Hematology

Management of pregnant women with antiphospholipid antibodies or the antiphospholipid syndrome

Management of pregnant women with antiphospholipid antibodies or the antiphospholipid syndrome
Authors
Charles J Lockwood, MD
Peter H Schur, MD
Section Editor
Susan M Ramin, MD
Deputy Editor
Vanessa A Barss, MD
Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last updated: Thu Jul 21 00:00:00 GMT 2011 (More)

INTRODUCTION — The antiphospholipid syndrome (APS) is characterized by vascular thrombosis and/or pregnancy complications in association with laboratory evidence of antiphospholipid antibodies (aPL).

The management of pregnant women with APS or aPL is discussed in this topic review. Pregnancy complications and general issues related to APS and aPL are reviewed separately:

 

  • (See “Obstetrical manifestations of the antiphospholipid syndrome”.)
  • (See “Clinical manifestations of the antiphospholipid syndrome”.)
  • (See “Diagnosis of the antiphospholipid syndrome”.)
  • (See “Treatment of the antiphospholipid syndrome”.)
  • (See “Pathogenesis of the antiphospholipid syndrome”.)

 

OVERVIEW OF INITIAL TREATMENT OPTIONS — Several treatment regimens have been proposed to prevent maternal thrombotic complications and improve pregnancy outcome in women with APS [1]. Interpretation of studies in this area is difficult due to a lack of well-designed trials and to the clinical complexity of the syndrome.

Aspirin — In addition to its antiplatelet effects, low dose aspirin (ASA) (50 to 100 mg) enhances leukocyte-derived interleukin-3 production, which stimulates normal trophoblast growth and hormone expression [2]. For prevention of fetal loss in women with APS, administration of low dose ASA alone has been associated with an increased frequency of successful pregnancy outcome in some studies [3], but was no better than supportive care in others [1,4].

Low dose ASA can be stopped anytime after 36 weeks of gestation, and, ideally, should be stopped 7 to 10 days before delivery because some studies have reported a slight increase in mostly minor perioperative bleeding with continuation of the drug [5]. In women with a past history of serious arterial thrombotic complications, such as stroke or myocardial infarction, the potential benefit of continuing ASA through labor and delivery outweighs the small risk of incisional bleeding. Use of low dose ASA has not been associated with either premature closure of the ductus arteriosus or increase in significant postpartum hemorrhage.

Heparin/heparin with aspirin — Heparin has several effects that may help prevent thromboembolic events and pregnancy loss:

 

  • Antithrombotic effects include potentiating the anti-thrombin effects of antithrombin and other endogenous antithrombin effectors, increasing levels of factor Xa inhibitor, and inhibiting platelet aggregation. (See “Therapeutic use of heparin and low molecular weight heparin”, section on ‘Use of heparin’.)
  • Heparin may also bind to aPLs and render them inactive [6,7].
  • Experiments in mice suggested that complement activation might be an essential component of aPL mediated decidual and placental injury [8,9]. In a mouse model, low dose heparin prevented aPL associated fetal loss by inhibiting complement activation [10].
  • Heparin may also block tissue factor-mediated placental bed immunopathology [11,12].

 

Like unfractionated heparin, low molecular weight heparins (LMWH) inactivate factor Xa, but they have a lesser effect on thrombin. As a result, LMWHs do not prolong the aPTT. Potential advantages of LMWH over unfractionated heparin are once daily dosing and lower risks of hemorrhage, thrombocytopenia, and osteoporosis. (See “Therapeutic use of heparin and low molecular weight heparin”, section on ‘Use of LMW heparin’.)

Subcutaneous administration of either unfractionated heparin or low molecular weight heparin (LMWH) has been used to treat pregnant women with APS. A number of studies have demonstrated successful pregnancy outcomes in women treated with these heparins at various doses either alone or with low dose ASA [3,13-22].

Three meta-analyses of randomized trials in women with APS concluded the combination of heparin and ASA significantly reduced pregnancy loss (RR 0.46, 95% CI 0.29-0.71) [1] or first trimester pregnancy loss (OR 0.39, 95% CI 24-0.65) [23] and increased live births (RR 1.3, 95% CI 1.04-1.63) [24] compared to ASA alone. However, there are several limitations to these analyses, including the small number of trials, the small sample size in each trial, and the low quality of the trials themselves. For example, information about patient dropout and some adverse outcomes was not always available and patients/providers were not blinded to the treatment. Both therapies were associated with relatively high live birth rates ranging from 71 to 84 percent for combined therapy and 42 to 80 percent for ASA alone. If there is an improvement in outcome with combined therapy versus aspirin alone, the difference appears to be modest at best. Further investigation is needed to determine whether there is a true benefit from combined therapy.

Unfractionated versus LMW heparin — There is limited information from randomized trials on pregnancy outcome with use of LMWH versus unfractionated heparin. A small pilot trial reported 9 of 13 women given dalteparin had a successful pregnancy compared to 4 of 13 women given unfractionated heparin [25]. Observational studies in pregnant women have also shown a benefit of LMWH [26], but a meta-analysis of two randomized trials did not show a reduction in late fetal loss [23].

Despite the paucity of data from randomized trials of pregnant women with APS, data from other patient populations have shown that LMWH is as effective as unfractionated heparin with the advantages stated above. There is no reason to think that this would not also be true in pregnant women with APS.

Glucocorticoids — Glucocorticoids (and other cytotoxic drugs such as cyclophosphamide) are of no proven utility in nonpregnant individuals with the APS. Levels of aPL appear to be relatively resistant to immunosuppressive therapy and there is little evidence that these drugs alter the course of the hypercoagulable state.

Studies evaluating the efficacy of glucocorticoids for reducing the risk of adverse pregnancy outcomes have yielded conflicting results [1,13,14,27-30]. However, an increased risk of adverse obstetrical and maternal consequences of steroid therapy, including premature rupture of membranes, preterm delivery, fetal growth restriction, infection, preeclampsia, gestational diabetes, maternal osteopenia (especially when used with heparin), and avascular necrosis, have been demonstrated consistently [14,27-29,31], and have led to abandonment of this approach. (See “Use of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation”, section on ‘Glucocorticoids’.)

RECOMMENDATIONS FOR TREATMENT — The paucity of data from large, well designed trials of different management options in comparable groups of pregnant women with this complex disease contributes to the difficulty in formulating recommendations for managing these pregnancies. Our approach is guided by the discussion above, additional observational studies, personal experience, and the opinions of others experienced in the management of such women [32-36]. Our recommendations are presented in the context of particular combinations of laboratory and clinical features.

Local reference standards should be checked when interpreting titers.

Women with prior thrombosis — Women with laboratory criteria for aPL and a prior history of arterial or venous thrombosis are at high risk of recurrence and are generally on lifelong anticoagulation with warfarin. (See “Treatment of the antiphospholipid syndrome”.)

These women should receive thromboprophylaxis during pregnancy and postpartum (table 1) [37]. Management of thromboprophylaxis is discussed in detail separately. (See “Deep vein thrombosis and pulmonary embolism in pregnancy: Prevention” and “Deep vein thrombosis and pulmonary embolism in pregnancy: Treatment”.)

Women with late fetal loss — For women with laboratory criteria for aPL and one or more fetal losses after 10 weeks of gestation, we suggest combined therapy with low dose ASA (81 mg per day begun as soon as conception is attempted) and prophylactic LMWH; low dose ASA and prophylactic or intermediate dose unfractionated heparin is a reasonable alternative [1,32,37-40]. Heparin/LMWH is begun upon confirmation of intrauterine pregnancy. Heparin and LMWH dosing in pregnancy are described separately. (See “Deep vein thrombosis and pulmonary embolism in pregnancy: Prevention”.)

As discussed above, we prefer LMWH to unfractionated heparin, as LMWH has the advantages of once a day dosing and lower risks of hemorrhage, thrombocytopenia, and osteoporosis, although it is generally more expensive than unfractionated heparin.

Heparin-induced osteoporosis with fracture has been reported as a complication in up to 2 percent of pregnant women on long-term heparin therapy [41]. Recovery of bone density occurs postpartum after the heparin is discontinued; it is unclear, however, if the recovery is complete. Supplemental calcium (1000 mg elemental calcium per day), vitamin D (800 international units), and weight bearing activity (eg, walking, lifting weights) are recommended to minimize the severity of bone loss. (See “Drugs that affect bone metabolism”.)

Women with recurrent embryonic losses — Management of women with laboratory criteria for aPL and multiple embryonic losses (less than 10 weeks of gestation) is controversial, as there are many causes of early recurrent pregnancy loss. (See “Definition and etiology of recurrent pregnancy loss”.)

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There is a paucity of data addressing management of these women (see ‘Heparin/heparin with aspirin’ above). If the woman has had three or more such losses and a structurally normal uterus and documentation of euploid losses, then we offer her low dose ASA and prophylactic or intermediate-dose heparin therapy or low dose ASA and prophylactic LMWH heparin during pregnancy [37]. ASA is begun as soon as conception is attempted and heparin/LMWH is begun upon confirmation of intrauterine pregnancy. Heparin and LMWH dosing in pregnancy are described separately. (See “Deep vein thrombosis and pulmonary embolism in pregnancy: Prevention”.)

Women with early and severe preeclampsia or growth restriction — We suggest low dose ASA therapy beginning at the end of the first trimester and continuing in the second and third trimesters for women with laboratory criteria for aPL and a history of preterm delivery less than 34 weeks necessitated by early and severe preeclampsia or fetal growth restriction [37,40]. (See “Prevention of preeclampsia” and “Fetal growth restriction: Evaluation and management”.)

We may prescribe heparin or LMWH with low dose ASA in cases of ASA failure or when placental examination shows extensive decidual inflammation and vasculopathy and/or thrombosis, although this approach has not been validated by a randomized trial.

aCL or lupus anticoagulant without APS — There is a paucity of data upon which to guide management of pregnant women with the incidental finding of persistent presence of aCL or LA, without meeting any of the clinical criteria for APS. Over 50 percent of such women will have a successful pregnancy without medical treatment (ASA, heparin, LMWH) [27,42].

Therapeutic options for these women include no therapy, low dose ASA alone, or low dose ASA and prophylactic heparin [38,43]. Treatment decisions should be made on an individual basis. The majority of the Advisory Board of the 10th International Congress on aPL favored using low dose ASA alone in these patients [32]. The American College of Chest Physicians Evidence-Based Clinical Practice Guidelines concluded these women are probably at increased risk of developing pregnancy-related venous thrombosis and suggested they be managed antepartum with either close clinical surveillance, prophylactic unfractionated heparin, or prophylactic low molecular weight heparin, and that they receive postpartum anticoagulation (table 1) [37]. Anticoagulation, if used, should begin in the first trimester after confirmation of intrauterine pregnancy.

Woman undergoing in vitro fertilization — We do not treat these women with antithrombotic therapy. The presence of aPL alone does not appear to adversely affect pregnancy rates or outcome in patients who are undergoing in vitro fertilization (IVF) [44,45]. A meta-analysis by the American Society for Reproductive Medicine (ASRM) Practice Committee found that assessment of aPL was not indicated among couples undergoing IVF and treatment was not justified in this population based upon existing data [46,47]. This issue remains controversial because of the heterogeneity of these studies and the different aCL assay methodologies used [48,49]. As an example, the American Society for Reproductive Immunology Antiphospholipid Antibody Committee strongly disagreed with the ASRM recommendation and called for studies to confirm under what circumstances evaluation and treatment of women with aPL undergoing fertility therapy are important [48].

Postpartum — There are no high quality data to guide postpartum management of women with aPL but no history of prior thrombosis. Whether to begin or continue anticoagulation in all or selected groups of these women is controversial [50]. As discussed above, the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines concluded these women are probably at increased risk of developing pregnancy-related venous thrombosis and suggested that they receive postpartum anticoagulation (table 1) [37].

In women who received heparin or LMWH antepartum, we continue anticoagulation postpartum. Unfractionated heparin (5000 units every 12 hours) is administered beginning 12 hours post-cesarean delivery and four to six hours post-vaginal birth if there is no significant bleeding, and either continued or replaced with warfarin (stopping the heparin when the INR is therapeutic) for four to six weeks [37,40]. We also continue low dose ASA postpartum for four to six weeks. (See “Deep vein thrombosis and pulmonary embolism in pregnancy: Epidemiology, pathogenesis, and diagnosis” and “Deep vein thrombosis and pulmonary embolism in pregnancy: Prevention”.)

Women with aPL should avoid estrogen containing hormonal contraceptives, which appear to work synergistically with aPL to increase the risk of arterial thrombotic events (table 2). In RATIO (Risk of Arterial Thrombosis In relation to Oral contraceptives), a multicentre population-based case-control study, the odds of ischemic stroke in women who took oral contraceptives and had lupus anticoagulant was OR 201 (95% CI 22.1-1828) versus OR 2.9 (95% CI 1.8-4.6) in oral contraceptive users without lupus anticoagulant [51]. The risk of myocardial infarction was also increased significantly in oral contraceptive users with lupus anticoagulant. The reference group included matched women without lupus anticoagulant or oral contraceptive use. Interestingly, there was no significant increase in risk of stroke in women with anticardiolipin IgG alone. A limitation of this study was that only 30 of 175 stroke patients and only six of 203 patients with myocardial infarction had lupus anticoagulant and, of these women, oral contraceptives were used by only 18 and 4 women, respectively. There was also no information on how many patients had systemic lupus erythematosus. (See “Menstrual function; menopause; and hormonal contraceptives in women with systemic lupus erythematosus” and “Risks and side effects associated with estrogen-progestin contraceptives”.)

As discussed above, women with laboratory criteria for aPL and a prior history of arterial or venous thrombosis are at high risk of recurrence and are generally on lifelong anticoagulation with warfarin, which should be resumed postpartum. (See “Treatment of the antiphospholipid syndrome”.)

TREATMENT FAILURE

Pregnancy loss — Some women have adverse pregnancy outcomes despite use of the treatments described above. In these cases, consideration of other, less well studied, and potentially more morbid, therapies is an option during the next pregnancy.

Intravenous immune globulin — Intravenous gamma globulin (IVIG) (0.4 g/kg per day for five days each month during the next attempted pregnancy) is one alternative treatment that has been proposed; however, the efficacy of this approach has not been demonstrated [21,52-54]. Use of IVIG should probably be confined to research studies.

The following are summaries of some selected clinical trials of IVIG for prevention of pregnancy loss:

 

  • A multicenter, randomized pilot study including 16 women with well-documented APS reported that treatment with IVIG did not significantly improve the rates of preeclampsia, IUGR, nonreassuring fetal heart rate patterns, and neonatal intensive care unit admission, or the gestational age at delivery and birth weight [54]. However, it is unclear whether this lack of benefit extends to those who fail initial treatment with low dose ASA plus heparin.
  • Among women with prior spontaneous abortions, no difference in live-birth rates was found when 53 women with APS who received IVIG at one obstetrical center were compared to another group of 29 women contemporaneously treated with prednisone and low dose ASA at another center (live birth rate 78 and 76 percent) [55]. However, a smaller percentage of women in the IVIG treated group developed hypertension or maternal diabetes (5 versus 14 percent).
  • A study including 40 women compared the efficacy of the combination of low dose ASA and LMWH to use of IVIG for the prevention of recurrent fetal loss [21]. Each group received either LMWH (5700 units/day subcutaneously) and ASA (75 mg/day) or IVIG (400 mg/kg intravenously for two days, followed by 400 mg/kg monthly). The percentage of live births was greater in the LMWH and low dose ASA group than the IVIG group (84 percent and 57 percent, respectively). There were no serious adverse effects of either therapy and no thromboembolic events in either group.

 

Plasmapheresis — Plasmapheresis has been used to treat pregnant women with documented APS when first line therapy (aspirin and/or heparin) failed to prevent pregnancy loss. Data are limited to case reports and a small case series [56-59]. Randomized trials and larger series are needed to determine whether these therapies have a role in clinical practice.

One report performed repeated exchanges of approximately three to four treatments per week starting at the 14th week of pregnancy and continuing until cesarean delivery at 34 weeks; another performed a total of six exchanges beginning at the 24th week followed by cesarean delivery at week 29. Both documented a reduction in antibody titers following apheresis [56,57]. A third report described a woman with a history of thrombotic events, a previous pregnancy loss at the 11th week of gestation, lupus anticoagulant activity, and high titers of IgG anticardiolipin antibodies [58]. Weekly plasma exchanges were performed, but the patient delivered in the 26th week due to fetal growth restriction and oligohydramnios. The female infant weighed 730 g and survived.

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The largest series included 18 pregnant women who received both prednisone (10 mg/day) and plasmapheresis for three sessions per week until lupus anticoagulant activity was suppressed and the IgG anticardiolipin titer decreased [59]. The live birth rate was 100 percent; pregnancy complications included preterm delivery (22 percent), oligohydramnios and fetal distress (16 percent), intrauterine growth restriction (11 percent), mild preeclampsia (5 percent), and thrombocytopenia (5 percent). There were no perinatal deaths, thrombotic events, or lupus flares.

Hydroxychloroquine — The antimalarial drug hydroxychloroquine appears to reverse platelet activation induced by human IgG aPL and reverse thrombogenic properties of aPL in mice [60,61], and also appears to depress aPL levels in humans [62]. These effects might be beneficial in women with APS-related recurrent pregnancy loss, but no data are available. Case series have not described teratogenicity with use of hydroxychloroquine in pregnant women with SLE and miscarriage rates have been similar in treated and untreated women. (See “Antimalarial drugs in the treatment of rheumatic disease” and “Use of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation”, section on ‘Hydroxychloroquine’.)

Interleukin -3 — Studies in an animal model of APS have shown a dramatic reduction in fetal loss by the administration of interleukin-3, which may act by increasing plasminogen activator activity and by directly stimulating trophoblast growth and hormone production [2,63]. The applicability of this observation to humans is unknown.

Venous thromboembolism during pregnancy — If venous thrombosis occurs despite prophylactic measures, the diagnostic and therapeutic approach is essentially the same as that for newly diagnosed idiopathic venous thrombosis in any pregnant woman. (See “Deep vein thrombosis and pulmonary embolism in pregnancy: Epidemiology, pathogenesis, and diagnosis” and “Deep vein thrombosis and pulmonary embolism in pregnancy: Treatment”.)

However, if venous thromboembolism develops during pregnancy despite therapeutic anticoagulation, it may be necessary to use an inferior vena cava filter in conjunction with anticoagulation. (See “Deep vein thrombosis and pulmonary embolism in pregnancy: Epidemiology, pathogenesis, and diagnosis” and “Deep vein thrombosis and pulmonary embolism in pregnancy: Treatment”.)

PREGNANCY MONITORING — Women with APS should be counseled regarding the medical and obstetrical consequences of the disorder prior to pregnancy. During pregnancy, close maternal and fetal monitoring are indicated to allow timely intervention in the event of maternal or pregnancy complications. In addition to routine prenatal care, surveillance includes [43]:

 

  • Serum creatinine concentration, urine protein-to-creatinine ratio, and assessment of serum AST/ALT at the beginning of the pregnancy to determine baseline renal and hepatic function.
  • Education regarding the signs and symptoms of thromboembolic disease and preeclampsia. (See “Clinical features, diagnosis, and long-term prognosis of preeclampsia” and “Approach to the diagnosis and therapy of lower extremity deep vein thrombosis”.)
  • Early sonography to establish a definitive estimated date of delivery, followed by serial sonograms [40] every three to four weeks in the late second and the third trimesters to evaluate fetal growth and amniotic fluid volume. (See “Diagnosis of fetal growth restriction”.)
  • Umbilical artery Doppler flow analyses if fetal growth restriction is diagnosed. Monitoring the growth restricted fetus with this technique reduces perinatal mortality. (See “Fetal growth restriction: Evaluation and management” and “Doppler ultrasound of the umbilical artery for fetal surveillance”.)
  • Antepartum fetal assessment. (See “Antepartum fetal heart rate assessment” and “The fetal biophysical profile”.)

 

Labor and delivery — For women who are being treated with anticoagulation, we suggest scheduled delivery at 39 weeks to minimize anticoagulant exposure and to decrease the risk that an anticoagulant dose will be given proximate to active labor. Management of anticoagulation proximate to labor and delivery is described separately. (See “Deep vein thrombosis and pulmonary embolism in pregnancy: Treatment”, section on ‘Labor and delivery’.)

PROGNOSIS — The prognosis for pregnancy outcome in those with APS depends upon the patient’s prior medical and obstetrical history and whether they have been treated.

In women with a prior history of two or more fetal losses, there is a 70 to 80 percent live birth rate for patients treated with some combination of the above modalities [13,14,18,64-67]. However, even among patients with live births, there is an increased risk of complications relating to the pregnancy (preterm birth, preeclampsia, growth restriction) [68].

The long-term effects of maternal APS on offspring are not clear. In one study of 55 infants born to women with aPL, no malformations, thromboses, neurodevelopmental delay, or significant problems were observed during the first five years of life [69]. However, in another study, 4 of 15 children born to aPL positive women had abnormal scores on reading and writing tests [70]. Further investigation of the long-term outcome of offspring is needed.

SUMMARY AND RECOMMENDATIONS — Pregnant women with APS are at increased risk for maternal thrombosis and for late fetal loss, early and severe preeclampsia, growth restriction, and, possibly, recurrent early pregnancy loss. The management of these women is controversial.

 

  • For women with aPL and prior thrombosis but no pregnancy complications, we suggest antepartum and postpartum thromboprophylaxis (Grade 2C). Doses are listed in the table (table 1). We suggest addition of low dose ASA for women who also have a history of APS-defining pregnancy complications (Grade 2C). (See ‘Women with prior thrombosis’ above.)
  • For women with aPL and no prior thrombosis and no pregnancy complications, acceptable options include close clinical surveillance, antepartum prophylactic unfractionated heparin or low molecular weight heparin, or antepartum low dose ASA. (See ‘aCL or lupus anticoagulant without APS’ above.)
  • For women with aPL and one or more fetal losses at or after 10 weeks of gestation, we suggest combined therapy with low dose ASA and prophylactic LMWH during pregnancy (Grade 2C). Doses are listed in the table (table 1). (See ‘Women with late fetal loss’ above.)
  • For selected women with aPL and a history of multiple embryonic losses in whom other etiologies have been excluded, we suggest low dose ASA and prophylactic LMWH therapy during pregnancy (Grade 2C). Doses are listed in the table (table 1). (See ‘Women with recurrent embryonic losses’ above.)
  • For women with aPL and a history of early and severe preeclampsia or fetal growth restriction necessitating delivery before 34 weeks of gestation, we suggest low dose ASA therapy in the second and third trimesters (Grade 2C). We may prescribe heparin or LMWH with low dose ASA in cases of ASA failure or when placental examination shows prior extensive thrombosis. Doses are listed in the table (table 1). (See ‘Women with early and severe preeclampsia or growth restriction’ above.)
  • Anticoagulation with heparin or low molecular weight heparin should be initiated in the first trimester, after confirmation of intrauterine pregnancy. (See ‘Recommendations for treatment’ above.)

 

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