Barbara Acaia1 , Federica Rossi1 and Cecilia Beatrice Chighizola2, 3
U.O. Ostetricia e Ginecologia I, U.O.S. Patologia della Gravidanza, IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, Via della Commenda 12, Milan, 20122, Italy
Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
Istituto Auxologico Italiano, Milan, Italy
Antiphospholipid syndromePregnancy morbidityTreatment
Obstetric manifestations enlisted in the classification criteria for the antiphospholipid syndrome (APS) comprise otherwise unexplained pregnancy loss (PrL) – either early (at least three consecutive events before the 10th gestational week) or late (one event at or after the 10th gestational week) – and/or premature birth (before the 34th gestational week) due to eclampsia, preeclampsia, or placental insufficiency, associated with the persistent positivity at medium–high titers for antiphospholipid antibodies (aPL) . Additional aPL-associated complications of pregnancy, not considered in the current APS criteria, include abruptio placentae, hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, and deep venous thrombosis. A precise estimates of the frequency of aPL-related obstetric complications is still lacking; in a multicenter prospective cohort of 590 pregnant APS women and 1,580 pregnancies, early miscarriages were reported in 35.4 % of cases, fetal death in 16.9 %, premature birth in 10.6 %, preeclampsia in 9.5 %, eclampsia in 4.4 %, and abruptio placentae in 2 % .
Three laboratory tests are routinely used to detect serum aPL: two solid-phase assays to evaluate antibodies against β2 glycoprotein I (anti-β2GPI antibodies) and cardiolipin (aCL), and the functional assay lupus anticoagulant (LA) . A given aPL profile confers a peculiar risk of clinical event: patients with a triple aPL positivity are at highest risk for both thrombosis and pregnancy failure; LA is the strongest predictor of clinical manifestations, increasing the risk of miscarriage by tenfold [3–5]. aPL titers and isotypes should also be considered, with IgG being clinically more meaningful compared to IgM . Additional risk factors for pregnancy morbidity include low C3 and C4 at baseline and at the time of pregnancy failure, a platelet decrease greater than 20 %, a previous history of obstetric complications, and an associated autoimmune condition [7, 8].
APS generally does not provide a contraindication for pregnancy, but in case of concomitant illness – such as severe pulmonary hypertension, heart failure, and renal failure – conception should be avoided, because of the high risk of maternal morbidity and mortality. Women carrying aPL who experience a disease flare within the previous 6 months, those who developed a thrombotic event in the previous semester and those with uncontrolled hypertension should also be discouraged to remain pregnant .
Without any treatment, approximately 20–30 % of pregnancies in aPL-positive women will end with a successful outcome. Therefore, women with APS should be considered at high risk and managed in a joint rheumatologic-obstetric clinic throughout the whole gestation. Preconceptional and multidisciplinary counselling is necessary in order to determine the risk of maternal as well as fetal complications. The general schedule should include more frequent visits as pregnancy progresses, with regular blood pressure measurement and urinalysis . Follow-up of these women should also include Doppler studies of the uteroplacental circulation to assess placental function and fetal growth and to predict the occurrence of complications such as preeclampsia and fetal distress [11, 12].
Clinical management of APS patients during pregnancy course aims at preventing obstetric recurrences and at avoiding thrombotic events. The association of low-dose aspirin (LDASA) and prophylactic doses of heparin, either synthetic unfractioned heparin (UFH) or low-molecular weight heparin (LMWH), is currently regarded as the standard of care for women with aPL-related obstetric manifestations . Thanks to such combo approach, more than 70 % of pregnant APS women deliver a viable infant . However, despite the advancements in the therapeutic management of obstetric APS, there still remain some critical issues, mainly due to the several limitations flawing the literature. First, some studies have included patients not fulfilling APS criteria: indeed, in most studies any type of PrL was regarded as a sufficient criterion for APS, without excluding other potential causes of pregnancy wastage. Other studies recruited women with any preterm birth because of preeclampsia, eclampsia, or placental insufficiency. However, since placenta-mediated obstetric complications are relatively common in the general population, APS classification criteria included only cases requiring delivery before 34 weeks . Another critical issue of available literature is provided by the inclusion of women with transient or low-titer aPL positivity: such positivity does not display a clinical significance, being reported in other diseases and in healthy individuals. Literature is also impinged by design bias, with most studies being of retrospective nature.
To highlight evidence about the treatment of obstetric APS, three systematic reviews have been performed to date (Empson et al. 2005 ; Mak et al. 2010 ; Ziakas et al. 2010 ). Available evidence about the therapeutic strategies in aPL-related pregnancy complication is hereby widely discussed.
16.2 Historical Notes of Treatment of Obstetric APS
Prednisone and LDASA constituted the mainstay of early APS treatment: thanks to the combination of high-dose prednisone and LDASA, a successful outcome was obtained in 75 % of treated pregnancies.
The first case series on steroids in obstetric APS dates back to 1983, when Lubbe treated with prednisone 6 LA positive women with recurrent PrL, observing a successful outcome in five cases . However, the enthusiasm about steroids was to wane rather quickly: critical issues were raised in 1989, with Lockshin observing a considerable rate of maternal and fetal morbidity in those receiving steroids, including gestational diabetes, hypertension, premature rupture of membranes, and preeclampsia .
Treatment with LDASA alone was first proposed in the management of obstetric APS in 1988 , since then conflicting results have been presented. Several observational studies reported pregnancy success rates as high as 79–100 % with LDASA alone [20–25], whereas in a randomized controlled trial, the rate of positive obstetric outcomes was comparable between the placebo group (84 %) and the group treated with LDASA (80 %), suggesting that LDASA is not beneficial in women with aPL and recurrent PrL . This finding was further supported by Tulppala who did not observe differences in obstetric outcomes between aCL-positive women receiving LDASA or placebo . On the other hand, prophylactic treatment with LDASA during pregnancy reduced the rate of miscarriages from 72 to 38 % in a retrospective study  and preconceptional prescription of LDASA appeared to be significantly associated with favorable neonatal outcome in a multivariate analysis .
The earlier reports of heparin use date back to 1990 ; the first randomized controlled study came in 1992, when Cowchock showed that the regimen of UFH plus LDASA was equally efficacious than prednisone plus LDASA, but associated with less morbidity ; this observation was later to be confirmed by many other studies [21, 30]. Furthermore, the addition of UFH to LDASA was shown to increase the rate of successful pregnancies in two early randomized controlled trials. Kutteh conducted the first prospective study in 1996; he treated 50 patients with at least three consecutive PrL and confirmed aPL positivity with either LDASA or LDASA plus UFH. UFH plus LDASA provided a significantly better pregnancy outcome than LDASA alone (rate of viable infants: 80 % versus 44 %, respectively) . Accordingly, Rai showed that the combination treatment (LDASA + UFH) was superior to LDASA alone. In this randomized controlled trial, 90 pregnant women with a history of at least three miscarriages and persistent aPL were recruited; the rate of live births was 71 % among women treated with LDASA + UFH and 42 % among those receiving LDASA alone . These two studies allowed defining the optimal management of obstetric APS, an approach that has remained substantially unchanged over time.
16.3 Mechanism of Action of Antiplatelet and Anticoagulant Agents in Obstetric APS
Antiplatelets as LDASA are more effective in preventing arterial thrombosis: in the high-flow, high-shear arterial circulation, platelet adhesion and aggregation play a major role. In obstetric APS, LDASA has been shown not only to prevent placental thrombosis but also to stimulate the production of interleukin (IL) -3, a cytokine that favors placental and fetal development .
Conversely, anticoagulants are especially active in the low-flow, low-shear venous vasculature where fibrin-rich clot forms. Anticoagulant drugs include vitamin K antagonists (VKA), heparin, and its derivatives. However, warfarin must be avoided throughout the first trimester of pregnancy, specifically during organogenesis between the 6th and the 10th week of gestation, because of the high risk of fetal malformations. After the 12th week, warfarin increases the risk of fetal bleeding. Therefore, heparin derivatives such as UFH and LMWH are preferred. To note, heparin’s activity in APS is not merely attributable to its anticoagulant action. Indeed, heparin directly interacts with β2 glycoprotein I (β2GPI), the main antigenic target of aPL. Similarly, it has been suggested that the protective effects exerted by heparin in obstetric APS may be related to its anticomplement activity, as it inhibits the activation of complement cascade induced by aPL . In vitro, heparin restores the placental expression of heparin-binding epidermal growth factor-like growth factor, a molecule involved in blastocyst implantation and prevents both in vitro and in vivo aPL-inhibited endometrial angiogenesis [35–37].
16.4 Current Management of Obstetric APS
The American College of Chest Physicians recently published guidelines for the management of obstetric APS :
· Women with APS without previous thrombosis:
LDASA together with either UFH (5,000–7,000 IU sc every 12 h) or LMWH in usual prophylactic doses (i.e., enoxaparin 40 mg sc every 24 h).
· Women with APS and previous thrombosis:
LDASA plus therapeutic UFH or LMWH in usual therapeutic doses (i.e., enoxaparin 1 mg/kg sc every 12 h).
The recommendations included in these guidelines are supported by the three available meta-analyses [14–16]. It should be noted that studies investigating the optimal management of women with obstetric APS focused mainly on the most common aPL-related clinical manifestation in pregnancy, namely, early PrL; much less evidence is available about other obstetrical complications due to aPL.
16.4.1 Treatment of Early Pregnancy Loss
The three available meta-analyses support the standard approach for obstetric APS with heparin plus LDASA: Empson considered six randomized and quasi-randomized controlled trials, concluding that LDASA plus UFH but not LMWH significantly reduced the rate of PrL compared with aspirin alone . Mak analyzed five randomized controlled trials, observing a significantly higher live birth rate among women receiving heparin (either UFH or LMWH) plus LDASA compared to those on LDASA alone . Ziakas evaluated five randomized controlled trials, reporting a treatment effect in favor of UFH but not LMWH . Indeed, LDASA plus UFH significantly reduced PrL compared with aspirin alone, whereas LMWH combined with LDASA displayed no statistically significant effect compared to LDASA alone or to IVIg, even though the point estimates were in the direction of benefit.
The lack of a significant effect by LMWH reported by the three meta-analyses should be ascribed to the randomized controlled trial by Laskin, who in 2009 observed no difference in pregnancy success between LMWH + LDASA and LDASA alone . To note, the two studies directly comparing LMWH to UFH in the management of APS pregnancies did not observe any difference in outcome [40, 41].
Heparin dosage represents a critical issue: in fact, a wide heterogeneity has been observed across the studies, with very few authors specifically addressing this point. A pharmacokinetics study identified dalteparin 5,000 U daily as the optimal dosing regimen . Consistently, Kutteh suggested that lower-dose UFH (5,000 U twice daily) was as affective as higher dose (10,000 U twice daily) in the treatment of aPL-associated PrL . Recently, Ruffatti reported a 97 % live-birth rate among APS women receiving prophylactic adjusted dose of LMWH, suggesting that LMWH dose adjustment as pregnancy progresses and maternal/fetal body weight increases may provide an efficacious treatment option .
Both UFH and LMWH display important side effects, such as heparin-induced thrombocytopenia and osteoporosis; it is therefore recommended to properly supplement pregnant women on heparin with calcium and vitamin D. Conversely, the bleeding risk seems to be rather low among pregnant women on heparin: in a series of 89 pregnancies treated with LMWH, bleeding complications were observed in 6.7 % of cases, but none was major .
As expected, in a meta-analysis of available studies, the association of prednisone and LDASA did not reduce the rate of PrL, but was associated with a three times greater risk of premature delivery and gestational diabetes compared to other regimens .
16.4.2 Treatment of Late Pregnancy Loss
The management of women with prior fetal loss follows the same indications than those for early miscarriages even if Ziakas didn’t find any significant effect of therapy with heparin plus LDASA on pregnancy outcome .
16.4.3 Treatment of Preeclampsia, Eclampsia, and HELLP Syndrome
aPL are among the most significant risk factors for preeclampsia ; however, this complication is reported rather rarely in APS treatment trials. A recent meta-analysis evaluating 31 randomized trials on primary prevention of preeclampsia in high-risk individuals (not only aPL-positive) showed that antiplatelet agents were associated with a 10 % reduction in preeclampsia and prematurity rates . On the other hand, in two aspirin only trials, preeclampsia rates were even a little higher among women receiving placebo compared to those treated with LDASA [31, 32].
HELLP syndrome complicates approximately 10–12 % of pregnancies with preeclampsia/eclampsia. A 2005 retrospective study of 16 cases of aPL-associated HELLP syndrome in 15 women showed that treatment with LDASA and LMWH substantially decreased the risk of HELLP in subsequent pregnancies, with all 16 pregnancies ending with a live birth . Apart from this large case series, 10 case reports about women with HELLP syndrome treated with heparin have been published, leading to a live birth in 3 cases [48–54].
16.4.4 Treatment of Other Pregnancy Complications
More than 10 % of untreated APS women deliver small for gestational age infants , while preterm birth is reported to complicate 12–35 % of pregnancies in aPL-positive women . With respect to these pregnancy complications, Empson observed that UFH maintained a treatment advantage when composite outcomes were considered (PrL or IUGR, PrL or premature delivery), while LDASA alone had no significant effect on any of the considered outcomes .
Even though the literature does not provide a solid evidence for the management aPL-related pregnancy complications other than early PrL, the rationale of using the same therapeutic approach lays in the observation that aPL-associated PrL, preeclampsia, eclampsia, IUGR, and HELLP syndrome are all mediated by the same pathogenic mechanisms: β2GPI-dependent aPL target placental tissues interfering with multiple physiologic pathways, leading to the inhibition of trophoblast differentiation, growth, and invasion and of endometrial endothelial cell differentiation, eventually resulting in defective placentation .
16.5 Management of Pregnant Women with Thrombotic APS
A history of vascular thrombosis was found to be significantly associated with a poor infant outcome together with LA and triple positivity . Moreover, Bramham observed that women with previous thrombosis display a worse obstetric prognosis compared to women with APS obstetric manifestations only, with significantly higher rates of preterm delivery and small for gestational age babies . Unfortunately, clinical studies have not included pregnant APS women who experienced thrombotic events. The management of these women is rather troublesome, as warfarin has a teratogenic potential; nevertheless, one study evaluated warfarin in APS pregnancies, without observing any difference with enoxaparin . Currently, it is recommended to switch warfarin to heparin as soon as pregnancy is confirmed. Treatment with full antithrombotic doses of LMWH plus LDASA throughout the entire pregnancy is an accepted approach . Warfarin could be exceptionally prescribed in the second trimester until close to delivery, when heparin must be resumed [13, 59, 60].
16.6 Treatment of Refractory Obstetric APS
Not all women receiving standard treatment succeed in having a live birth. The heterogeneity in pregnancy outcomes may be related to differences in the clinical features and the serologic profile. Besides aPL profile, traditional risk factors, such as advanced maternal age, increased BMI, and proinflammatory maternal diseases (i.e., metabolic syndrome), could affect pregnancy outcome.
To date, no evidence-based recommendation is available about which treatment should be instituted when first-line therapies fail. In a 2008 survey of physicians experienced in obstetric APS management, the most common therapeutic strategy in case of refractory obstetric APS consisted in increasing LMWH from a prophylactic to a therapeutic dose, even though this approach is not supported by any evidence . Another strategy envisages the combination of standard treatment with one or more therapeutic tool among IVIg, prednisone, and plasma exchange.
It should be noted that to date there is no evidence of a clear beneficial effect of IVIg in obstetric APS. The first report of IVIg use in obstetric APS was that of Carreras et al. , followed by few more anecdotal reports [63–66] and case series [67–72] supporting the benefits of IVIg. However, a Cochrane analysis considering five studies concluded that IVIg are associated with an increased risk of PrL or premature birth compared with heparin and LDASA .
Prednisone might provide another therapeutic option for refractory cases because of its action on inflammatory mechanisms underlying obstetric APS. However, low-dose prednisone only can be an option. In fact, even if steroids are mostly inactivated by placental metabolism allowing just a small percentage to cross into the fetal circulation, high-dose corticosteroids are clearly associated with an increased rate of complications, as previously discussed. Indeed, a UK group recently reported a marked increase in the live-birth rate in women with refractory events (from 4 to 61 %) thanks to the addition of prednisone 10 mg daily in the first trimester . The early administration allows an effect on placentation without inducing the premature rupture of membranes.
Plasma exchange is an additional therapeutic tool; the rationale behind apheretic treatments lays in the removal of aPL from bloodstream. Some authors support the safety and tolerability of plasma exchange during pregnancy , even though available evidence of the efficacy of this treatment in obstetric APS is merely restricted to case reports from a single center [75, 76].
16.7 Management of Pregnant Women with Secondary APS
In approximately 40 % of cases, pregnant aPL-positive patients carry an autoimmune disease, mainly systemic lupus erythematosus (SLE). These women carry a consistent obstetric risk factor, since lupus itself, and to a lesser extent other rheumatic conditions, exerts a strong impact on pregnancy course.
Women with SLE should be counselled preconceptionally, in order to schedule pregnancy during remission; in particular, the disease should have been stable for at least 6 months. Pregnancies in these patients must be strictly followed by a joint team of obstetricians and rheumatologists to precisely assess the individual risk and to modify the pharmacological treatment avoiding teratogen compounds. During pregnancy course and in the postpartum, women should be carefully monitored for any possible disease flare . It should be remembered that some of the immunosuppressive drugs used to control disease activity during pregnancy are contraindicated during lactation .
16.8 Treatment of aPL-Positive Women Not Fulfilling APS Criteria
The optimal management of low-titer aPL-positive pregnant women is a matter of debate, as currently available evidence is inconsistent. Some studies were not supportive of a treatment benefit [77, 78], and recently aPL-positive women on LDASA were found to present a pregnancy outcome similar to controls, suggesting that in this setting, an approach with LDASA only might be sufficient . On the other hand, another study reported that untreated patients with low aPL levels and APS-like obstetrical events have a poor pregnancy outcome, similar to those with full-blown APS . Consistently, women with aPL positivity at low titers have been shown to be at high risk of developing severe obstetric APS, thus warranting full treatment .
Although there is no recommendation on how to treat women not fulfilling APS criteria, most physicians experienced in obstetric APS management prescribe LDASA , since aPL-positive women display an increased risk of preeclampsia and LDASA was reported to decrease such risk .
16.9 Peripartum Management
Proper peripartum management of anticoagulation is crucial. In case of epidural anesthesia or analgesia, epidural anesthesia can be safely performed 12 h after the last dose of LMWH at thromboprophylactic doses, and it can be resumed 6–8 h after the procedure. LDASA does not add a significant risk for spinal hematoma, and it can be safely maintained. For induction or scheduled cesarean, UFH and prophylactic LMWH should be discontinued 12 h before admission .
During puerperium the thrombotic risk is very high, with a procoagulant state compensating for excessive maternal bleeding at delivery. Therefore, it is recommended to continue thromboprophylaxis with LDASA plus UFH or LMWH for 4–6 weeks after delivery in women with obstetric manifestations only . In this regard, it has recently emerged that, despite treatment with LDASA, APS women with at least three early losses present a higher annual thrombotic risk as compared to women with recurrent abortions due to thrombophilic defects, women with PrL but negative thrombophilic profile, and asymptomatic aPL carriers, with a greater 12-year cumulative thrombotic incidence compared to control women [82, 83]. Therefore, these patients definitely are worth a primary thromboprophylaxis. When administered at full antithrombotic doses, LMWH should be stopped 24 h before epidural anesthesia or it should be replaced by thromboprophylactic dose 12 h before, and it can be resumed not earlier than 24 h afterwards. After delivery, women receiving long-term anticoagulation can be safely switched to warfarin [84, 85]. Both heparin and warfarin have been shown to be safe for breastfeeding mothers .
Antiplatelet and anticoagulant agents currently provide the cornerstone of the treatment of obstetric APS: there is consensus that the regimen combining preconceptional LDASA and heparin should be the first-line treatment for obstetric APS while IVIg, steroids, and plasma exchange should be reserved to refractory cases. Many clinical issues remain still unresolved, such as the optimal treatment of cases not responsive to conventional treatment or the management of patients not fulfilling clinical and laboratory APS criteria (e.g., women with a history of two early events or with low-titer aPL positivity). In particular, no treatment trial has ever investigated the optimal treatment of aPL women stratifying upon the different risk profile (aPL profile, associated autoimmune conditions, previous obstetrical history). Hopefully, these critical issues will be soon overcome thanks to a clear-cut evidence, even though we reckon it is not straightforward to conduct well-designed, large, multicenter trials in pregnant APS women due to ethical issues.
Miyakis S, Lockshin MD, Atsumi M et al (2006) International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 4:295–306PubMedCrossRef
Cervera R, Piette JC, Font J et al (2002) Antiphospholipid syndrome: clinical, and immunologic manifestations and pattern of disease expression in a color of 1000 patients. Arthritis Rheum 46:1019–1027PubMedCrossRef
Neville C, Rauch J, Kassis J et al (2009) Antiphospholipid antibodies predict imminent vascular events independently from other risk factors in a prospective cohort. Thromb Haemost 101:100–107PubMedCentralPubMed
Pengo V, Ruffatti A, Legnani C et al (2010) Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost 8:237–242PubMedCrossRef
Rai RS, Clifford K, Cohen H et al (1995) High prospective fetal loss rate in untreated pregnancies of women with recurrent miscarriage and antiphospholipid antibodies. Hum Reprod 10:3301–3304PubMed
De Groot PG, Lutters B, Derksen RHWM et al (2004) Lupus anticoagulants and the risk of a first episode of deep venous thrombosis. J Thromb Haemost 3:1993–1997CrossRef
Rai R, Regan L (1997) Obstetric complications of antiphospholipid antibodies. Curr Opin Obstet Gynecol 9:387–390PubMed
Ruffatti A, Del Ross T, Ciprian M et al (2009) Risk factors for a first thrombotic event in antiphospholipid antibody carriers. A multicenter, retrospective follow-up study. Ann Rheum Dis 68:397–399PubMedCrossRef
Ruiz-Irastorza G, Khamashta MA (2011) Lupus and pregnancy: integrating clues from the bench and bedside. Eur J Clin Invest 41:672–678PubMedCrossRef
Danza A, Ruiz-Irastorza G, Khamashta MA (2012) Antiphospholipid syndrome in obstetrics. Best Pract Res Clin Obstet Gynaecol 26:65–76PubMedCrossRef
Le Thi Huong D, Wechsler B, Vauthier-Brouzes D et al (2006) The second trimester Doppler ultrasound examination is the best predictor of late pregnancy outcome in systemic lupus erythematosus and/or the antiphospholipid syndrome. Rheumatology (Oxford) 45:332–338CrossRef
Cnossen JS, Morris RK, ter Riet G et al (2008) Use of uterine artery Doppler ultrasonography to predict pre-eclampsia and intrauterine growth restriction: a systematic review and bivariable meta-analysis. CMAJ 178:701–711PubMedCentralPubMedCrossRef
Ruiz-Irastorza G, Khamashta MA (2007) Antiphospholipid syndrome in pregnancy. Rheum Dis Clin North Am 33:287–297PubMedCrossRef
Empson M, Lassere M, Craig J et al (2005) Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev. doi:10.1002/14651858.CD002859
Mak A, Cheung MW, Cheak AA et al (2010) Combination of heparin and aspirin is superior to aspirin alone in enhancing livebirths in patients with recurrent pregnancy loss and positive anti-phospholipid antibodies: a meta-analysis of randomized controlled trials and meta-regression. Rheumatology 49:281–288PubMedCrossRef
Ziakas PD, Pavlou M, Voulgarelis M (2010) Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: a systematic review and meta-analysis. Obstet Gynecol 115:1256–1262PubMedCrossRef
Lubbe WF, Butler WS, Palmer SJ et al (1983) Foetal survival after prednisolone suppression of maternal lupus-anticoagulant. Lancet 18:1361–1363CrossRef
Lockshin MD, Druzin ML, Qamar T (1989) Prednisone does not prevent recurrent fetal death in women with antiphospholipid antibody. Am J Obstet Gynecol 160:439–443PubMedCrossRef
Elder MG, de Swiet M, Robertson A et al (1988) Low dose aspirin in pregnancy. Lancet 1:410PubMedCrossRef
Carmona F, Font J, Azulay M et al (2001) Risk factors associated with fetal losses in treated antiphospholipid syndrome pregnancies: a multivariate analysis. Am J Reprod Immunol 46:274–279PubMedCrossRef
Silver RK, MacGregor SN, Sholl JS et al (1993) Comparative trial of prednisone plus aspirin versus aspirin alone in the treatment of anticardiolipin antibody-positive obstetric patients. Am J Obstet Gynecol 169:1411–1417PubMedCrossRef
Lima F, Khamashta MA, Buchanan NMM et al (1996) A study of sixty pregnancies patients with the antiphospholipid syndrome. Clin Exp Rheumatol 14:131–136PubMed
Granger KA, Farquharson RG (1997) Obstetric outcome in antiphospholipid syndrome. Lupus 6:509–513PubMedCrossRef
Huong DLT, Wechsler B, Bletry O et al (2001) A study of 75 pregnancies in patients with antiphospholipid syndrome. J Rheumatol 28:2025–2030PubMed
Munoz-Rodriguez FJ, Font J, Cervera R et al (1999) Clinical study of 100 patients with the antiphospholipid syndrome. Semin Arthritis Rheum 29:182–190PubMedCrossRef
Pattison NS, Chamley LW, Birdsall M et al (2000) Does aspirin have a role in improving pregnancy outcome for women with the antiphospholipid syndrome? A randomized controlled trial. Am J Obstet Gynecol 183:1008–1012PubMedCrossRef
Tulppala M, Marttunen M, Soderstrom-Anttila V et al (1997) Low-dose aspirin in prevention of miscarriage in women with unexplained or autoimmune related recurrent miscarriage: effect on prostacyclin and thromboxane A2 production. Hum Reprod 12:1567–1572PubMedCrossRef
Rosove MH, Tabsh K, Wasserstrum N et al (1990) Heparin therapy for pregnant women with lupus anticoagulant or anticardiolipin antibodies. Obstet Gynecol 75:630–634PubMed
Cowchock FS, Reece EA, Baldan D et al (1992) Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low dose heparin treatment. Am J Obstet Gynecol 166:1318–1327PubMedCrossRef
Laskin CA, Bombardier C, Hannah ME et al (1997) Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. N Engl J Med 337:148–153PubMedCrossRef
Kutteh WH (1996) Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol 174:1584–1589PubMedCrossRef
Rai R, Cohen H, Dave M et al (1997) Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 314:253–257PubMedCentralPubMedCrossRef
Fishman P, Falach-Vaknin E, Sredni B et al (1996) Aspirin-interleukin-3 interrelationships in patients with anti-phospholipid syndrome. Am J Reprod Immunol 35:80–84PubMedCrossRef
Girardi G, Redecha P, Salmon JE (2004) Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med 10:1222–1226PubMedCrossRef
Di Simone N, Marana R, Castellani R et al (2010) Decreased expression of heparin-binding epidermal growth factor-like growth factor as a newly identified pathogenic mechanism of antiphospholipid-mediated defective placentation. Arthritis Rheum 62:1504–1512PubMedCrossRef
D’Ippolito S, Marana R, Di Nicuolo F et al (2012) Effect of low molecular weight heparins (LMWHs) on antiphospholipid antibodies (aPL)–mediated inhibition of endometrial angiogenesis. PLoS One. doi:10.1371/journal.pone.0029660PubMedCentralPubMed
de Carvalho JF, de Oliveira RM, Rodrigues CEM et al (2012) Heparin increases HLA-G levels in primary antiphospholipid syndrome. Clin Dev Immunol. doi:10.1155/2012/232390
Bates SM, Greer IA, Pabinger I et al (2008) Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133:844S–886SPubMedCrossRef
Laskin CA, Spitzer KA, Clark CA et al (2009) Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA trial. J Rheumatol 36:279–287PubMedCrossRef
Stephenson MD, Ballem PJ, Tsang P et al (2004) Treatment of antiphospholipid antibody syndrome (APS) in pregnancy: a randomized pilot trial comparing low molecular weight heparin to unfractionated heparin. J Obstet Gynaecol Can 26:729–734PubMed
Noble LS, Kutteh WH, Lashey N et al (2005) Antiphospholipid antibodies associated with recurrent pregnancy loss: prospective, multicenter, controlled pilot study comparing treatment with low-molecular-weight heparin versus unfractionated heparin. Fertil Steril 83:684–690PubMedCrossRef
Ensom MH, Stephenson MD (2004) Pharmacokinetics of low molecular weight heparin and unfractionated heparin in pregnancy. J Soc Gynecol Investig 11:377–383PubMedCrossRef
Kutteh WH, Ermel LD (1996) A clinical trial for the treatment of antiphospholipid antibody-associated recurrent pregnancy loss with lower dose heparin and aspirin. Am J Reprod Immunol 35:402–407PubMedCrossRef
Ruffatti A, Gervasi MT, Favaro M et al (2011) Adjusted prophylactic doses of nadroparin plus low dose aspirin therapy in obstetric antiphospholipid syndrome. A prospective cohort management study. Clin Exp Rheumatol 29:551–554PubMed
De Sancho MT, Khalid S, Christos PJ (2012) Outcomes in women receiving low-molecular weight heparin during pregnancy. Blood Coagul Fibrinolysis 23:51–755CrossRef
Duckitt K, Harrington D (2005) Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ 330:565PubMedCentralPubMedCrossRef
Askie LM, Duley L, Henderson-Smart DJ, PARIS Collaborative Group et al (2007) Antiplatelet agents for prevention of preeclampsia: a meta-analysis of individual patient data. Lancet 369:1791–1798PubMedCrossRef
Sinha J, Chowdhry I, Sedan S, Barland P (2002) Bone marrow necrosis and refractory HELLP syndrome in a patient with catastrophic antiphospholipid antibody syndrome. J Rheumatol 29:195–197PubMed
Pauzner R, Dulitzky M, Carp H et al (2003) Hepatic infarctions during pregnancy are associated with the antiphospholipid syndrome and in addition with complete or incomplete HELLP syndrome. J Thromb Haemost 1:1758–1763PubMedCrossRef
Haram K, Trovik J, Sandset PM et al (2003) Severe syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP) in the 18th week of pregnancy associated with the antiphospholipid-antibody syndrome. Acta Obstet Gynecol Scand 82:679–680PubMedCrossRef
Roberts G, Gordon MM, Porter D et al (2003) Acute renal failure complicating HELLP syndrome, SLE and anti-phospholipid syndrome: successful outcome using plasma exchange therapy. Lupus 12:251–257PubMedCrossRef
Ilbery M, Jones AR, Sampson MB, Samson J (1995) Lupus anticoagulant and HELLP syndrome complicated by placental abruption, hepatic, dermal and adrenal infarction. Aust N Z J Obstet Gynaecol 35:215–217PubMedCrossRef
Alsulyman OM, Castro MA, Zuckerman E et al (1996) Preeclampsia and liver infarction in early pregnancy associated with the antiphospholipid syndrome. Obstet Gynecol 88:644–646PubMedCrossRef
Amant F, Spitz B, Arnout J, Van Assche FA (1997) Hepatic necrosis and haemorrhage in pregnant patients with antiphospholipid antibodies. Lupus 6:552–555PubMedCrossRef
Alijotas-Reis J (2013) Treatment of refractory obstetric antiphospholipid syndrome: the state of the art and new trends in the therapeutic management. Lupus 22:6–17CrossRef
Ruffatti A, Calligaro A, Hoxha A et al (2010) Laboratory and clinical features of pregnant women with antiphospholipid syndrome and neonatal outcome. Arthritis Care Res 62:302–307CrossRef
Bramham K, Hunt BJ, Germain S et al (2010) Pregnancy outcome in different clinical phenotypes of antiphospholipid syndrome. Lupus 19:58–64PubMedCrossRef
Pauzner R, Dulitzki M, Langevitz P et al (2001) Low molecular weight heparin and warfarin in the treatment of patients with antiphospholipid syndrome during pregnancy. Thromb Haemost 86:1379–1384PubMed
Østensen M, Khamashta M, Lockshin M et al (2006) Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Res Ther 8:209PubMedCentralPubMedCrossRef
Lockshin MD (2013) Anticoagulation in management of antiphospholipid antibody syndrome in pregnancy. Clin Lab Med 33:367–376PubMedCentralPubMedCrossRef
Erkan D, Patel S, Nuzzo M et al (2008) Management of the controversial aspects of the antiphospholipid syndrome pregnancies: a guide for clinicians and researchers. Rheumatology 47:23–27CrossRef
Carreras LO, Perez GN, Vega H et al (1988) Lupus anticoagulant and recurrent fetal loss: successful treatment with gammaglobulin. Lancet 2:393–394PubMedCrossRef
Parke A, Maier D, Wilson D et al (1989) Intravenous gamma-globulin, antiphospholipid antibodies, and pregnancy. Ann Intern Med 110:495–496PubMedCrossRef
Scott JR, Branch DW, Kochenour NK et al (1989) Intravenous immunoglobulin treatment of pregnant patients with recurrent pregnancy loss caused by antiphospholipid antibodies and Rh immunization. Am J Obstet Gynecol 159:055–1056
Wapner RJ, Cowchock FS, Shapiro SS (1989) Successful treatment in two women with antiphospholipid antibodies and refractory pregnancy losses with intravenous immunoglobulin infusions. Am J Obstet Gynecol 161:1271–1272PubMedCrossRef
Ron-el R, Vinder A, Golan A et al (1993) The use of intravenous gammaglobulin, heparin and aspirin in the maintenance of a pregnancy of freeze thawed embryo in a patient with lupus anticoagulant. Eur J Obstet Gynecol Reprod Biol 52:131–133PubMedCrossRef
Kaaja R, Julkunen H, Ammala P et al (1993) Intravenous immunoglobulin treatment of pregnant patients with recurrent pregnancy losses associated with antiphospholipid antibodies. Acta Obstet Gynecol Scand 72:63–66PubMedCrossRef
Spinnato JA, Clark AL, Pierangeli SS et al (1995) Intravenous immunoglobulin therapy for the antiphospholipid syndrome in pregnancy. Am J Obstet Gynecol 172:690–694PubMedCrossRef
Valensise H, Vaquero E, De Carolis C et al (1995) Normal fetal growth in women with antiphospholipid syndrome treated with high-dose intravenous immunoglobulin (IVIG). Prenat Diagn 15:509–517PubMedCrossRef
Clark AL, Branch DW, Silver RM et al (1999) Pregnancy complicated by the antiphospolipid syndrome: outcomes with intravenous immunoglobulin therapy. Obstet Gynecol 93:437–441PubMedCrossRef
Marzusch K, Dietl J, Klein R et al (1996) Recurrent first trimester spontaneous abortion associated with antiphospholipid antibodies: a pilot study of treatment with intravenous immunoglobulin. Acta Obstet Gynecol Scand 75:922–926PubMedCrossRef
Triolo G, Ferrante A, Accardo-Palumbo A et al (2004) IVIG in pregnancy. Lupus 13:731–735PubMedCrossRef
Bramham K, Thomas M, Nelson-Piercy C et al (2011) First-trimester low-dose prednisolone in refractory antiphospholipid antibody-related pregnancy loss. Blood 117:6948–6951PubMedCrossRef
Bontadi A, Ruffatti A, Tison T et al (2012) Plasma exchange and immunoadsorption effectively remove antiphospholipid antibodies in pregnant patients with antiphospholipid syndrome. J Clin Apher 27:200–204PubMedCrossRef
Bortolati M, Marson P, Chiarelli S et al (2009) Case reports of the use of immunoadsorption or plasma exchange in high-risk pregnancies of women with antiphospholipid syndrome. Ther Apher Dial 13:157–160PubMedCrossRef
Ruffatti A, Marson P, Pengo V et al (2007) Plasma exchange in the management of high risk pregnant patients with primary antiphospholipid syndrome. A report of 9 cases and a review of the literature. Autoimmun Rev 6:196–202PubMedCrossRef
Cowchock S, Reece EA (1997) Do low-risk pregnant women with antiphospholipid antibodies need to be treated? Organizing group of the antiphospholipid antibody treatment trial. Am J Obstet Gynecol 176:1099–1100PubMedCrossRef
Del Ross T, Ruffatti A, Visentin MS et al (2013) Treatment of 139 pregnancies in anti-phospholipid positive women not fulfilling criteria for antiphospholipid syndrome: a retrospective study. J Rheumatol 40:425–429PubMedCrossRef
Soh MC, Pasupathy D, Gray G et al (2013) Persistent antiphospholipid antibodies do not contribute to adverse pregnancy outcomes. Rheumatology 52:1642–1647PubMedCentralPubMedCrossRef
Mekinian A, Loire-Berson P, Nicaise-Roland P et al (2012) Outcomes and treatment of obstetrical antiphospholipid syndrome in women with low antiphospholipid antibody levels. J Reprod Immunol 94:222–226PubMedCrossRef
Gardiner C, Hills J, Machin SJ et al (2013) Diagnosis of antiphospholipid syndrome in routine clinical practice. Lupus 22:18–25PubMedCentralPubMedCrossRef
Gris JC, Bouvier S, Molinari N et al (2012) Comparative incidence of a first thrombotic events in purely obstetric antiphospholipid syndrome with pregnancy loss: the NOH-AOS observational study. Blood 119:2624–2632PubMedCrossRef
Martinez-Zamora MA, Peralta S, Creus M et al (2012) Risk of thrombotic events after recurrent abortion in anti-phospholipid syndrome: a case-control study. Ann Rheum Dis 71:61–66PubMedCrossRef
Horlocker T, Wedel D, Rowlingson J et al (2010) Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med 35:64–101PubMedCrossRef
Douketis JD, Berger P, Dunn A et al (2008) The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133:299S–339SPubMedCrossRef