Obstetric APLA syndrome

Obstetric  Antiphospholipid Syndrome Obstetric antiphospholipid syndrome has been recognized since the mid twentieth century . the earliest antiphospholipid antibody assay described in 1906 by Wasserman et al was complement fixation test for syphilis identifying antibodies subsequent  shown  to bind cardiolipin Development of the more specific treponemal immobilization test identified individuals with positive Wasserman tests who were negative for the confirmatory assay these  patients results were termed biologic false positive serologic tests for syphilis When systemic lupus erythematosus patients with BEP – STS desmonstrate prolonged in vitro coagulation times that were consistent with a circulating inhibitor the inhibitor was termed a lupus anticoagulant . Despite the name LAC was subsequently associated with thrombosis and pregnancy loss rather than hemorrhage While requires plasma rather than serum and is challenging to standardize. The radioimmunoassay using a cardiolipin test antigen developed in 1983 provided a simpler alternative and was followed by the present day anticardiolipin ELISA . Finally identification of an aCL cofactor beta  2 glycoprotein 1 led to development of the current aB2GPI ELISA assay and also make it clear that pathogenic aPL do not bind phospholipid directly rather they bind to an exposed epitope on the phospholipid bound protein . Despite  the common name applied to a spectrum of various  laboratory tests aPL assays do not all identify the same antibodies furthermore the various aPL likely convey differing risks for thrombosis and pregnancy complications. The prevalence of aPL in the general population is low but up to 30% of patients SLE are positive for aPL making this a significant concern for SLE pregnancies in particular APL may be seen in the setting of acute or chronic infections including syphilis Lyme disease leprosy viral hepatitis and human immunodeficiency virus and may be induced by various medications. In general infection and drug induced aPL are more often transient and are far less likely than autoimmune aPL to be associated with clinical complications. Spectrum of aPL Antibodies Classification criteria for APS were designed primarily for research purposes rather than clinical diagnosis . the initial criteria were revised in 2006 to include aBGPI  antibodies and to further restrict the aCL titer positive cut offs as a result the newer  criteria are highly specific for APS . APS patients must have one laboratory and one clinical criterion for classification Laboratory criteria include presence of persistent LAC,or persistent moderate high titer igG or IgM isotypes of aCL or aBGPL . Clinical criteria include documented  arterial or venous thrombosis or pregnancy complications that may include recurrent early  loss a single late loss or early delivery due to sever preeclampsia or placental insufficiency Current criteria recommend a cut off of 40 GPL or MPL units for aCL positivity and >99% for aBGPI positivity The appropriateness of the higher cut off is a subject of ongoing discussion among clinicians especially for OB-APS as some groups describe obstetric complications in the setting of lower titers of ACL or aB2GPI antibodies. For examples weh Ruffatti and colleagues compared a cut off of 40 GPL units versus the alternatives >99% had positive aCL only without LAC or aBGPL of this group 20/24 had GPL values between 17.4 GPL units and 40 GPL units and importantly a majority of those with lower GPL values met clinical criteria for pregnancy morbidity. In addition to concern regarding appropriate cutoff levels for classic aPL antibodies in OB- APS the usefulness of non criteria aPL are defined as antiphospholipid antibodies determined by tests that are not included in the formal APS criteria either due to lack of supporting clinical data or lack of assay standardization. For example IgA isotypes are commonly available through commercial assays but they are not included in th current criteria due to lack of conclusive data however isolated high titer igA aCL and igA aB2GPI have been suggested to have an associate with APS complications. Antibodies to other negatively charged phospholipids  have significant overlap with aCL these are rarely positive if standard aPL are negative . Since the assays are poorly standardized and offer little additional value these tests are not generally recommended An exception ay be antiphosphatidylethanolamine qantibody which has been suggested as an independent risk factor for early unexplained fetal loss while not confirmed some clinicians do check this non standardized test in other wise seeronegative patients  with clinical histories consistent with APS. AntiB2GPI antibodies are generally less closely associated with clinical complications than are LAC and aCL this may be because they represent diverse antibody populations that are heterogeneous in their binding antiB2GPI  domains Domain I, however contains the primary epitope for aPL binding and igG antidomain I antibodies are reported to be more closely associated with risk of thrombosis and with obstetric complications tan are antibodies directed against other domains Further prospective clinical data stqandardization and validation of the antidomain iaBGPI assay are necessary before consideration is given to widespread clinical use . Prothrombin is a phospholipid binding proein tht has been postulated to be cirtical in LAC activity Antiprothrombin antibooides have been studied for a number of years with various tests developed Binding of PT to phosphatidylserine in the ELISA enhances assay sensitivity however and the resulting antiphosphatidylserine prothrombin antibody test appear to correlate strongly with presence of LAC and increased risk of complications More conclusive standardization and clinical validation studies are in progress. Pathogenesis While it is clear that aPL are pathogenic for both thrombosis and pregnancy complications the pathophysiology leading to end stage damage appears to be complex and mutifactorial . A variety of mechanisms have been suggested and supported by both in vitro experiments and in vivo murine studies Thrombosis the most clinically evident complication has long been considered th hallmark of APS Investigation of thrombogenic mechanisms has documented important interference with traditional hemostatic pathways of coagulation and fibrinolysis but also significant activation of multiple cellular elements aPL may bind to endothelial cells generating a proinflammatory and prothrombotic phenotype to monocytes causing induction of tissue factor and to platelets leading to activation and aggregation. Purely thrombotic mechanisms were initially invoked for all APS manifestations including pregnancy loss but thrombosis alone does not explain manifestations such as heart valve abnormalities serizures chorea thrombocytopenia early pregnancy loss or those cases of late pregnancy pls where placental pathology reveals no evidence  for thrombosis As a result recent research has focused on local inflammatory mechanisms. Varied but interrelated these include complement activation disturbance of innate immunity through activation of toll like receptors and effects mediated through cytokines and chemokines. It is likely that OB- APS mechanisms differ at least in part from those involved in more straight forward arterial or venous thrombosis since direct effects of aPL on trophoblastic tissue have been demonstrated OB APS has been studied in vitro and through murine models of pregnancy loss . Pregnancy loss models result in lower numbers of embryos increased fetal resorption and lower fetal and placental weights as compared with control mice  . A local thrombotic effect within placental villi is likely supported by demonstration of an aPL induced decrease in annexin A5 levels Annein A5 is a phospholipid binding protein hypothesized to provide a protective anticoagulant shield over invading trophoblast. Specific inflammatory mechanisms are suggested to contribute to pregnancy loss. These include placental injury and dysfunction secondary to classical and alternative pathway complement activation with generation f anaphylatoxin C3a and C5a and subsequent release of proinflammatory cytokines alpha and tissue and antiangiogenic factors . Administration of an antiC5 monoclonal antibody prevented aPl induced murine pregnancy complications in one model as did heparin Fondaparinux did not prevent complications suggesting an anticomplement rather than an anticoagulant mechanism for heparin Mutations in complement regulatory proteins have been associated with varying risk for placental pathology and preeclampsia in patients with APS and SLE further supporting a role of complement mechanisms in OB- APS. A direct effect of aPL on Placental trophoblast is also likely aPl may target the maternal decidua and invading trophoblast  directly leding to defective placentation. In vitro studies have demonstrated aPL induced tissue injury and apoptosis altered syncytial proliferation impaired trophoblast invasion and decreased production of human chorionic gonadotropin and growth factors. Obstetric Manifestations. Clinical manifestations of APS during pregnancy include recurrent early pregnancy loss late pregnancy loss intrauterine growth restriction early severe pe eclampsia ,HELLP syndrome and pregnancy related maternal thromboembolic disease including pregnancy related catastrophic antiphospholipid syndrome Non criteria complications may also complicate pregnancy particularly thrombocytopenia. Recurrent Early Micarriae Although included in the formal APS criteria the association of recurrent early miscarriage wit OB- APS is still debated. Early losses may occur in up to 20-30 % normal pregnancies making it difficult to  rule out other etiologies when aPL are present. In addition chromosomal abnormality the most likely etiology for early miscarriage is not frequently evaluated in early losses . although the literature is somewhat contradictory , one systematic review of 25 studies of recurrent early miscarriage and aPL found positive associations with both aCL and LAC with odds ratios of 3.4 and 2.7 respectively  . A comprehensive 2014 literature review of 46 studies of aPL with REM identified 27 studies that found no association and 12 studies that lacked controls and were unable to comment on association. Although observational studies consistently demonstrate higher levels of aPK in women with REM than in controls the studies are quite disparate with regard to definition of early loss exclusion of other etiologies number of early losses aPl and use of confirmatory testing Inclusion of recurrent early miscarriage and late pregnancy loss in th same analysis also complicates some studies. Of note few studies utilized criteria that concur with current classification guidelines for both clinical and laboratory APS criteria. Late Pregnancy Loss The data supporting an association of aPL with late pregnancy loss are stronger than those for recurrent early miscarriage One retrospective study of women with > two pregnancy losses found 50% of ll losses were fetal deaths in the aPL positive group as compared to less than 15% in th aPL negative group  A recent literature review found a positive association of fetal death with aPL in a large number of case control and cohort studies. Another systematic review confirms a strong association between aCL with late pregnancy loss and a metaanalysis confirms the association of high titer IgG aCL and LAC but not aB2GPI  with late pregnancy loss Finally th multicenter population based study conducted b th stillbirth collaborative Research Network confirmed an association between aCL and aB2GPI with stillbirth although LAC was not measured in this study. Pregnancy Morbidity Patients with pregnancy complications of severe preeclampsia or eclampsia or delivery due to placental insufficiency before 34 weeks gestation in association with a moderate to high titer of aPL met criteria for OB APS , the incidence of preeclampsia in APS patients has been estimated to be as high as 48% although other series suggest aPL positivity in 20-30% women with severe early pre eclampsia the recent meta analysis by Do Prado et al found a closer association of APL with early and severe pre eclampsia rather than later mild preeclampsia . they identified an overall elevated risk of pre eclampsia in aCL positives women with an odds ratio of 2.86 which rose to 11.15 when only severe pre eclampsia was included  . Incidence of HELLP syndrome considered a severe variant of pre eclampsia is similarly elevated in aPL positives women Hellp syndrome in these patients is often early and severe it occurs more frequently in the second rather than the third trimester has a 33% rate of hepatic infraction and is frequently associated with other thrombotic complications therefore requiring aggressive treatment. Studies looking at association of IUGR with aPL are equally divided and heterogeneous Chauler et al found an adjusted odds ratio for IUGR in aPL positives pregnancy to be 4.64 however with the strongest association with positives LAC. Maternal Morbidity Risk of maternal thrombosis is increased in aPl positives pregnant patients and is estimated at 5-12% In one cohort of female APS patients one quarter of all thromboses occurred during pregnancy or the postpartum period Catastrophic antiphospholipid syndrome represents a fulminant life threatening form of APS with multiple thrombotic complications occurring within a short period of time often involving small vessels thromboses Fifteen cases of CAPS related to pregnancy have been described roughly half presented during pregnancy HELLP syndrome preceded CAPS in 8 of the 15 patients Maternal mortality was 46% and combined fetal and neonatal mortality was 54%. Neonatal Morbidity Neonatal morbidity is primarily related to risks associated with prematurity and intrauterine growth restriction risk factors for these outcomes are similar to those associated with pregnancy loss in aPL positives patients. In one study poor neonatal outcome in treated pregnancies of primary was patients was associated with ;ac triple positive apl profile and a history of vascular thrombosis History of pregnancy morbidity alone without previous thrombosis was associated with a more favorable neonatal outcome. Transplacental passage o IgG has been documented and fetal or neonatal thromboses in offspring of aPL positives mothers whiles rare have been reported Fewer than twenty infants with thrombotic complications have been reported with cerebrovasclar accident most common other thromboses included mesenteric renal vein inferior vena cava aortic vessels and neonatal caps It should be noted however that most infants had additional risk factors for thrombosis including use of catheters and other instrumentation. Therapy Comprehensive care for  aPL positive pregnant patients requires careful risk assessment to determine optimal monitoring nd medial therapy which may include low dose aspirin heparin or rarely intravenous immunoglobulin.  Assessment of risk also permits appropriate counseling allowing patients a realistic appreciation of likely outcome and may impact expectations and future pregnancy decisions. Stratifying risk for patients with aPL should be based on antiphospholipid antibody type titer and persistence as well as other demonstrated risk factors such as previous thrombosis and underling SLE Persistent high titer antibodies are generally considered most significant one retrospective case control study compared 57 PAPS patients with unsuccessful pregnancy outcomes Independent risk factors for pregnancy failure included concomitant diagnosis of SLE history of both thrombosis and pregnancy morbidity and triple aPL positivity Patients diagnosed on the basis of a single positives test or pregnancy morbidity alone were more likely to have successful pregnancies Low complement levels may also predict poor outcome low complement levels were associated with fetal death preterm delivery and low birth weight in another study of PAPS pregnancies.  Results from the promise study support the long held assumption that  LAC is most closely associated with complications as suggested by previous meta analysis . PROMISSE  was a large multicenter observational study of pregnancies of healthy with apl sle or both as well as pregnancies of healthy controls. Lupus anticoagulant was identified as the strongest predictor of adverse pregnancy outcome as defined by fetal death neonatal death preterm delivery before 34 weeks or small  for gestational age in 144 aPl positive pregnancies after adjusting for confounding variables . Patients were enrolled at up to 12 weeks gestation therefore REM was not studied in this cohort Confounders included lower age history of thrombosis and sle which were independently associated with increased risk of adverse pregnancy outcome Surprisingly acl and aB2GPi status were not independently associated with adverse pregnancy outcome Patients with low titer apl with negative lac who do not have a historyof thrombosis or underlying sle appear to bea t low risk for fetal or neonatal loss and preterm delivery due to apl complications Lupus anticoagulant high risk profiles for adverse obstetric outcome previous thrombosis and underlying sle likely further increase risk. Current Therapies Current therapy for Ob-APS is low dose aspirin with prophylactic dose heparin usually given as either unfractionated heparin 5000 units sq BID or low molecular weight heparin commonly enoxaparin 40 mg or deltaparin 5000 units subcutaneous once daily One major difficulty with assessing optimal treatment is th current assumption that therapy should be identical for patients with different OB manifestations i.e. recurrent early miscarriage versus fetal death. A number of reviews and meta analyses haves attempted to reach firm conclusions regarding efficacy of low dose aspirin and heparin based on available data.  A meta analysis by Mak et al found a positive effect of therapy with low dose aspirin and heparin in patients with positive aPl and recurrent pregnancy loss when compared to aspirin alone. A 2014 systematic literature review of randomized controlled trials for treatment of recurrent early miscarriage only identified ten eligible studies live birth rates for identified ten eligible studies live birth rates for low dose aspirin alone ranged from 42 -80% and lives birth rates for low dose aspirin plus low dose heparin were 71-85% . However only unfractionated heparin in combination with low dose aspirin had a benefit and data on low dose aspirin and LMWH were in conclusive Results are thus conflicting for recurrent early miscarriage and even more so for patients with low titer antibody who do not  meet current APS criteria cut offs Despite the conflicting literature however when APS experts were surveyed regarding clinical treatment practices they reported commonly treating with low dose aspirin plus heparin for REM with either low or high titer antibodies  and many treated even when the number of early losses was less than three. The meta analysis of OB-APS treatment trials including both recurrent early miscarriage and fetal death by Ziakas et al included five randomized controlled trials of low dose aspirin plus heparin  versus low dose aspirin alone with a total of 398 patients . They  found that low dose aspirin plus heparin reduced first trimester pregnancy loss but not late pregnancy loss when compared to low dose aspirin alone . LMWH plus low dose aspirin was no better than low dose aspirin alone for first trimester or late pregnancy loss in this analysis while early studies looking at recurrent early miscarriage suggested significant benefit the more recent trials did not confirm those findings and of noe the latter studies used LMWH rather than UFH studies directly comparing the two formulations of heparin however have not confirmed a differ3ence in efficacy for treatment of OB- APS . Confounding variables contributing to th disparate study results include different inclusion criteria different aPL tests variable aPL cut offs  and different entry times in addition to the different treatment regimens. Fetal deaths  account for 50% losses in women with aPL . Few controlled studies document the efficacy of low dose aspirin and heparin for fetal death However patients with a history of APS associated thrombosis are frequently not included in randomized trials as they require treatment with therapeutic levels of heparin throughout pregnancy Higher risk patients such as those with sle are also frequently excluded from randomized treatment trials making it difficult to accrue large numbers  of patients for controlled studies . While low dose aspirin is frequently recommended for use in pregnancies with a history of one or two apl related early pregnancy losses the only controlled trial of low dose aspirin did not find a difference when compared to placebo both groups had very good outcomes. Empiric second line therapy for low dose aspirin plus heparin failures usually involves the addition of intravenous immunoglobulin . The range of doses varies from 400 to 1000 mg/kg daily for 1 to 5 days per month. Case reports have been supportive but controlled studies have not demonstrated additional benefit . Plasmapheresis and plasma exchange  have been used in refractory cases with successes reported Glucocorticoids are not  generally recommended for use in OB APS in the absence of other indications based on underlying sle Early studies suggested efficacy of high dose corticosteroid but demonstrated significant maternal morbidity including maternal hypertension diabetes preterm premature rupture of membranes preterm delivery and IIUGR. Hydroxychloroquine has anticoagulant and anti-inflammatory effects and has been suggested to inhibit aPL mediated trophoblast effects on migratin invasion and differentiation . A recent retrospective analysis of non sle patients with apl associated refractory obstetric losses suggested benefit of HCQ when added to standard low dose aspirin plus heparin therapy prospective studies will be necessary to truly determine any benefit of HCQ on aPL pregnancy outcome. While early reports proposed an association between apl infertility and poor in vitro fertilization outcome more recent controlled studies do not support this association . Treatment aPL in infertile women to improve IVF outcome is not recommended However although supporting data are limited prophylactic aspirin and /or heparin therapy for patients is often administered to-patients with positives aPL, who are undergoing controlled ovarian stimulation to protect against increased thrombosis risk. Future therapies may build on effective treatments  demonstrated in murine OB-APS models including complement inhibition. TNF inhibition ad interleukin . A protein peptide that minics the pospholipid binding site of aB2GP”I may also prove to be protective against development of complications Conclusions OB-APS may have recurrent early miscarriage fetal death or stillbirth as well as increased risk or severe early preeclampsia syndromes and intrauterine growth restriction . Identification  of high risk patients should be based on both antibody  characteristics and clinical history Highest risk for adverse pregnancy  outcome is associated with lupus anticoagulant high titer acl or triple positivity history of thrombosis an presence of underlying sle Lower titer apl antibody titers likely carry a better prognosis although some studies still suggest a degree of risk Based on available data it seems reasonable to treat when there is a history consistent with OB APS even if aPL values are low to moderate given ongoing discussion regarding the appropriate cut offs for OB APS as compared to thrombotic aps Non criteria apl tests are not standardized and checking these is generally not suggested however one might rarely consider checking antiphosphatidylethanolamine antiphosphatidylserine or others I so negative patients with a history strongly suggestive of OB-APS . Antidomain 1 B 2 GPI and anti PT/PS assays are promising but await further widespread validation studies. Low dose aspirin plus heparin remains the standard treatment for OB- APS in general aspirin is started preconception and heparin at the time of a positive pregnancy test. It remains unclear whether UFH is superior to LMWH either is acceptable until further studies are available Low dose aspirin may be discontinued and LMWH  switched to shorteracting   UFH at 36 weeks in anticipation of labor and delivery Low dose aspirin therapy is frequently given to patients with apl who do not meet APS criteria although data are lacking However given the association of apl with preeclampsia low dose aspirin may be reasonably considered for a patient with a significant positives apl test simply to reduce her  risk of pre eclampsia. In clinical practice certain high risk patients e g those with advanced maternal age requiring aisted reproductive technology may be treated more aggressively despite the lack of formal APS criteria. For second line treatment one can consider addition of monthly IIVIG or plasmpheresis/plasma exchange . Aggressiveness of medical therapy depends in part on th individual patient’s clinical situation particularly when additional risk factors are present. Counseling should include the relative risk of poor outcome  based on the patient’s individual constellation of risk factors including the risk of long term complications associated with IUGR and preterm birth . Fetal monitoring is  recommended in the third trimester and may include non stress tests vascular Doppler studies or serial sonograms. Finally anticoagulation should be continued postpartum for 6-12 weeks to prevent maternal thrombotic complications. ReplyForward