo" => 171802 ] ] "descripcion" => array:1 [ "en" => "Antiphospholipid antibodies and their main cofactors." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: Miyakis et al.<a class="elsevierStyleCrossRef" href="#bib0410">1</a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 4169 "Ancho" => 2730 "Tamanyo" => 805416 ] ] "descripcion" => array:1 [ "en" => "Classification criteria for obstetric antiphospholipid syndrome." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1220 "Ancho" => 1657 "Tamanyo" => 209194 ] ] "descripcion" => array:1 [ "en" => "Laboratory categories of antiphospholipid syndrome. Category I, double or triple positivity; category II, single positivity." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 2460 "Ancho" => 3451 "Tamanyo" => 897898 ] ] "descripcion" => array:1 [ "en" => "Various scenarios in terms of aFL, SAF and SAFO. Abbreviations: aPL: antiphospholipid antibodies; APS: antiphospholipid syndrome; OAPS: obstetric antiphospholipid syndrome." ] ] 4 => array:8 [ "identificador" => "fig0025" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: Alijotas-Reig.<a class="elsevierStyleCrossRef" href="#bib0745">68</a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 2163 "Ancho" => 3417 "Tamanyo" => 354510 ] ] "descripcion" => array:1 [ "en" => "Proposed therapeutic regimen for cases of refractory OAPS. The majority of recommended drugs and the proposed combinations in steps 3, 4 and 5 should be evaluated in appropriate clinical studies before routine use. Progesterone supplements may be administered if considered appropriate." ] ] 5 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "Abbreviations: C3/C4, complement system proteins; IL, interleukins; NK, natural killer cells; TNF: tumor necrosis factor; Tregs: regulatory T lymphocytes." "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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Thrombotic \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">Inhibition of protein C activity (acquired resistance to protein C) \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">Inhibition of cofactor activity of protein S \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">Inhibition of antithrombin III activity \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">Tissue factor upregulation in monocytes and endothelial cells \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">Inhibition of tPA activity \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">Reduction of prostacyclin production by endothelial cells \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">Increased production of von Willebrand factor. Induction of platelet activation and aggregation. Resistance to annexin A5 \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">Inhibition of β2-glycoprotein I activity \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">Reduction in thrombomodulin levels \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">Increased microparticle production \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">Proinflammatory cytokine synthesis \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">Inflammatory (trophoblastic damage) \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">Reduction in trophoblast invasive capacity \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">Increase in apoptosis of trophoblastic cells and decrease in β-HCG levels \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">Increase in NT-α, IL-6 and IL-1 levels \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">Reduction in IL-3 levels \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">In situ activation of classical and alternative complement pathways \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">Increase in Fc and protein C4 \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">In situ generation of anaphylatoxins \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">Reduction in peripheral C3 and C4 levels \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">Increase in inflammatory cell concentration, particularly macrophages, neutrophils and decidual NK cells \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">Reduction of decidual Tregs–CD4+CD25+FoxP3+ \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1024396.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Pathogenic mechanisms related to obstetric antiphospholipid syndrome." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:81 [ 0 => array:3 [ "identificador" => "bib0410" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "International consensus statement on an update of the classification criteria for the definite antiphospholipid syndrome (APS)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. 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Obstetric antiphospholipid syndrome

Síndrome antifosfolipídico obstétrico

E. Esteve-Valverdea,c, R. Ferrer-Oliverasb, J. Alijotas-Reigc,

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jalijotas@vhebron.net
16297jar@comb.cat

Corresponding author.

a Servicio de Medicina Interna, Althaia, Xarxa Assistencial de Manresa, Barcelona, Spain

b Servicio de Obstetricia y Ginecología, Hospital Universitari Vall d’Hebron, Barcelona, Spain

c Unidad de Enfermedades Autoinmunes Sistémicas, Servicio de Medicina Interna, Hospital Universitari Vall d’Hebrón, Universitat Autònoma, Barcelona, Spain

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This appears to be especially the case for OAPS&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">According to the current definitions&#44; OAPS includes recurrent spontaneous miscarriages before the 10th week of pregnancy that are not explained by other causes&#44; as well as fetal losses&#44; prematurity&#44; fetal growth delay and early onset preeclampsia&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">1</span></a> We consider OAPS to comprise those cases that meet the obstetric APS criteria and that have not previously presented thrombotic episodes according to the Sydney criteria&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">1</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Some patients have obstetric problems&#44; such as recurrent implantation failure&#44; up to 2 consecutive miscarriages&#44; late or puerperal preeclampsia&#44; premature rupture of the membranes and retroplacental hematoma and yet do not meet the clinical or laboratory criteria for OAPS&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">1</span></a> This situation is known as incomplete OAPS or&#44; following the nomenclature of the European Registry on Obstetric Antiphospholipid Syndrome &#40;EUROAPS Project&#41;&#44; obstetric morbidity related to antiphospholipid antibodies &#40;OMAPS&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">2</span></a> The paramount importance of recognizing OAPS lies in the fact that this is one of the few treatable causes of obstetric complications&#46; The proper management of OAPS can also prevent the maternal thromboembolic complications associated with aPL during pregnancy and postpartum&#46; Nevertheless&#44; due to the fact that the prevalence of aPL in the healthy population reaches 5&#37;&#44;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">3</span></a> its routine measurement in previously healthy pregnant patients is not recommended&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">4</span></a> In this clinical review&#44; we aim to address all of these issues&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Brief historical background</span><p id="par0020" class="elsevierStylePara elsevierViewall">Although there have been references to similar clinical&#8211;biological conditions since the 1950s<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">5</span></a> &#40;and especially in the 1970s<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">6</span></a>&#41;&#44; the &#8220;modern&#8221; APS appeared in the 1980s &#40;1983&#8211;1986&#41;&#44; described by the medical team at the Rayne Institute St Thomas&#8217; Hospital of London&#44; led by professor Graham RV Hughes&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">7&#44;8</span></a> Laurell and Nilson<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">5</span></a> had previously reported the correlation between a syphilis false positive on one hand and the coagulation disorder and recurrent miscarriage on the other&#46; Reaginic tests &#40;e&#46;g&#46;&#44; rapid plasma regain and the venereal disease research laboratory test&#41; for lues&#44; which are known to be in reality a type of aPL&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">9&#44;10</span></a> From this&#44; we base the concept of patients with a false positive syphilis serology&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">11</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In 1980&#44; Firkin et al&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">12</span></a> suggested the relationship between recurrent miscarriage and lupus anticoagulant &#40;LA&#41;&#46; In 1981&#44; Carreras et al&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">13</span></a> described the presence of an antibody that interferes with the formation of prostacyclins and related it to arterial thrombosis and intrauterine fetal death&#46; In 1983&#44; Lubbe et al&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">14</span></a> established for the first time the use of low-dose corticosteroids as treatment for patients with APS&#44; with the aim of preventing fetal death by inhibiting the effects of these antibodies&#46; Later&#44; Harris et al&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">15</span></a> standardized the technique for measuring anticardiolipin antibodies &#40;aCL&#41;&#44; thereby better delimiting its role in APS&#46; In 1987&#44; a group of experts met in Sapporo &#40;Japan&#41; to define the first ever classification criteria for APS&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">16</span></a> At the beginning of the 1990s&#44; the associations between aPL and gestational morbidity were described and strengthened&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">17</span></a> In 1990&#44; it was shown that &#946;2-glycoprotein I is the main aPL cofactor&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">18</span></a> The classification criteria and treatment strategies have since been revised&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Epidemiology</span><p id="par0030" class="elsevierStylePara elsevierViewall">The prevalence of APS in the general population is unknown&#44; although it has been estimated at 0&#46;5&#8211;1&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">19</span></a> APLs can be detected in 1&#8211;5&#37; of healthy women of reproductive age&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">20</span></a> Approximately 40&#37; of women with systemic lupus erythematosus have aPL&#44; and it is estimated that less than 40&#37; of women ultimately present thrombotic events&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">21</span></a> Between 10&#37; and 25&#37; of recurrent miscarriages are due to aPL&#46; The prevalence of aPL in women with obstetric morbidity varies widely from 5&#37; to 50&#37;&#46; The prevalence of LA varies between 0&#37; and 14&#37;&#44; but for women with fetal losses after week 20&#44; the rate increases up to 30&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">22</span></a> The differences in these results can be explained by the diversity of the study groups&#44; the different inclusion criteria and the lack of standardization of many of the aPL detection methods&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">23</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">In a cohort of 590 pregnant women belonging to the Euro-Phospholipid Project&#44; which included 1000 patients with APS&#44; Cervera et al&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">24</span></a> observed that the prevalence of preeclampsia&#44; eclampsia and <span class="elsevierStyleItalic">abruptio placentae</span> was 9&#46;5&#37;&#44; 4&#46;4&#37; and 2&#37;&#44; respectively&#46; The authors also observed that the prevalence of early and late fetal losses in 1580 pregnancies was 35&#46;4&#37; and 16&#46;9&#37;&#44; respectively&#44; with a 48&#37; rate of live births&#46; Alijotas-Reig et al&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">2&#44;25</span></a> reported the preliminary data from the EUROAPS study&#44; which included 211 women and 530 pregnancies&#46; The prevalence of recurrent miscarriages was 43&#46;3&#37;&#44; and the rate of late fetal losses was 32&#46;4&#37;&#44; while the rate of live births reached 80&#37; in the treated women and was only 20&#37; in those who were not treated&#46; The unpublished data from a second EUROAPS study on the same group&#44; which this time included 338 women with OAPS&#44; showed that the most common complications were prematurity &#40;47&#37;&#41;&#44; early preeclampsia &#40;25&#46;6&#37;&#41;&#44; fetal losses &#40;22&#46;5&#37;&#41; and recurrent miscarriages &#40;16&#46;5&#37;&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The prevalence of aPL in preeclampsia&#47;eclampsia is not well established&#46; In a recent study&#44; the prevalence of aPL in women with preeclampsia was 14&#37; and 28&#37; in hemolysis&#44; raised liver enzyme and thrombocytopenia syndrome&#44;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">25</span></a> a syndrome that complicates 0&#46;01&#8211;0&#46;2&#37; of pregnancies in healthy pregnant women and in up to 10&#8211;12&#37; of patients with OAPS&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">26</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Catastrophic APS is a severe and life-threatening form of APS&#46; The condition represents only 1&#37; of APS cases&#59; however&#44; 5&#8211;6&#37; of catastrophic APS cases occur during pregnancy or the postpartum&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">27</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Antiphospholipid antibodies</span><p id="par0050" class="elsevierStylePara elsevierViewall">APLs are autoantibodies that mainly target anionic phospholipids &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; As a practical manner&#44; aPLs can be divided into those capable of extending the basic coagulation tests in vitro&#44; mainly the cephalin test or dilute tissue thromboplastin time &#40;LA activity&#41;&#44; and those targeted at molecules similar to cardiolipin&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">It was initially thought that aPLs react directly with the negatively charged phospholipids&#46; However&#44; it has been shown that aPLs target epitopes of certain proteins called cofactors&#44; including proteins C and S&#44;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">28</span></a> annexin A2 and A5 and high-molecular-weight kininogen&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">29</span></a> Nevertheless&#44; the 2 cofactors most related to aPL pathogenicity are beta2-glycoprotein I &#40;&#946;2GPI&#41; and prothrombin&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">30</span></a> The aPLs directed against &#946;2GPI and against prothrombin &#40;aPT&#41; are the ones most often related to laboratory test positivity and clinical manifestations&#46;<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">31&#8211;33</span></a> &#946;2GPI consists of 5 domains &#40;DI&#8211;DV&#41;&#44; with DV the one touching the cell receptor and DI the one that binds to aPL&#44; specifically through certain oxidized thiol groups in the -Gly40-Arg43- position&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">34</span></a> It is interesting that the &#946;2GPI molecule is in circular form in plasma and that to exert its pathogenic properties it must dimerize on the cell membrane surface&#44; at which point it can be immunogenetic&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">35</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">In 2003&#44; 2 systematic reviews confirmed that LA activity better correlates with the risk of thrombosis and probably with the risk of experiencing obstetric complications&#46; The revisions also confirmed that AL-&#946;2GPI is a more powerful risk marker than AL-aPT&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">36</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Etiopathogenesis</span><p id="par0065" class="elsevierStylePara elsevierViewall">The activation of endothelial cells&#44; monocytes and platelets is boosted by aPL&#44; with a subsequent increase in cell adhesion molecules &#40;ICAM&#44;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">37</span></a> VCAM and tissue factor&#41; and coagulation pathway activation&#46; However&#44; pathology observations in animal models and in humans have led to the conclusion that this thrombotic model is not unique&#46; Therefore&#44; there are 2 mechanisms&#44; prothrombotic and proinflammatory&#44; which can explain the aPL-related pathogenesis&#44; especially during gestation&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">It has been reported that &#946;2GPI-dependent aPLs are the most relevant in the pathogenic effect on implantation and this is believed to be due to placental overexpression of &#946;2GPI&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">38</span></a> At the same time&#44; the formation of &#946;2GPI-anti&#946;2GPI complexes activates the complement system by the classical pathway&#44; inducing local inflammatory damage&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">39</span></a> Out et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">40</span></a> Girardi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">41</span></a> and Holers et al&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">42</span></a> analyzed placentas from women with recurrent miscarriages due to OAPS and demonstrated that thrombotic phenomena were missing in more than half of the cases&#44; although there were inflammatory signs&#46; This hypothesis has been validated by the Girardi et al&#46; group&#44;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">43</span></a> suggesting that local activation of the complement would be a lesional mechanism for trophoblasts and the vascular endothelium&#46; Therefore&#44; inflammatory changes have been observed in many cases without evidence of placental thrombosis&#44;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">44</span></a> which is probably due to complement activation<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">45</span></a> and&#47;or a negative balance of angiogenic factors&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">46</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">It has been reported that the increase in CD16<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>CD56<span class="elsevierStyleSup">dim</span> natural killer &#40;NK&#41; cells and the decrease in CD16<span class="elsevierStyleHsp" style=""></span>&#8722;<span class="elsevierStyleHsp" style=""></span>CD56<span class="elsevierStyleSup">bright</span> NK cells in the endometrium are risk factors for recurrent miscarriages&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">47</span></a> It has been shown that aPLs interfere with implantation and subsequent placentation by increasing trophoblastic apoptosis&#44; with a consequent reduction in human chorionic gonadotropin levels and perhaps progesterone levels&#46; This hormonal reduction could change the activity of NK cells&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">48</span></a> Carp and Shoenfeld<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">49</span></a> and Perricone et al&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">50</span></a> observed that women with APS and recurrent miscarriages had higher levels of NK cells than those with APS but without miscarriages&#46; Berman et al&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">51</span></a> observed that tumor necrosis factor alpha is a significant effector of placental injury&#46; Recent studies on animal models have demonstrated a direct effect of aPLs on trophoblastic cells&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">52</span></a> Di Simone et al&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">53</span></a> have demonstrated the capacity of aPL to harm the maternal side of the placenta&#44; by directly acting on the human endometrial endothelial cells&#46; We can conclude that aPLs act on trophoblastic cells&#44; endothelial cells&#44; platelets and placental bed&#44; ultimately reducing the trophoblastic invasion&#44; weakening the differentiation of human endometrial endothelial cells and interfering with proper placentation&#46; We should emphasize the correlation between aPLs and the direct lesional effect of the membrane attack complex &#40;C5b-9&#41;&#44; the activation of innate immune cells by C3a and especially C5a&#44; with the consequent increase in the production of free radicals and antiangiogenic cytokines&#44; which&#44; as a whole&#44; cause irreversible lesions&#46; A prothrombotic condition is then produced&#44; given that aPLs&#44; in addition to increasing tissue factor synthesis and release&#44; have the ability to trigger endothelial cells through nuclear factor &#954;B and protein kinase p38&#46;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">54</span></a> All of this contributes to the increases in the already increased prothrombotic state during gestational and puerperal periods &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Clinical signs and symptoms</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">General obstetric signs and symptoms</span><p id="par0080" class="elsevierStylePara elsevierViewall">The typical clinical complications of OAPS are those that determine obstetric morbidity&#44; according to the Sydney criteria &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; We are referring to recurrent miscarriages that occur before week 10 of pregnancy with no other known causes that could explain them&#59; fetal losses starting from week 10&#59; preeclampsia&#47;eclampsia&#47;hemolysis&#44; raised liver enzyme and thrombocytopenia syndrome &#40;&#60;34 weeks of gestation&#41;&#59; and delayed fetal growth &#40;&#60;10th percentile&#41;&#46; It is not uncommon for patients to experience more than one episode of preeclampsia before being diagnosed with OAPS&#46; Early onset preeclampsia and prematurity are believed to be related to placental vascular insufficiency&#46; The experts who drafted the Sydney criteria defined in more detail the concept of placental insufficiency&#44; namely&#46; &#40;1&#41; abnormal or uncertain fetal survival test results &#40;e&#46;g&#46;&#44; lack of reactivity in the fetal heart rate monitoring test&#44; suggestive of fetal hypoxia&#41;&#59; &#40;2&#41; abnormal results from Doppler flow velocity waveform analyses&#44; suggestive of fetal hypoxemia &#40;e&#46;g&#46;&#44; absent end diastolic flow in the umbilical artery&#41;&#59; &#40;3&#41; oligohydramnios &#40;e&#46;g&#46;&#44; amniotic fluid index &#8804;5<span class="elsevierStyleHsp" style=""></span>cm&#41;&#59; or &#40;4&#41;&#44; postnatal weight less than the 10th percentile for the gestational age&#46;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">55</span></a> These disorders complicate 15&#8211;30&#37; of cases in most series&#46; Although a number of studies have suggested that fetal losses are the most common obstetric complication of APS&#44;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">56</span></a> other authors have found that recurrent miscarriages are the most common&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">57</span></a> Although it is classically accepted that these patients have miscarriages without previous living children&#44; it is not uncommon to find women with a living child &#40;occasionally premature or low weight&#41; and who subsequently have multiple miscarriages or recurrent fetal losses&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">Additionally&#44; there is another series of obstetric complications related to aPLs that is worth considering&#58; subchorionic or retroplacental hematoma&#44; <span class="elsevierStyleItalic">abruptio placentae</span>&#44; premature membrane rupture&#44; late onset preeclampsia and puerperal preeclampsia&#46; The relationship between aPLs and recurrent implantation failure syndrome is also the subject of debate&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">58</span></a> Lastly&#44; the following clinical&#8211;biological disorders can accompany or precede obstetric complications and can suggest the possible presence of aPLs&#58; associated autoimmune disease&#44; <span class="elsevierStyleItalic">livedo reticularis</span>&#44; ulcers in the lower limbs&#44; recent onset migraine&#44; chorea&#44; thrombocytopenia&#44; hemolytic anemia and false positive luetic serology&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Effects of antiphospholipid antibodies and antiphospholipid syndrome on gestation and vice versa</span><p id="par0090" class="elsevierStylePara elsevierViewall">Women with untreated aPL&#47;OAPS are at much higher risk than the general pregnant population of experiencing gestational losses at any point in the pregnancy&#46; Various studies have shown a clear association between preeclampsia &#40;especially early preeclampsia&#41; and APS&#46; In the Spanish population&#44; the association between preeclampsia and the presence of LA and&#47;or IgM aCL has been demonstrated&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">25</span></a> Preeclampsia and severe preeclampsia &#40;especially early onset&#41; have been reported in up to 50&#37; and 25&#37; of pregnant women with APS&#44; respectively&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">APL&#47;OAPS has also been associated with the new assisted reproduction techniques&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">58</span></a> For a number of authors&#44; pre-embryonic miscarriage is the equivalent of implantation failure in cases in which in vitro fertilization or intracytoplasmic sperm injection was employed as the pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">58</span></a> Lastly&#44; aPLs further increase the already higher risk of thrombosis in pregnant women&#46; Thrombosis can appear at any time during pregnancy&#44; with more venous thrombosis than arterial&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">2</span></a> Occasionally&#44; the onset of thrombotic phenomena can coincide with the interruption of prophylactic treatment with aspirin and heparin&#46; Venous thrombosis tends to affect the usual territories&#44; followed by the veins in the upper extremities&#44; the portal system and cerebral venous sinuses&#46; The most common arterial thrombotic complications are those that affect the intracranial vessels&#44; in the form of stroke&#46;<a class="elsevierStyleCrossRefs" href="#bib0700"><span class="elsevierStyleSup">59&#44;60</span></a> Thrombocytopenia can be difficult to assess&#44; because it is sometimes multifactorial or due to some other cause &#40;e&#46;g&#46;&#44; gestational&#44; autoimmune but not related to aPL or to a pharmaceutical&#41;&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Classification criteria</span><p id="par0100" class="elsevierStylePara elsevierViewall">OAPS is defined by the persistent presence of aPLs in patients with obstetric morbidity&#46; The classification criteria&#44; which in daily clinical practice have become synonymous with the diagnostic criteria&#44; were reviewed in Sydney in 2005&#46; At least one laboratory criterion and one clinical criterion are needed to establish a diagnosis of classical APS&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">1</span></a> By extrapolating&#44; a diagnosis of OAPS requires that the clinical criterion of obstetric morbidity be met&#44; along with a laboratory criterion&#46; Patients with OAPS can be classified into 3 major clinical groups &#40;a&#44; b and c&#41;&#44; depending on the gestational period during which the clinical event occurred &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Given the fact that aPLs can be temporarily positivized&#44; the diagnosis should be established with at least a positive result in 2 different measurements&#44; separated by at least 12 weeks&#46; This underscores the importance of persistent positivity&#44; which&#44; if accompanied by an appropriate clinical manifestation&#44; gives the diagnosis a high degree of certainty&#46; The Sydney meeting recommended subclassifying aPLs into 4 laboratory categories&#44; according to the predominant type and isotype&#58; I&#44; IIa&#44; IIb and IIc &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; These categories are dynamic and can vary among pregnancies&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">The current criteria&#44; envisaged more for research purposes&#44; can result in false negative diagnoses&#44; given their restrictive character&#46; Alijotas-Reig<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">30</span></a> established the need to modify these criteria to encapsulate all patients with aPL and obstetric complications not included in the current criteria &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46; Various prospective studies have been designed for this reason&#44; including the EUROAPS study&#44; which reported on 338 consecutive patients with complete or incomplete OAPS and a total of 1253 recorded pregnancies&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">2&#44;61</span></a> It is worth emphasizing that all laboratory categories have been related to obstetric morbidity&#44;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">2&#44;60</span></a> although a number of authors believe that aCLs could have a residual role&#44; given that the wells in ELISA detection kits include not only cardiolipin but also &#946;2GPI&#46;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">61</span></a> Nevertheless&#44; there are patients who only have aCL as the only aPL&#46; There are cases yet to be clarified and classified that do not meet the current Sydney criteria &#40;partial forms&#41;&#44; which are known as obstetric morbidity related to antiphospholipid antibodies &#40;see <a id="intr0010" class="elsevierStyleInterRef" href="http://www.euroaps.wordpress.com/">www&#46;euroaps&#46;wordpress&#46;com</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Preconception recommendations and gestational management</span><p id="par0115" class="elsevierStylePara elsevierViewall">Patients should be informed about the fetal and maternal risk&#44; with and without treatment&#46; Although the diagnosis of OAPS has already been established&#44; we recommend a new aPL reading to determine the potential variations in the antibody type and concentration&#46; The importance of aspirin treatment before starting a pregnancy should be explained&#46;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">62</span></a> Treatment with low-molecular-weight heparins &#40;LMWHs&#41; should be started as soon as possible&#44; given that&#44; in the authors&#8217; experience&#44; their effectiveness is likely more related to the starting time than to the administered dose&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Patients with OAPS should be monitored by specialized multidisciplinary units&#46; Periodic ultrasound checkups&#44; with Doppler studies if possible&#44; are recommended&#46; Starting on week 20&#8211;24&#44; Doppler velocimetry studies are mandatory&#44; with an initial periodicity of 2&#8211;4 weeks&#44; every 2 weeks starting on week 32&#44; and weekly starting on week 37&#46; If the results of the ultrasound checkup are normal&#44; the pregnancy will be completed according to the obstetrician criterion&#46; If complications such as preeclampsia and intrauterine growth restriction occur&#44; specific protocols should be applied for each condition&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Treatment</span><p id="par0125" class="elsevierStylePara elsevierViewall">With appropriate treatment&#44; more than 70&#37; of pregnant women with OAPS will give birth to a living child&#46;<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">63</span></a> Aspirin in combination with heparin &#40;preferentially LMWHs&#41; are the gold standard for treatment of OAPS&#46; Aspirin was the first drug that showed a change in the prognosis of patients with primary APS&#46;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">64</span></a> Aspirin&#39;s mechanism of action is based on inhibiting platelet cyclooxygenase &#40;reduced thromboxane A production&#41; and reducing the proinflammatory and pro-oxidant state&#44; also promoting implantation through an increase in IL-3&#46;<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">65</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Heparin&#44; both fractionated and unfractionated&#44; has shown benefits in both monotherapy and when combined with low-dose aspirin&#46; This result is due not only to its anticoagulant effect but also to its anti-inflammatory and immunomodulatory properties&#46; Heparin is able to prevent aPLs from binding to trophoblastic membrane cells&#44; reduce complement system activation and decrease TNF-&#945; levels&#46;<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">66</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Prednisone was the first treatment for preventing fetal death linked to OAPS&#44; combining it with aspirin&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">14&#44;67</span></a> Prednisone&#39;s adverse effects on pregnancy &#40;hypertension and gestational diabetes&#44; increased rate of asymptomatic infections and prematurity&#41; were later demonstrated&#46; Nevertheless&#44; prednisone is indicated for controlling the symptoms of systemic lupus erythematosus and for autoimmune thrombocytopenia&#46; There are studies that suggest its use at low doses&#44; combining it with aspirin and heparin&#44; for women who are refractory to conventional treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">68</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Antimalarial agents&#44; mainly hydroxychloroquine&#44; are widely studied in the treatment of systemic autoimmune diseases&#44; as is its safety during pregnancy and breastfeeding&#46; Hydroxychloroquine is able to dissociate the aPL immune complexes&#44; reduce the binding of aPL to syncytium and restore the expression of annexin A5 on cell membranes&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">69</span></a> The addition of hydroxychloroquine to treatment with LMWHs and aspirin could improve the pregnancy&#39;s progression&#46;<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">70</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Intravenous immunoglobulins can be used in selected cases in which the combination of heparin&#44; aspirin and hydroxychloroquine has failed&#46; A meta-analysis confirmed the benefit of IVIGs in patients with other associated autoimmune diseases &#40;e&#46;g&#46;&#44; autoimmune thrombocytopenia&#44; Evans syndrome&#41; and recurrent implantation failure&#46;<a class="elsevierStyleCrossRef" href="#bib0760"><span class="elsevierStyleSup">71</span></a> The mechanism of action of intravenous immunoglobulins is not known but appears to suppress the production of antibodies by B lymphocytes and acts on the circulating immunoglobulins by binding to the Fc-IgG-idiotype-anti-idiotype&#46;<a class="elsevierStyleCrossRef" href="#bib0765"><span class="elsevierStyleSup">72</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Thus&#44; the currently recommended treatment for OAPS<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">73</span></a> is<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#40;a&#41;</span><p id="par0155" class="elsevierStylePara elsevierViewall">Low-dose aspirin &#40;100<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; combined with unfractionated heparin &#40;5000&#8211;7500<span class="elsevierStyleHsp" style=""></span>IU&#47;12<span class="elsevierStyleHsp" style=""></span>h subcutaneously&#41; or LMWHs &#40;enoxaparin 40<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h subcutaneously or equivalent dosage of tinzaparin&#44; bemiparin or dalteparin&#41;&#46; Puerperal thromboprophylaxis with LMWHs should be extended for a minimum of 6 weeks&#44; and the use of aspirin at prophylactic dosages should be continued&#46; The duration of prophylaxis with aspirin has not been determined&#44; although we recommend maintaining the prophylaxis until 2 consecutive years of aPL negativity have been documented&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#40;b&#41;</span><p id="par0160" class="elsevierStylePara elsevierViewall">For pregnant women who have a thrombotic event during pregnancy&#44; the recommended regimen is low-dose aspirin combined with LMWHs at anticoagulant dosages &#40;e&#46;g&#46;&#44; enoxaparin 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#40;c&#41;</span><p id="par0165" class="elsevierStylePara elsevierViewall">It is important to start treatment as soon as possible&#44; even prior to conception&#46; For patients with OAPS who weigh more than 80<span class="elsevierStyleHsp" style=""></span>kg or those who weigh 130<span class="elsevierStyleHsp" style=""></span>kg and require thromboprophylaxis with LMWHs&#44; the enoxaparin dosage should be increased to 60<span class="elsevierStyleHsp" style=""></span>mg and 80<span class="elsevierStyleHsp" style=""></span>mg daily&#44; respectively&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#40;d&#41;</span><p id="par0170" class="elsevierStylePara elsevierViewall">For cases of OAPS refractory &#40;15&#8211;20&#37;&#41; to conventional treatment&#44; other drugs may be tried&#44;<a class="elsevierStyleCrossRef" href="#bib0775"><span class="elsevierStyleSup">74</span></a> although&#44; with the exception of antimalarial drugs&#44; there are no verified data on their efficacy&#46; Alijotas-Reig<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">68</span></a> recently suggested a new therapeutic algorithm for these cases &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia></li></ul></p><p id="par0175" class="elsevierStylePara elsevierViewall">Progesterone supplements may be added at any of the previous steps&#44; due to their immunomodulatory effect&#46;<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">75</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Puerperium monitoring and subsequent follow-up</span><p id="par0180" class="elsevierStylePara elsevierViewall">A checkup during the first days of the postpartum and another at 6 weeks is recommended to check for normalization of laboratory and clinical parameters&#46; It is also recommended that aPL levels be again measured at 6&#8211;12 months to determine their progression&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">The progression of OAPS to other autoimmune diseases&#44; particularly systemic lupus erythematosus and autoimmune thrombocytopenic purpura&#44; is much lower than that found in cases of classical APS&#46;<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">76</span></a> With regard to the subsequent onset of thrombotic phenomena in women&#44; the prevalence is also much lower than in cases of classical APS&#46;<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">77</span></a> The aPLs negativize in a small percentage of women&#44; although they frequently return to positivity in a new pregnancy&#46;<a class="elsevierStyleCrossRef" href="#bib0795"><span class="elsevierStyleSup">78</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">There is a European registry of newborns of mothers with OAPS that has shown&#44; as has the EUROAPS study&#44; a high percentage of prematurity compared with the general population and a lower than expected gestational age &#40;up to 17&#37; lower&#41;&#44; despite many of these cases undergoing treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">79</span></a> It has been reported that the premature babies of women with OAPS might have an increased probability of neurocognitive development disorders the &#40;autism&#44; learning difficulties&#41; at 2 years of follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib0805"><span class="elsevierStyleSup">80</span></a> Nevertheless&#44; further studies are needed to establish a causal relationship&#46;<a class="elsevierStyleCrossRef" href="#bib0810"><span class="elsevierStyleSup">81</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Funding</span><p id="par0195" class="elsevierStylePara elsevierViewall">This manuscript was created within the framework of the Gestation-related Autoimmune Disorders project &#40;<span class="elsevierStyleItalic">Trastornos autoinmunitarios relacionados con la gestaci&#243;n</span>&#44; VHIR-2009&#47;298&#41; and was partially funded by ONAGRUP Espa&#241;a&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflicts of interest</span><p id="par0200" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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        1 => array:2 [
          "identificador" => "xpalclavsec637913"
          "titulo" => "Keywords"
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          "identificador" => "xres624509"
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          "identificador" => "xpalclavsec637912"
          "titulo" => "Palabras clave"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Background"
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        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Brief historical background"
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        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Epidemiology"
        ]
        7 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Antiphospholipid antibodies"
        ]
        8 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Etiopathogenesis"
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        9 => array:3 [
          "identificador" => "sec0030"
          "titulo" => "Clinical signs and symptoms"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "General obstetric signs and symptoms"
            ]
            1 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Effects of antiphospholipid antibodies and antiphospholipid syndrome on gestation and vice versa"
            ]
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        10 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Classification criteria"
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        11 => array:2 [
          "identificador" => "sec0050"
          "titulo" => "Preconception recommendations and gestational management"
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        12 => array:2 [
          "identificador" => "sec0055"
          "titulo" => "Treatment"
        ]
        13 => array:2 [
          "identificador" => "sec0060"
          "titulo" => "Puerperium monitoring and subsequent follow-up"
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        14 => array:2 [
          "identificador" => "sec0065"
          "titulo" => "Funding"
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        15 => array:2 [
          "identificador" => "sec0070"
          "titulo" => "Conflicts of interest"
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        16 => array:1 [
          "titulo" => "References"
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    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2015-07-13"
    "fechaAceptado" => "2015-09-09"
    "PalabrasClave" => array:2 [
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec637913"
          "palabras" => array:6 [
            0 => "Recurrent miscarriages"
            1 => "Antiphospholipid antibodies"
            2 => "Pregnancy"
            3 => "Fetal loss"
            4 => "Preeclampsia"
            5 => "Obstetric antiphospholipid syndrome"
          ]
        ]
      ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec637912"
          "palabras" => array:6 [
            0 => "Abortos recurrentes"
            1 => "Anticuerpos antifosfolip&#237;dicos"
            2 => "Embarazo"
            3 => "P&#233;rdidas fetales"
            4 => "Preeclampsia"
            5 => "S&#237;ndrome antifosfolip&#237;dico obst&#233;trico"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Obstetric antiphospholipid syndrome is an acquired autoimmune disorder that is associated with various obstetric complications and&#44; in the absence of prior history of thrombosis&#44; with the presence of antiphospholipid antibodies directed against other phospholipids&#44; proteins called cofactors or PL-cofactor complexes&#46; Although the obstetric complications have been related to the procoagulant properties of antiphospholipid antibodies&#44; pathological studies of human placenta have shown the proinflammatory capacity of antiphospholipid antibodies via the complement system and proinflammatory cytokines&#46; There is no general agreement on which antiphospholipid antibodies profile &#40;laboratory&#41; confers the greatest obstetric risk&#44; but the best candidates are categories <span class="elsevierStyleSmallCaps">I</span> and IIa&#46; Combined treatment with low doses of aspirin and heparin achieves good obstetric and maternal outcomes&#46; In this study&#44; we also review the therapeutic possibilities in refractory cases&#44; although the likelihood of progressing to other autoimmune diseases is low&#46; We briefly comment on incomplete obstetric antiphospholipid syndrome&#44; also known as antiphospholipid antibody-mediated pregnancy morbidity syndrome&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El s&#237;ndrome antifosfolip&#237;dico obst&#233;trico es una alteraci&#243;n autoinmune adquirida que asocia diversas complicaciones obst&#233;tricas&#44; en ausencia de historia tromb&#243;tica previa&#44; junto con la existencia de anticuerpos antifosfolip&#237;dicos dirigidos contra fosfol&#237;pidos&#44; prote&#237;nas denominadas cofactores o contra complejos fosfol&#237;pidos-cofactor&#46; Aunque las complicaciones obst&#233;tricas se han relacionado con sus propiedades procoagulantes&#44; estudios anatomopatol&#243;gicos en placentas humanas han demostrado su capacidad proinflamatoria v&#237;a sistema del complemento-citocinas proinflamatorias&#46; No hay acuerdo general sobre cu&#225;l es el perfil de anticuerpos antifosfolip&#237;dicos &#40;categor&#237;a de laboratorio&#41; que confiere m&#225;s riesgo obst&#233;trico&#44; aunque las denominadas categor&#237;as <span class="elsevierStyleSmallCaps">I</span> y IIa son las mejores candidatas&#46; El tratamiento combinado con dosis bajas de aspirina y heparina consigue buenos resultados obst&#233;tricos y maternos&#46; Se revisan tambi&#233;n las posibilidades terap&#233;uticas en los casos refractarios&#46; La evoluci&#243;n a otras enfermedades autoinmunes es baja&#46; Se comenta brevemente el denominado s&#237;ndrome antifosfolip&#237;dico obst&#233;trico incompleto&#44; tambi&#233;n conocido como s&#237;ndrome de morbilidad obst&#233;trica asociada a anticuerpos antifosfolip&#237;dicos&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Esteve-Valverde E&#44; Ferrer-Oliveras R&#44; Alijotas-Reig J&#46; S&#237;ndrome antifosfolip&#237;dico obst&#233;trico&#46; Rev Clin Esp&#46; 2016&#59;216&#58;135&#8211;145&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Antiphospholipid antibodies and their main cofactors&#46;</p>"
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        "tipo" => "MULTIMEDIAFIGURA"
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        "fuente" => "<span class="elsevierStyleItalic">Source</span>&#58; Miyakis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">1</span></a>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Classification criteria for obstetric antiphospholipid syndrome&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Laboratory categories of antiphospholipid syndrome&#46;</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Category I&#44; double or triple positivity&#59; category II&#44; single positivity&#46;</p>"
        ]
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Various scenarios in terms of aFL&#44; SAF and SAFO&#46; Abbreviations&#58; aPL&#58; antiphospholipid antibodies&#59; APS&#58; antiphospholipid syndrome&#59; OAPS&#58; obstetric antiphospholipid syndrome&#46;</p>"
        ]
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        "etiqueta" => "Figure 5"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
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        "fuente" => "<span class="elsevierStyleItalic">Source</span>&#58; Alijotas-Reig&#46;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">68</span></a>"
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Proposed therapeutic regimen for cases of refractory OAPS&#46; The majority of recommended drugs and the proposed combinations in steps 3&#44; 4 and 5 should be evaluated in appropriate clinical studies before routine use&#46; Progesterone supplements may be administered if considered appropriate&#46;</p>"
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          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; C3&#47;C4&#44; complement system proteins&#59; IL&#44; interleukins&#59; NK&#44; natural killer cells&#59; TNF&#58; tumor necrosis factor&#59; Tregs&#58; regulatory T lymphocytes&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Thrombotic</span>&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"><span class="elsevierStyleHsp" style=""></span>Inhibition of protein C activity &#40;acquired resistance to protein C&#41;&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"><span class="elsevierStyleHsp" style=""></span>Inhibition of cofactor activity of protein S&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"><span class="elsevierStyleHsp" style=""></span>Inhibition of antithrombin III activity&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"><span class="elsevierStyleHsp" style=""></span>Tissue factor upregulation in monocytes and endothelial cells&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"><span class="elsevierStyleHsp" style=""></span>Inhibition of tPA activity&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"><span class="elsevierStyleHsp" style=""></span>Reduction of prostacyclin production by endothelial cells&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"><span class="elsevierStyleHsp" style=""></span>Increased production of von Willebrand factor&#46; Induction of platelet activation and aggregation&#46; Resistance to annexin A5&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"><span class="elsevierStyleHsp" style=""></span>Inhibition of &#946;2-glycoprotein I activity&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"><span class="elsevierStyleHsp" style=""></span>Reduction in thrombomodulin levels&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"><span class="elsevierStyleHsp" style=""></span>Increased microparticle production&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"><span class="elsevierStyleHsp" style=""></span>Proinflammatory cytokine synthesis&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"><span class="elsevierStyleItalic">Inflammatory &#40;trophoblastic damage&#41;</span>&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"><span class="elsevierStyleHsp" style=""></span>Reduction in trophoblast invasive capacity&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"><span class="elsevierStyleHsp" style=""></span>Increase in apoptosis of trophoblastic cells and decrease in &#946;-HCG levels&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"><span class="elsevierStyleHsp" style=""></span>Increase in NT-&#945;&#44; IL-6 and IL-1 levels&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"><span class="elsevierStyleHsp" style=""></span>Reduction in IL-3 levels&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"><span class="elsevierStyleHsp" style=""></span>In situ activation of classical and alternative complement pathways&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"><span class="elsevierStyleHsp" style=""></span>Increase in Fc and protein C4&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"><span class="elsevierStyleHsp" style=""></span>In situ generation of anaphylatoxins&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"><span class="elsevierStyleHsp" style=""></span>Reduction in peripheral C3 and C4 levels&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"><span class="elsevierStyleHsp" style=""></span>Increase in inflammatory cell concentration&#44; particularly macrophages&#44; neutrophils and decidual NK cells&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"><span class="elsevierStyleHsp" style=""></span>Reduction of decidual Tregs&#8211;CD4&#43;CD25&#43;FoxP3&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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Article information

ISSN: 22548874
Original language: English

DOI:10.1016/j.rceng.2015.11.003

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