Antiphospholipid Antibody Syndrome. Rare Diseases of the Immune System

16. Treatment of Pregnancy Complications

Barbara Acaia , Federica Rossi1 and Cecilia Beatrice Chighizola2, 3

(1)

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

(2)

Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

(3)

Istituto Auxologico Italiano, Milan, Italy

Barbara Acaia

Email: barbara.acaia@gmail.com

Keywords

Antiphospholipid syndromePregnancy morbidityTreatment

16.1 Introduction

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) [1]. 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 % [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) [1]. 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 [35]. aPL titers and isotypes should also be considered, with IgG being clinically more meaningful compared to IgM [6]. 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 [78].

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 [9].

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 [10]. 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 [1112].

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 [13]. Thanks to such combo approach, more than 70 % of pregnant APS women deliver a viable infant [10]. 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 [1]. 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 [14]; Mak et al. 2010 [15]; Ziakas et al. 2010 [16]). 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 [17]. 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 [18].

Treatment with LDASA alone was first proposed in the management of obstetric APS in 1988 [19], since then conflicting results have been presented. Several observational studies reported pregnancy success rates as high as 79–100 % with LDASA alone [2025], 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 [26]. This finding was further supported by Tulppala who did not observe differences in obstetric outcomes between aCL-positive women receiving LDASA or placebo [27]. On the other hand, prophylactic treatment with LDASA during pregnancy reduced the rate of miscarriages from 72 to 38 % in a retrospective study [25] and preconceptional prescription of LDASA appeared to be significantly associated with favorable neonatal outcome in a multivariate analysis [20].

The earlier reports of heparin use date back to 1990 [28]; 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 [29]; this observation was later to be confirmed by many other studies [2130]. 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) [31]. 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 [32]. 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 [33].

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 [34]. 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 [3537].

16.4 Current Management of Obstetric APS

The American College of Chest Physicians recently published guidelines for the management of obstetric APS [38]:

·               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 [1416]. 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 [14]. 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 [15]. Ziakas evaluated five randomized controlled trials, reporting a treatment effect in favor of UFH but not LMWH [16]. 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 [39]. To note, the two studies directly comparing LMWH to UFH in the management of APS pregnancies did not observe any difference in outcome [4041].

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 [42]. 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 [43]. 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 [44].

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 [45].

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 [14].

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].

16.4.3 Treatment of Preeclampsia, Eclampsia, and HELLP Syndrome

aPL are among the most significant risk factors for preeclampsia [46]; 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 [47]. 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 [3132].

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 [45]. 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 [4854].

16.4.4 Treatment of Other Pregnancy Complications

More than 10 % of untreated APS women deliver small for gestational age infants [52], while preterm birth is reported to complicate 12–35 % of pregnancies in aPL-positive women [39]. 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 [14].

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 [55].

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 [56]. 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 [57]. 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 [58]. 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 [38]. Warfarin could be exceptionally prescribed in the second trimester until close to delivery, when heparin must be resumed [135960].

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 [61]. 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. [62], followed by few more anecdotal reports [6366] and case series [6772] 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 [14].

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 [73]. 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 [74], even though available evidence of the efficacy of this treatment in obstetric APS is merely restricted to case reports from a single center [7576].

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 [9]. It should be remembered that some of the immunosuppressive drugs used to control disease activity during pregnancy are contraindicated during lactation [59].

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 [7778], 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 [79]. 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 [80]. 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 [81].

Although there is no recommendation on how to treat women not fulfilling APS criteria, most physicians experienced in obstetric APS management prescribe LDASA [61], since aPL-positive women display an increased risk of preeclampsia and LDASA was reported to decrease such risk [47].

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 [38].

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 [38]. 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 [8283]. 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 [8485]. Both heparin and warfarin have been shown to be safe for breastfeeding mothers [59].

16.10 Conclusions

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.

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