Management of Antiphospholipid Syndrome During Pregnancy

Since it was first described a quarter of a century ago, antiphospholipid syndrome (APS) has been associated with multiple medical and obstetric complications. Antiphospholipid syndrome is defined by characteristic clinical features and the presence of circulating antiphospholipid antibodies (aPL). Although several antiphospholipid antibodies have been described, the two most clinically useful are the lupus anticoagulant (LA) and anticardiolipin antibodies (aCL), which have been associated with recurrent pregnancy loss and thromboembolism. 1–4 Antiphospholipid syndrome pregnancies resulting in surviving infants are often complicated by fetal growth impairment, preeclampsia, placental insufficiency, and preterm birth. 5,6 Appropriate treatment of APS during pregnancy, however, may significantly improve both maternal and neonatal outcomes. This review outlines management plans for pregnancies complicated by APS. Pathogenesis of Antiphospholipid Syndrome Abnormal placental function is most likely the underlying cause of the obstetric complications of fetal death, growth impairment, preeclampsia, and abnormal heart rate tracings associated with APS. These observations, as well as the association of aPL with thrombosis, have led to the assumption that thrombosis in the uteroplacental circulation is the basis for pregnancy loss and other complications in women with APS. Extensive infarction, necrosis, and thrombosis have been identified in the placentas from failed pregnancies in women with APS. 7–11 A spiral arterial vasculopathy in decidual vessels also has been linked to aPL-related fetal loss. 7,11 This decidual vasculopathy is characterized by acute atherosis, intimal thickening, fibrinoid necrosis, and an absence of the normal physiologic changes in the spiral arteries and also has been associated with preeclampsia and fetal growth retardation. 12 A recent large case-control study confirmed these findings, reporting evidence of thrombosis or infarction in 82% of placentas from women with aPL and fetal death. 13 The placental thrombosis, decidual vasculopathy, and episodic vascular thrombosis associated with aPL may be a result of the ability of aPL to initiate a cascade of thrombogenic mediators after binding to damaged endothelium, platelets, or gestational tissues. 14 Antiphospholipid antibodies can induce endothelial cell production of E-selectin, vascular cell adhesion molecule-1, and intracellular adhesion molecule-1, leading to monocyte adhesion and thrombogenicity. 15 Increased synthesis of platelet-activating factor, tissue factor, thrombin generation, increased platelet activation and aggregation, as well as inhibition of protein-C activation and placental anticoagulant protein I (annexin V) function also have been linked to aPL. 16–23 Some authors have emphasized the heterogeneity of pathologic findings in patients with APS. 24 The histologic abnormalities seen in APS cases are nonspecific and are not always present in gestational tissues of women with aPL. 12,24 Therefore, it may be that factors other than placental thrombosis are relevant to some cases of pregnancy loss and other complications associated with aPL. Abnormal eicosanoid metabolism also may be involved because increased levels of thromboxane relative to prostacyclin in gestational tissues has been associated with preeclampsia and fetal growth retardation, conditions also linked to aPL. 25 Peaceman and Rehnberg 26,27 demonstrated that aPL can increase placental thromboxane production without affecting prostacyclin formation. The same group showed that aspirin reduced placental explant production of thromboxane in response to aPL, providing a rationale for the use of low-dose aspirin in APS pregnancies. 28 Thromboxane blockade also can reduce fetal loss in a murine model of APS. 29 Although promising, the role of ecosanoids in human fetal loss associated with aPL remains uncertain. Several investigators have failed to observe changes in arachidonic acid metabolism in response to aPL. 30,31 The poor obstetric outcome in untreated pregnancies has inspired the use of medical therapy to improve fetal outcome in women with APS. Treatments are intended to suppress the immune system (prednisone and intravenous immune globulin [IVIG]), prevent thrombosis (heparin and aspirin), and improve placental blood flow by decreasing the thromboxane to prostacyclin ratio (aspirin). Although many studies are nonrandomized and poorly controlled, most investigators conclude that fetal outcomes in APS pregnancies are dramatically improved with treatment. Management of Antiphospholipid Syndrome During Pregnancy The correct diagnosis of clinically significant APS is crucial to the appropriate counseling and treatment of pregnant patients. Unlike recurrent pregnancy loss, obstetric complications such as preeclampsia, growth restriction, and preterm delivery are not found in all populations of women with aPL, suggesting that a spectrum of APS may exist. For example, women with a history of systemic lupus erythematosus (SLE), thrombosis, fetal or neonatal death, or severe preeclampsia who also have medium-to-high levels of aPL are at significantly increased risk for complications during pregnancy, compared with those with low levels of antibodies or those identified with early recurrent pregnancy loss as their only clinical feature of the disease. Consequently, treatment of these patients also may differ. A classification system for APS, as proposed elsewhere in this symposium, may aid in determining appropriate treatment for a given patient and addressing treatment controversies in some subset of patients. The classification system includes: 1) definite, or classic, APS defined as patients with LA or medium-to-high levels of IgG or IgM aCL and fetal death, recurrent preembryonic or embryonic pregnancy loss, thrombosis, or neonatal death after delivery for severe preeclampsia or fetal distress; 2) syndrome of low levels of IgG or IgM aCL associated with fetal death or recurrent preembryonic or embryonic pregnancy loss; and 3) syndrome of aPL other than LA and aCL associated with fetal death or recurrent preembryonic or embryonic loss. 32 For the purpose of this review, we discuss the management of APS during pregnancy in the three specific populations described in this classification system. MANAGEMENT OF DEFINITE OR CLASSIC ANTIPHOPHOLIPID SYNDROME Preconception Counseling Appropriate treatment of classic APS begins with a frank discussion of the risks associated with this condition during pregnancy. Ideally, patients should undergo preconception counseling to discuss their medical and obstetric risks, including fetal loss, thrombosis or stroke, preeclampsia, fetal growth impairment, and preterm delivery. If the diagnosis is uncertain, the presence of LA and aCL should be confirmed. Although advocated by some, there is no proven benefit to serial testing during pregnancy or in titrating medicines to suppress antibody levels. A detailed medical and obstetric history must be obtained because women with related conditions such as SLE, renal disease, hypertension, autoimmune thrombocytopenia, and hemolytic anemia may need additional specialized care. In patients with SLE, issues related to exacerbation of lupus should be discussed. All patients with APS should be evaluated for anemia and thrombocytopenia because both of these conditions have been associated with APS. Underlying renal disease may be identified by evaluation with 24-hour urine collection for creatinine clearance and total protein, urinalysis, and serum creatinine. Treatment Regimens During Pregnancy Prevention of Pregnancy Loss. The first regimen used for the prevention of pregnancy loss was high-dose prednisone (40 mg/day or more) in combination with low-dose aspirin (LDA; approximately 80 mg/day). 8,9 Although one group using lower doses of prednisone found no benefit, 33 a majority of case series reported a 60–70% success rate in pregnancies managed with this regimen. 6,34–39 Heparin therapy was first reported as a successful treatment for aPL-associated pregnancy loss in 1984. 6,5 Since that time, several case series also have reported an approximately 70% rate of live births in women with APS treated with thromboprophylactic doses of unfractionated sodium heparin in combination with LDA. 6,39,40 A small, randomized trial indicated that heparin and LDA and prednisone and LDA are equally efficacious in the prevention of aPL-related fetal loss. 39 Women treated with prednisone had considerably more complications, however, including preeclampsia and preterm premature rupture of membranes. 39 The association of prednisone with these problems was confirmed in another randomized trial of prednisone in women with aPL. 41 Recently, Rai et al 42 published a landmark randomized trial of heparin treatment for APS. The selected population differed from that in other large cases series of women with APS in that: 1) the majority of patients had LA but not aCL; 2) women with a history of thrombosis or SLE were not included; and 3) most of the patients had recurrent early pregnancy loss rather than second or early-third trimester losses. Patients were randomized to LDA or heparin in thromboprophylactic doses (5,000 units twice daily) at the first detection of fetal cardiac activity and continued until 34 weeks gestation. The rate of live births was significantly higher in the heparin-treated patients (P = 0.01). In a separate trial, Kutteh 56 compared pregnancy outcomes in women with a history of three or more pregnancy losses and aPL levels ≥27 IgG or ≥23 IgM phospholipid units who were randomized to receive LDA with or without heparin therapy. Patients with a previous thrombosis, SLE, or who were positive for the LA were excluded from the study, and 40% of the patients included had only IgM aCL antibodies. Treatment consisting of 10,000 to 20,000 units of heparin administered twice daily began when fetal cardiac activity was first detected and was continued until term. The number of live births was significantly greater for patients treated with heparin compared with those who received LDA alone (80% heparin group vs 44% LDA group). 56 These studies prove that heparin and LDA are more effective than LDA alone in achieving successful pregnancy. Heparin and LDA treatment should be initiated after the identification of a viable pregnancy documented by ultrasound (usually 6 weeks gestation). If possible, heparin should not be used in combination with high-dose prednisone because of concern for an increased risk for osteopenic fractures. Also, fetal outcome is probably no better using both drugs than using either drug alone; therefore, we recommend the use of heparin alone or in combination with LDA. 6 Thromboprophylaxis. Women with definite APS are at increased risk for thrombosis during pregnancy. 6,43 Patients with APS with no previous history of thrombosis should be maintained on prophylactic doses (15,000–20,000 units/day in divided doses) throughout the pregnancy. We favor using higher doses (20,000 units/day) of heparin in the second and third trimester because lower doses may not provide adequate maternal thromboprohylaxis. 44 Authorities now recommend that women with APS and a history of thrombosis should be fully anticoagulated throughout pregnancy. 45 Patients with APS and acute thrombosis during pregnancy obviously require full anticoagulation through the pregnancy as well. Appropriate thromboprophylaxis during the postpartum period should be included in management, and patients may be switched to sodium warfarin even if breastfeeding. Despite its benefits, heparin use also has the potential for untoward effects including bleeding, thrombocytopenia, and osteoporosis with fracture. The risks of bleeding and osteopenic fracture increase with increasing doses of heparin. Calcium and vitamin D supplementation, as well as axial skeleton weight-bearing exercise, should be encouraged. Low-molecular-weight heparin has been safely used during pregnancy and appears promising in the treatment of APS. 46,47 Recent data suggest that low-molecular-weight heparin is associated with increased risk of bleeding complications during placement of regional anesthesia. Therefore, if low-molecular-weight heparin is prescribed during pregnancy, the management at term requires due consideration. Epidural or spinal anesthesia should be delayed until 24 hours after the last dose of low-molecular-weight heparin. Some physicians suggest switching to unfractionated heparin at 36 weeks gestation. Prevention of Complications of Placental Insufficiency. Despite improvements in fetal outcome, successful pregnancies after heparin therapy are still plagued by obstetric complications. In a cohort of 31 pregnancies treated with heparin at the University of Utah, two-thirds had preeclampsia, more than 40% had fetal growth impairment, and 25% delivered at less than 32 weeks gestation. 6 Another large case series of women with medium-to-high levels of aPL and past medical histories that included systemic lupus erythematosus, fetal demise, or thrombosis confirms that the obstetric complication rates in treated, prospectively monitored pregnancies remain high. 43 Thus, a search for improved therapies in women with definite APS is ongoing. The use of high-dose intravenous immune globulin during pregnancy in women with aPL has generated interest because of anecdotal reports of successful pregnancy outcomes using this treatment, usually in combination with prednisone, heparin, or LDA. 48–50 Most of these were more severe cases of aPL-related pregnancy loss (“refractory” cases) that had not benefited from other therapies. In the largest case series, patients treated with monthly intravenous immune globulin infusions, unfractionated heparin, and LDA had few pregnancy-related complications. 48 None of 16 pregnancies had fetal growth restriction, all were delivered after 34 weeks gestation, and preeclampsia was diagnosed in only 25%. Similarly, investigators noted no cases of preeclampsia and few preterm deliveries in a small case series of women with definite APS treated with a regimen that included intravenous immune globulin. 51 However, a prospective, randomized, controlled, pilot study of women with definite APS, all of whom received heparin and LDA, found no difference in obstetric or maternal outcomes between those who were treated with intravenous immune globulin versus placebo (5% albumin solution). 52 This study included 16 well-characterized patients with LA and medium-to-high levels of IgG aCL antibodies. All had successful pregnancies, and the rates of complications were fairly low, though one woman had a postpartum deep vein thrombosis. Thus, it appears that intravenous immune globulin is not of significant benefit beyond heparin treatment in women with APS. It remains possible (and untested), though, that women for whom previous heparin therapy during pregnancy has failed may derive sufficient benefit from the addition of intravenous immune globulin for a successful pregnancy. Patients should undergo intensive surveillance, eg, weekly clinic visits and biweekly nonstress tests, for the early identification of preeclampsia, fetal growth impairment, and uteroplacental insufficiency. Fetal ultrasound should be performed every 4 to 6 weeks, starting at 18 to 20 weeks gestation. Surveillance should consist of twice-weekly nonstress testing and amniotic fluid evaluation usually beginning at 32 weeks gestation. Patients also should be taught to monitor fetal movements. Fetal testing may be useful in selected cases as early as 24 to 25 weeks gestation. 53 Judicious use of antenatal betamethasone treatment is recommended; however, repeated doses of antenatal steroids should be avoided. Postpartum Treatment. After delivery, women with APS should be counseled about their substantial risk for the development of nonobstetric disorders associated with aPL. A recent study indicated that up to half of women with APS experienced a major medical complication during a 5-year follow-up interval, and many women having had pregnancy loss alone had new disorders develop, such as thrombosis or SLE. 54 We advocate that thromboprophylaxis be continued through the sixth week postpartum to minimize the risk of maternal thromboembolism. This can be safely accomplished with sodium warfarin. Patients with previous thromboses and APS should receive lifelong anticoagulation with sodium warfarin to achieve an international normalized ratio of 2.5 to 3.0. 55 Finally, estrogen containing oral contraceptives are contraindicated in women with aPL. TREATMENT OF PATIENTS WITH LOW LEVELS OF ANTIBODIES The treatment of women with low levels of aPL during pregnancy remains controversial. Women with LA or moderate-high positive levels of IgG aCL and a history of thrombosis are at much greater risk for aPL-related disorders than those with only IgM aCL or low-positive IgG aCL. 16 Thus, data about the treatment of women with APS cannot be extrapolated to those with low-titer aPL. Recent prospective trials included some women with low levels of aPL. One study demonstrated identical fetal survival rates after treatment with prednisone and LDA versus LDA alone. 41 The findings of a recent well-designed trial were similar. 57 Experienced investigators in New Zealand included 50 women with predominantly preembryonic or embryonic losses and with LA and aCL at any positive level in their trial. Women with previous thrombosis or SLE were excluded. The women were randomized to receive either LDA or a placebo; no heparin was administered. Live birth rates were more than 80% in both the aspirin and placebo-treated women! The rate of serious obstetric or medical complication was low. Though nearly 25% of the women included in this trial had LA, more than half of the women had only low levels of IgG or IgM aCL and thus did not qualify as having APS. Nonetheless, the authors appropriately emphasize that some women labeled as having antiphospholipid-related recurrent pregnancy loss do not require heparin treatment to have successful pregnancy. MANAGEMENT OF SYNDROME OF ANTIPHOSPHOLIPID ANTIBODIES OTHER THAN LUPUS ANTICOAGULANT OR ANTICARDIOLIPIN Lupus anticoagulant and aCL are well characterized and generally accepted as being clinically relevant. Several other aPL can be detected using a variety of immunoassays. Examples include antibodies binding phosphatidylserine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol, and phosphatidic acid. Antiphosphatidylserine antibodies may be present in patients with APS or clinical disorders associated with aPL. 58,59 Most of these individuals also have LA or aCL, however, casting doubt on an independent association between the clinical features of APS and aPL other than LA and aCL. 57 Because LA and aCL are the most strongly correlated with medical problems, they are the two aPL antibodies recommended for routine clinical use. There is no information available about the need for or efficacy of treatment in women found to be positive for antibodies other than LA or aCL. Therefore, we do not currently recommend treatment in this group. Conclusion Despite the significant risks associated with pregnancy in patients with definite APS, the initiation of appropriate treatment in a timely fashion results in improved outcomes. Experts agree that generous thromboprophylactic doses of heparin or anticoagulant doses of heparin are indicated for women with definite APS. Current data suggest that women with repeatedly positive low levels of aCL, recurrent preembryonic or embryonic pregnancy loss, and no history of thrombosis or SLE do not require heparin treatment.