Rheum Dis Clin N Am 33 (2007) 287297

Antiphospholipid Syndrome in Pregnancy

Guillermo Ruiz-Irastorza, MD, PhDa, Munther A. Khamashta, MD, FRCP, PhDb,*
Department of Internal Medicine, Hospital de Cruces, University of the Basque Country, 48903-Bizkaia, Spain b Lupus Research Unit, The Rayne Institute, St. Thomas Hospital, Kings College University, London SE1 7EH, UK
a

Obstetric complications, together with thrombosis, are the major clinical manifestations of the antiphospholipid syndrome (APS). There is a strong relationship between antiphospholipid antibodies (aPL) and pregnancy loss [1]. A recent meta-analysis has analyzed the relationship between the dierent aPL (lupus anticoagulant [LA], anticardiolipin antibodies [aCL] and antibeta2 glycoprotein I antibodies [anti-B2GPI)] with recurrent fetal loss in women without known autoimmune diseases [2]. LA has shown the strongest association with recurrent fetal losses before 24 weeks gestation (odds ratio [OR] 7.79, 95% condence interval [CI] 2.30 to 26.45). Data were insucient to analyze the association of LA with early (!13 weeks) miscarriage. Both IgG and IgM aCL also were clearly related with recurrent losses before 24 weeks (OR 3.57, 95% CI 2.26 to 5.65 and OR 5.61, 95% CI 1.26 to 25.03, respectively). IgG aCL also showed an association with early miscarriage (OR 3.56, 95% CI 1.48 to 8.59). On the contrary, anti-B2GPI failed to show a similar relationship with any form of recurrent miscarriage. Pregnant women with APS are at increased risk for miscarriage and thrombotic events [1]. In fact, both features are connected, and previous adverse obstetric events may herald the occurrence of thrombotic complications [3]. However, pregnancies in women with aPL are subject to other types of additional complications, such as systemic and pulmonary hypertension, prematurity, and intrauterine growth restriction. APS is dened from the laboratory point of view by the persistent positivity of aPL. Until recently, the Sapporo criteria for the classication of

* Corresponding author. E-mail address: munther.khamashta@kcl.ac.uk (M.A. Khamashta). 0889-857X/07/$ - see front matter 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.rdc.2007.02.003 rheumatic.theclinics.com

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APS have been used [4]. Sapporo laboratory criteria required the positivity on two occasions, at least 6 weeks apart, of anticardiolipin antibodies (aCL) at medium-high titers or LA. In 2004, an update of the Sapporo criteria was proposed in Sydney [5], including the positivity for anti-B2GPI in addition to aCL and LA. However, the sensitivity and specicity of anti-B2GPI have been called into question [6]. Indeed, the meta-analysis by Opatrny and colleagues [2] failed to show an association between anti-B2GPI and recurrent miscarriage. Although this debate is still open, clinical criteria for APS have remained mostly unchanged. A recent review focused on the pharmacologic therapy of miscarriage in APS by Petri and Qazi [7] was published in 2006 in this journal. That article included a comprehensive critical analysis of controlled studies with aspirin, heparin, warfarin, prednisone, and intravenous immunoglobulins (IVIG). Thus, we will not repeat such a review. Instead, we will comment on specic issues that help situate the current recommendations in their clinical context with their limitations. We will also focus on the general management of pregnancy in APS and in other complications linked to aPL such as thrombosis, hypertension, pulmonary hypertension, and heparin-induced osteoporosis. Pathogenesis Several mechanisms have been proposed to explain the occurrence of recurrent thrombosis and pregnancy losses in patients with APS, including interference with the prostacyclin/thromboxane balance at the endothelial level, inhibition of annexin V (a natural placental anticoagulant), inhibition of antithrombin, protein C and protein S, and activation of platelets [1]. The pathologic ndings in placentas of women with APS reinforce the role of thrombosis leading to placental insuciency as the main mechanism of pregnancy loss in APS [8]. However, other mechanisms may also be involved, including abnormalities in placentation in early miscarriages [8,9]. More recently, an alternative explanation has been presented. Complement activation has always been considered characteristic of SLE and strongly related with damage mediated by inammation. Conversely, APS often is dened as a vasculopathy without vasculitis, ie, with no inammation. However, data from mouse models point to a crucial role of complement activation in thrombosis [10] and fetal loss [11] induced by aPL. Girardi and colleagues [11] have shown that low-dose heparin, without anti factor X activity, but retaining the capacity of complement inactivation, prevented aPL-induced miscarriage in mice. On the contrary, full antithrombotic doses of fondaparinux and hirudin, both of which have no eect on complement activation, were ineective. Although data in humans are still lacking, this line of research may help us understand the complex and wide range of APS manifestations and design more targeted therapies. It is possible that women with recurrent early miscarriage, fetal losses, or

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thrombosis belong to dierent pathogenetic subgroups of APS, and thus, treatment may dier for these dierent manifestations of APS. Preembryonic and embryonic losses (before the 10th week of gestation) are frequent events in the general population, in most cases caused by genetic abnormalities [1]. Recurrent (three or more) early pregnancy losses are more rare, and among other causes (genetic, hormonal, uterine abnormalities), APS plays a denite role. Fetal deaths, after the 10th week of gestation, are infrequent in the general population. Uterine abnormalities, maternal disease (such as hypertension or diabetes mellitus), and Rh alloimmunization are the most usual causes. APS also is an important cause of fetal death [1]. Isotype and levels of aCL are important in making clinical decisions. Low-titer aCL has a questionable association with features of APS [12]. Women with persistent aCL at medium-high titers, particularly of the IgG isotype or LA are at the other end of the spectrum. Another important factor is the past obstetric history, previous miscarriage, or fetal death being the strongest predictor of further complications in women with APS [13]. On the other hand, the signicance of aPL found in women without an adverse obstetric history or other features of APS is probably low, with most women in this group having uneventful pregnancies [14].

Pharmacologic management of pregnancy losses in antiphospholipid syndrome Historically, prednisone, aspirin, heparin, and immunoglobulins have been used in the treatment of pregnancy losses in women with APS. In the above-mentioned recent review by Petri and Qazi [7], the nal recommendation for women with APS and one fetal loss or multiple rst trimester losses is aspirin plus heparin, either unfractionated heparin (UFH) or lowmolecular weight heparin (LMWH). Also in 2006, a Cochrane collaboration review on the therapy of miscarriage in women with aPL has been published [15]. In a similar way, combined treatment with aspirin and heparin (they advocate for UFH in this case) is recommended. Currently, prednisone and immunoglobulins are not considered useful for treating miscarriage in women with APS. Prednisone, usually in combination with aspirin, was used initially for the obstetric manifestations of APS. However, case series [16] and two small randomized clinical trials [17,18] showed that the actual eect of corticosteroids on pregnant women with APS represented no superiority over regimes containing aspirin with or without heparin. In fact, an increased rate of complications such as prematurity and hypertension was seen. Likewise, use of immunoglobulins has not shown superiority against heparin and aspirin [19,20]. Thus, low-dose aspirin and heparin are the drugs of choice for obstetric APS. However, the optimal regime is still in debate. Two randomized clinical trials (RCT) have investigated whether combined therapy is superior to

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monotherapy with aspirin [21,22], with conicting results. Rai and colleagues [21] found that the combination of low-dose aspirin plus calcium heparin, 5000 IU/12 h, was superior to aspirin alone (71% versus 42% successful pregnancies, respectively). On the contrary, the study by Farquharson and colleagues [22] obtained similar results with low-dose aspirin alone or in combination with dalteparin 5000 IU/d (72% versus 78% live births, respectively). A major criticism to the universal recommendation of combined therapy (aspirinheparin) is that it relies almost entirely on the study by Rai and colleagues [21], which has important limitations with regard to the population included in the trial. Sixty-three percent of the women had a history of early miscarriage only, versus just 4.4% with fetal losses only; 83% were positive for LA alone versus 9% positive for both aCL plus LA. In a large series of patients with denite APS, aCL are present in more than 80% of patients, whereas LA alone is less than 15% [23]. These features raise concerns on the use of a too-sensitive test for LA, which could have classied as APS women with otherwise idiopathic recurrent early miscarriage. In addition, the study by Rai and colleagues [21] showed an atypical behavior of the aspirin-only arm, in contrast with the results of a number of published series showing that a subset of women with APS and poor obstetric history do well with low-dose aspirin in monotherapy, with 79% to 100% success rates [13,17,2426]. Indeed, a recent study of 77 pregnancies in women with APS found that preconceptional treatment with aspirin predicted a successful nal outcome [27]. Another argument to support the insucient eect of low-dose aspirin in monotherapy is supported by the studies of Cowchock and Reece [28], a subgroup analysis of an RCT, and Pattison and colleagues [29], an RCT, showing no superiority of aspirin versus usual care in preventing miscarriage. However, women included in both studies were at a low risk for obstetric complications, because of either the lack of signicant adverse obstetric histories [28] or the presence of aCL at low titer [29,30]. This low risk is illustrated by the high rate of successful pregnancies among untreated women. In terms of the optimal type of heparin, the Cochrane review recommends UFH [15]. Two small studies have not found dierences between UFH and LMWH, both combined with aspirin [31,32]. The small sample size and the resulting wide CIs do not completely exclude superiority of one of the arms. However, the similar behavior of both types of heparin as antithrombotic drugs and the more convenient and safe prole of LMWH make the latter the rst-line option. Although routine use of heparin plus aspirin generally is advocated for all pregnant women with APS and adverse obstetric history, this approach is not supported by unquestionable data [1,3335]. Combination treatment could be the rst option in women with previous fetal losses that are more typical of APS and with a greater impact on the mother, although these women are underrepresented in the RCTs. On the other hand, aspirin

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in monotherapy still has a role to play in women with recurrent early miscarriages, especially younger patients with several fertile years ahead. It is important that every option, with its pros and cons, be discussed in detail with the woman considering pregnancy, so that a joint decision can be made. Whatever the chosen option, aspirin should form part of any treatment of pregnant women with APS and is best started before conception. LMWH can be administered safely as an alternative to UFH.

Thromboprophylaxis in antiphospholipid syndrome during pregnancy This group has been excluded systematically from clinical trials. However, good clinical sense indicates that all women with APS and previous thrombosis should maintain antithrombotic treatment throughout their entire pregnancy and during the postpartum period [36]. Therefore, combined treatment with low-dose aspirin and full antithrombotic doses of LMWH should be given to these patients. Moreover, postpartum LMWH is also mandatory in all women with purely obstetric APS and is also recommended in asymptomatic women with aPL, especially those with SLE [36]. Thromboprophylaxis may represent a risk during labor and, particularly, with the use of epidural anesthesia. Stopping heparin use in the 12 hours before and 12 hours after any interventional procedure is generally considered safe. Many anesthesiologists would also require a minimum of 3 to 7 days without using aspirin to perform a spinal tap, although some of them would feel more comfortable using general anesthesia [37]. Despite optimal thromboprophylaxis, recurrent thrombotic events do occur in some patients with APS. Pregnant women are not an exception, in fact, protection against arterial thrombosis given by heparin plus aspirin may not be enough. Women with previous arterial events, particularly stroke, must be considered as high risk, both in terms of recurrent thrombosis and pregnancy complications [38]. Warfarin may be needed in cases of recurrent thrombosis despite therapeutic doses of heparin [39]. Pauzner and colleagues [40] treated 11 pregnant women with APS with warfarin between weeks 15 and 34 and did not see signicant dierences in pregnancy outcomes with a group of 31 women receiving enoxaparin. Moreover, no serious fetal or maternal bleeding was seen in either group. Therefore, warfarin can be used in some patients during pregnancy only after organogenesis (6th to 12th weeks) because of the high risk of fetal malformations. The international normalized rate must be controlled closely to minimize the probabilities of serious fetal bleeding. Nursing is safe during warfarin or heparin therapy [41].

Hypertensive disorders Hypertension is a cause of major complications in both the mother and the baby [42]. This is dened as a systolic or diastolic blood pressure of

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140/90 mm Hg or higher, which can be present before or develop as a complication of pregnancy, usually after 20 weeks gestation [42]. Preeclampsia is dened as the presence of pregnancy-induced hypertension plus proteinuria of at least 300 mg/d [42]. Positivity for aPL has been shown to be one of the most signicant risk factors for preeclampsia in a recent systematic review [43]. Similar changes in placental arteries have been observed in women with APS and preeclampsia. aPL may be particularly linked with severe forms of preeclampsia and a complication of severe preeclampsia with renal failure, hemolysis, thrombocytopenia, and liver involvement, the so-called HELLP syndrome [4447]. This latter condition is fortunately rare; however, the rate of associated fetal death is very high, particularly if presenting early during the second trimester [47]. Women at high risk for the development of preeclampsia must undergo close follow-up during pregnancy, including frequent monitoring of blood pressure and proteinuria. Doppler studies of the uterine arteries may identify those women more prone to suer toxemia (see below) [48]. Medical management of pregnancy-induced hypertension includes alphamethyl-dopa as rst-line therapy, with calcium-channel antagonists (such as nifedipine) and beta blockers (such as labetalol) as second-line agents [49]. Angiotensin-converting enzyme inhibitors are contraindicated during pregnancy because of the risk of oligohydramnios and renal failure in the fetus [49]. In cases of severe preeclampsia, intensive care unit management and early delivery must be considered [49]. Low-dose aspirin has been shown to decrease the risk of preeclampsia and related adverse fetal outcomes. Although the magnitude of this eect is modest in unselected populations [50], treatment with aspirin may help prevent preeclampsia in high-risk women with APS, and this is an additional good reason for including aspirin in any therapeutic schedule in these patients. Pulmonary hypertension Connective tissue diseases, particularly systemic sclerosis, mixed connective tissue disease, SLE, and APS [51], can be a direct cause of pulmonary hypertension (PHT)dclass 1.3.1 of the World Health Organization classication for PHT. In addition, chronic thromboembolic diseasedclasses 4.1 and 4.2dcan be the consequence of hypercoagulability states, including APS [51]. The prognosis of untreated PHT is poor, with median survival rate less than 3 years after diagnosis [51]. Fortunately, several eective therapies, including prostacyclin analogs, endothelin-receptor antagonists, phosphodiesterase inhibitors, and nitric oxide, have been developed and have improved the quality of life and even survival of patients with PHT [51]. Pregnancy and particularly labor increase the cardiac burden substantially. Pregnancy-related mortality has been estimated up to 50%, usually within the early postpartum period [52]. Therefore, PHT has been considered

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a major contraindication for pregnancy, and eective contraception is recommended to aected fertile women. A recent retrospective review of 15 pregnanciesdfrom 1992 to 2002din a referral center for PHT has shown a maternal mortality rate of more than 35% [52]. The mortality rate in pregnant women with SLE/APS-related PHT was very high in a series from Birmingham Universitydtwo out of three patientsddespite the use of nitric oxide and prostacyclin analogs [53]. Thus, PHT continues to be a very high risk condition in pregnant women despite advances in clinical management. High maternal mortality justies the contraindication of pregnancy in women with all forms of PHT. If pregnancy occurs under any circumstance, women must be treated by a combined team, including physicians with experience in PHT, in a center with fully equipped intensive care and neonatal units. Inhaled nitric oxide and intravenous as well as inhaled prostacyclin analogs can be used with close monitoring of hemodynamic parameters [51]. The choice between vaginal and caesarean delivery is not straightforward, and the decision must be taken by the whole responsible team (obstetric, medical, and anesthetic). In general terms, regional anesthesia is preferred. In addition, intensive care monitoring of the mother in the postpartum period with full anticoagulation with heparin is indicated [51]. Pregnancy, heparin, and osteoporosis The complex relationship between pregnancy, osteoporosis, and heparin treatment has been recently reviewed [54]. Calcium demands rise during pregnancy. This may result in an increased turnover from bone, especially during the rst and second trimesters. However, the process usually reverses during the third trimester, resulting in only minor reductions of bone mineral density (BMD) after normal pregnancy. Lactation may result in a delayed recovery of BMD. Although the risk for symptomatic osteoporosis is not high during pregnancy, it may be increased in women with low preconceptual BMD or those treated with drugs that favor bone loss, such as corticosteroids. The eect of heparin on bone is not completely dened, although osteoporosis is included among its side eects. However, there may be a dierential eect related to age, and bone fractures are rare in pregnant women receiving heparin, reported in 2.2% of women treated with UFH [54]. This complication is even rarer with LMWH, below 0.5%. Because heparin is essential for many pregnant women with APS, its use should not be limited for fear of complications such as osteoporosis. Steroids, drugs that lower BMD to a greater extent than heparin, must be limited and never used to treat features of APS other than thrombocytopenia or hemolytic anemia. The concomitant administration of calcium, 1000 mg/d, plus vitamin D, 800 IU/d, the use of LMWH rather than UH, and adherence to strict guidelines regarding indications for heparin use are also measures that can lower the frequency of serious side eects. Finally, women deemed to be at

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increased risk because of preconceptual low BMD should receive advice regarding lactation, whose deleterious eects on bone mass can be more pronounced that those of heparin itself [54]. General care of pregnancy in women with antiphospholipid syndrome Ideally, preconceptual counseling should be performed to explain the risks of pregnancy within the specic context of each patient. In general, women with APS should know that, under correct management, the likelihood of a live birth is around 75% to 80%. However, they must also be informed that there is an increased risk of serious complications (eg, hypertension/preeclampsia, prematurity, or thrombosis) that can take place during pregnancy and the puerperium. A complete aPL prole, including at least repeated aCL and LA, must be available before planning pregnancy. Pregnancy should be postponed whenever a recent thrombotic event, particularly stroke, has taken place and in the setting of uncontrolled hypertension. Pregnancy should be discouraged in all women with pulmonary hypertension (Box 1). Once pregnant, registration into a high-risk obstetric clinic should be as early as possible. All women should be seen more frequently as pregnancy advances. Blood pressure and the presence of protein in the urine must be monitored closely at each visit, more closely during the second and third trimesters. Once a woman is known to have persistently positive aCL or LA, there is no need to repeat these tests, because a negative result does not eliminate the risk of complications. The usual obstetric care should include frequent ultrasound scans and other methods to check adequate fetal growth and well-being. In addition, uterine and umbilical artery Doppler blood ow analyses during the second trimester have proved extremely useful in predicting complications such as preeclampsia and placental insuciency in women with APS [48,55,56]. A recent study by Huong and colleagues [56] has found that women with SLE or APS and persistently abnormal second-trimester Doppler studies are very likely (13 of 18 women) to experience preeclampsia, fetal death, prematurity, and/or growth restriction. On the other hand, 64 of 72 women with normal Doppler studies had uncomplicated live births. The presence of absent or reversal diastolic ow in the umbilical artery and the nding

Box 1. Contraindications to pregnancy in women with antiphosphospholipid syndrome  Pulmonary hypertension  Uncontrolled arterial hypertension  Recent (<6 months) thrombotic event

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of persistent early-diastolic notches in the uterine arteries are warning signs that should alert for the occurrence of fetal growth restriction and preeclampsia. Therefore, Doppler studies of the uterine arteries should be performed in all pregnant women with APS at the 20th and 24th weeks of gestation, with serial examinations of umbilical arteries afterwards. If all the studies are normal, the patient can be reassured of the high probability of a successful pregnancy free of adverse events. All women with APS should be closely followed up with during the postpartum period, which is a period of high risk for recurrent thrombosis. Those with oral anticoagulant before pregnancy should be put back on warfarin as soon as possible after delivery. References
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