Treatment for APA

 

Monitoring and Treatment of Pregnant Women With the Antiphospholipid Antibody Syndrome

Charles J Lockwood, MD, Editor — Obstetrics, Stanley H Kaplan Professor and Chair, New York University School of Medicine; Peter H Schur, MD, Editor-in-Chief — Rheumatology, Professor of Medicine, Harvard Medical School.

[UpToDate © 2000]

Introduction

Antiphospholipid antibodies, such as lupus anticoagulants (LA) and anticardiolipin antibodies (aCL), are recognized causes of thromboembolic phenomenon, thrombocytopenia, and several adverse obstetrical outcomes. This disorder is referred to as the primary antiphospholipid antibody syndrome (APS) when these antibodies occur alone. It is called secondary antiphospholipid syndrome when they are found in association with systemic lupus erythematosus (SLE), other rheumatic diseases, and with certain infections and drugs.

The treatment and monitoring of pregnancies complicated by antiphospholipid antibodies are discussed in this review. The diagnosis and complications of antiphospholipid antibodies in the reproductive setting are discussed separately. Detailed discussions on antiphospholipid antibodies in the nonpregnant population are also reviewed elsewhere.

Diagnosis of Antiphospholipid Antibody Syndrome

A detailed discussion of the diagnosis of the antiphospholipid antibody syndrome is presented separately. To facilitate an understanding of the treatment of these women, the diagnostic criteria are repeated in this section.

Definite APS is considered present if at least one of the following clinical criteria and at least one of the following laboratory criteria are satisfied (table 1):

table1

Table 1.

Clinical — Either one or more episodes of venous, arterial, or small vessel thrombosis, and/or morbidity with pregnancy (table 1). Table 1 also provides a detailed discussion concerning the specific complications with pregnancy that satisfy these criteria.
Laboratory — The presence of either IgG and/or IgM anticardiolipin antibody (measured by a standardized enzyme-linked immunosorbent assay for ß2-glycoprotein 1-dependent anticardiolipin antibodies) (20 GPL or MPL units), and/or lupus anticoagulant activity; the antibodies and/or activity should be found on two or more occasions, at least six weeks apart.

Studies of Different Treatment Regimens

Women with the antiphospholipid antibody syndrome are at increased risk for fetal loss, especially during the late first trimester and second trimester. Several treatment regimens have been evaluated to improve pregnancy outcome in these women. The following clinical observations were obtained primarily in women with antiphospholipid antibodies and a prior history of two or more fetal losses.

Prednisone and Aspirin

Early studies suggested that the combination of corticosteroids and low dose aspirin reduced the risk of adverse pregnancy outcome.[1, 2] However, subsequent reports were unable to confirm this benefit.[3, 4, 5] In addition, steroid therapy was associated with side effects such as premature rupture of membranes, preterm delivery, fetal growth restriction, infection, preeclampsia, diabetes, osteopenia, and avascular necrosis.[3, 4, 5, 6]

Heparin and Aspirin

A number of studies have demonstrated successful pregnancy outcomes in women treated with heparin and low dose aspirin:[2, 7, 8, 9, 10]

In one trial, aspirin was given to all patients, beginning prior to conception.[9] As soon as a viable intrauterine pregnancy was confirmed, patients were then randomized to receive either prednisone (20 mg every 12 hours) or heparin (10,000 units subcutaneously every 12 hours) for the remainder of the pregnancy. The heparin dosage was adjusted until a midinterval aPTT was similar to baseline levels. Both treatments resulted in 75 percent live birth rates. However, the incidence of preterm delivery, usually from premature rupture of membranes or preeclampsia, was higher with the prednisone-aspirin combination.
Another report evaluated the efficacy of combination therapy with heparin and aspirin versus aspirin alone.[10] Aspirin was initiated in all patients once pregnancy was confirmed with a positive urine pregnancy test. Ninety patients were subsequently randomized to either low dose aspirin alone (75 mg every day) or low dose aspirin and subcutaneous heparin (5,000 units subcutaneously every 12 hours) once a fetal heart beat was established via ultrasonography. Combination therapy resulted in a significantly higher number of live births than therapy with aspirin alone (71 versus 42 percent).

Heparin appears to be effective in this setting because it potentiates the anti-thrombin effects of antithrombin III and other endogenous antithrombin effectors, increases levels of factor Xa inhibitor, inhibits platelet aggregation, and binds to antiphospholipid antibodies rendering them inactive.

Although low molecular weight heparin is currently generally used (see below), its efficacy in this clinical setting, compared with unfractionated heparin, has not been evaluated.

Aspirin

A few studies have shown that low dose aspirin alone is associated with successful pregnancy outcomes.[11, 12, 13] In addition to its antiplatelet effects, low dose aspirin enhances leukocyte-derived interleukin-3 production, which stimulate normal trophoblast growth and hormonal function.[14]

Recommendations for Treatment

We recommend different treatment regimens in pregnant women with antiphospholipid antibodies based upon the presence or absence of some combination of the following additional clinical features:

Group 1 — Women with antiphospholipid antibodies and a diagnosis of the antiphospholipid antibody syndrome, but without a history of an non-placental vascular thrombotic event (eg, deep venous thrombosis).
Group 2 — Women with antiphospholipid antibodies and a history of two or more unexplained spontaneous abortions before 10 weeks' gestation. Such women do not necessarily fulfill the criteria for the diagnosis of the antiphospholipid antibody syndrome. There is controversy regarding the utility of anticoagulant therapy in these patients.
Group 3 — Women with antiphospholipid antibodies, a diagnosis of the antiphospholipid antibody syndrome, and a history of a thrombotic event (non-placental thrombosis). These women are distinguished from group 1 women because they should already be chronically anticoagulated independent of pregnancy.

Groups 1 and 2

The management of these women is based upon combined therapy with aspirin and heparin:

A baby aspirin (81 mg per day) is begun as soon as conception is attempted.[15]

AND

Subcutaneous heparin (10,000 units every 12 hours) is added as soon as a viable intrauterine pregnancy is documented, generally at approximately seven weeks' gestation.

The heparin dose is then adjusted to achieve a midinterval aPTT level which is similar to baseline levels. Heparin should be continued until term and stopped once labor has begun. It is subsequently resumed postpartum (12 hours post-cesarean section and 6 hours post-vaginal birth) and either continued or switched to warfarin for six weeks. This recommendation is different than that for patients with a history of maternal thrombosis (see below for recommendations for group 3).

For patients undergoing amniocentesis or scheduled induction, heparin should be discontinued the night before the procedure and resumed six hours post-amniocentesis or post-vaginal birth.[15] Among those with scheduled cesarean delivery, heparin should also be discontinued the night before the procedure and resumed 12 hours post-procedure.[15]

Heparin-induced osteoporosis with fracture has been reported as a complication in up to two percent of pregnant women on long term heparin therapy.[16] Recovery of bone density occurs postpartum after the heparin is discontinued; it is unclear, however, if the recovery is complete. Supplemental calcium (eg, 1500 mg calcium carbonate), vitamin D, and weight bearing activity (eg, walking) are recommended to minimize the severity of bone loss.

Alternatively, we prefer to use low molecular weight heparin (LMWH) with an initial weight adjusted dose: enoxaparin 1 mg/kg sq once daily or dalteparin 50 U/kg sq once daily. The dose is then titrated to maintain a peak anti-factor Xa level of 0.2 to 0.3 U/mL four hours after injection in each trimester.

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. Caution must be exercised near term because of the risk of epidural hematomas associated with LMWH therapy in patients receiving regional anesthesia. Thus, LMWH therapy should be stopped at 36 weeks' gestation, or earlier if preterm delivery is anticipated, with the substitution of unfractionated heparin therapy.[17, 18]

Warfarin is teratogenic and is usually contraindicated in pregnancy in the United States.

Group 3

Women with APS and a history of thrombosis (even remote) should already be chronically anticoagulated, of whom most are being given warfarin. As mentioned, warfarin is a well-known teratogen. There is no consensus about the optimal management of such patients who are planning pregnancy. The potential risks and benefits of any strategy must be discussed in depth with the patient and her family. Therapeutic recommendations broadly include two options:

Replacing warfarin with heparin before conception and continuing heparin throughout gestation. This probably carries the least risk of direct toxicity to the fetus, but is associated with the highest risk for maternal complications (eg, osteoporosis).
Replacing warfarin with heparin as soon as pregnancy is established. This must be performed prior to the sixth week of gestation to avoid warfarin-induced embryopathy. This may be an option with women with regular periods who can be relied upon to obtain a blood pregnancy test as soon as a missed period occurs.

Some investigators (PHS) believe that warfarin should be replaced with heparin before conception whenever possible to avoid the potential teratogenic risk of the oral anticoagulant in early gestation. Awaiting a positive pregnancy test before discontinuing warfarin is a less reliable option, because of inadvertent exposure to teratogenic risk after the sixth week of gestation.

We recommend low dose aspirin and full anticoagulation because of the increased risk of maternal venous and arterial thrombotic complications during pregnancy.[19] Full anticoagulation is defined as a PTT that is 1.5 to 2.0 times the control value. Heparin or low molecular weight heparin can be administered. Details concerning exact dosing for heparin or LMWH are discussed separately.

Anticoagulation may be switched to warfarin postpartum.

Pregnant Women with Antiphospholipid Antibodies Alone

There is a paucity of data upon which to guide management of pregnant women with antiphospholipid antibodies alone who do not fulfill the diagnostic criteria for the APS and who have the following clinical features:

No prior pregnancies
No more than one unexplained spontaneous abortion before 10 weeks' gestation.
No history of thrombosis

During a first pregnancy, for example, such untreated women with antiphospholipid antibodies have a greater than 50 percent chance of a successful pregnancy.[3, 20] Therapeutic options for these women include no therapy, low dose aspirin alone, or low dose aspirin and prophylactic heparin (10,000 to 15,000 units daily).[17] Treatment decisions should be made on an individual basis. One of us (PHS) recommends either no therapy or low dose aspirin alone in these patients. Another view (CJL) is to treat only those patients with a documented lupus anticoagulant or anticardiolipin antibodies of 50 GPL or MPL units with low dose aspirin and prophylactic doses of heparin.

Presence of Antiphospholipid Antibodies Alone in a Women Undergoing in Vitro Fertilization

The presence of antiphospholipid antibodies alone does not adversely affect pregnancy rates in patients who are undergoing in vitro fertilization.[21] Thus, these women do not require antithrombotic therapy.

Treatment Failure

Some women have adverse pregnancy outcomes despite treatment with low dose aspirin and heparin. In these cases, consideration of other, less well studied, and potentially more morbid therapies is an option during the next attempted pregnancy.

Immune Globulin

If heparin and aspirin therapy fails, intravenous gamma globulin (IVIG) (0.4 g/kg per day for five days each month during the next attempted pregnancy) may be effective.[22, 23] One study, for example, evaluated IVIG in five patients with a history of 17 unsuccessful pregnancies; four were also treated with heparin and four received low-dose aspirin (81 mg/day).[23] Three women gave birth to healthy term infants, and a fourth delivered an infant diagnosed with fetal distress at 32 weeks.

However, results of a multicenter, randomized pilot study found that no benefit with the addition of IVIG to a low-dose aspirin-heparin regimen.[24] Among 16 women with well-documented APS, treatment with the immune globulin did not significantly improve the rates of preeclampsia, IUGR, fetal distress, and neonatal intensive care unit admission, or the gestational age at delivery and birth weight. There was a trend toward fewer cases of IUGR. It is unclear whether this lack of benefit extends to those who fail initial treatment with low-dose aspirin plus heparin.

Prednisone and Aspirin

If IVIG fails, prednisone (20 to 40 mg/day) and low-dose aspirin can be tried in the next pregnancy.[9, 10, 25] Prednisone is associated with an increased risk of gestational diabetes, premature rupture of membranes, and hypertension.[26] In addition, prednisone can potentiate the osteopenic effects of heparin. The drug results in an 8 percent reduction in bone density with doses as low as 10 mg/day for 20 weeks in nonpregnant patients.[26] For this reason, the combination of prednisone and heparin is generally not recommended. Calcium supplementation is mandatory in this setting.

The increased risk of premature rupture of membranes (PROM) with prednisone therapy likely reflects the inhibitory effects of glucocorticoids on fetal membrane extracellular matrix synthesis.[27] Alternatively, PROM may be the result of prednisone's stimulatory effects on fetal membrane, placental, and decidual corticotropin releasing hormone.[28]

Plasmapheresis

There are two reports in which plasmapheresis was used to remove antiphospholipid antibodies in an attempt to avoid spontaneous abortion in women with multiple previous miscarriages.[29, 30] One report performed repeated exchanges of approximately three to four treatments per week starting at the 14th week of pregnancy and continuing until successful delivery; the other performed a total of six exchanges beginning at the 24th week followed by successful cesarean section at week 29. Both documented a reduction in antibody titers following apheresis.

Others

Experimental studies in animals have also shown a dramatic reduction in fetal loss by the administration of interleukin-3, which may act by increasing plasminogen activator activity.[31] The applicability of this observation to humans is uncertain.

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 should include:[17]

Maternal echocardiography; 24 hour urine collection for creatinine clearance and protein; and assessment of serum AST/ALT at the beginning of the pregnancy to assess for and/or exclude underlying cardiac, renal, or liver disease, respectively.
Weekly assessment of the patient's platelet count during the first three weeks of heparin therapy and monthly thereafter, given the potential for heparin-induced thrombocytopenia.
Education regarding the signs and symptoms of thromboembolic disease.
Frequent assessment of maternal weight, blood pressure, and urine protein to rule out preeclampsia. Renal and liver function tests and platelet count should be monitored in patients with signs or symptoms suggesting preeclampsia or HELLP syndrome.
Early sonography to establish a definitive due date followed by serial sonograms (every four to six weeks starting at 18 to 20 weeks' gestation) to evaluate fetal growth.
Umbilical artery Doppler flow analyses in the setting of IUGR as an adjunct to fetal assessment.
Fetal heart rate and biophysical profile testing beginning at 32 to 34 weeks' gestation or earlier if fetal or maternal complications are diagnosed prior to 34 weeks.
Early delivery for deteriorating maternal or fetal condition.

More intensive maternal and fetal monitoring should be performed when preeclampsia or IUGR is detected, and in women with poor obstetrical histories or active medical problems.

Prognosis

The prognosis for pregnancy outcome in those with antiphospholipid antibodies 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.[6, 32, 33, 34, 35, 36, 37] However, even among patients with live births, there is an increased risk of complications relating to the pregnancy, including preeclampsia, prematurity, fetal distress and intrauterine growth retardation.[38]

Nevertheless, babies who are born, although at increased risk of prematurity, appear to be essentially healthy and grow normally. As an example, in one study of 55 infants born to women with antiphospholipid antibodies (many of whom were premature), no signs of malformations, thromboses, neurodevelopmental delay, or significant problems were observed after five years of life.[39]

References

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  2. Branch, WD, Silver, RM, Blackwell, JL, et al. Outcome of treated pregnancies in women with antiphospholipid syndrome: An update of the Utah experience. Obstet Gynecol 1992; 80:614.
  3. Lockshin, MD, Druzin, ML, Qamar, T. Prednisone does not prevent recurrent fetal death in women with antiphospholipid antibody. Am J Obstet Gynecol 1989; 160:439.
  4. Harris, EN, Pierangeli, SS. Antiphospholipid antibodies and the antiphospholipid syndrome. Springer Semin Immunopathol 1994; 16:223
  5. Laskin, CA, Bombardier, C, Hannah, ME, et al. Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. N Engl J Med 1997; 337:148.
  6. Cowchock, FS, Reece, EA, Balaban, D, et al. Repeated fetal losses associated with antiphospholipid antibodies: A collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am J Obstet Gynecol 1992; 166:1318.
  7. Lockshin, MD. Answers to the antiphospholipid-antibody syndrome? (editorial). N Engl J Med 1995; 332:1025.
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  9. Cowchock, FS, Reece, EA, Balaban, D, et al. Repeated fetal losses associated with antiphospholipid antibodies: A collaborative randomized trial comparing prednisone to low-dose heparin. Am J Obstet Gynecol 1992; 166:1318.
  10. Rai, R, Cohen, H, Dave, M, Regan, L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997; 314:253.
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  12. Julkunen, H, Jouhikainen, T, Kaaja, R. Fetal outcome in lupus pregnancy: The prognostic significance of an untreated and treated lupus anticoagulant. J Rheumatol 1994; 21:970.
  13. Derksen, RH, Bruinse, HW, deGroot, PG, Kater, L. Pregnancy in SLE: A prospective study. Lupus 1994; 3:149.
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  15. Kutteh, WH, Rote, NS, Silver, R. Antiphospholipid antibodies and reproduction: the antiphospholipid antibody syndrome [see comments]. Am J Reprod Immunol 1999; 41:133.
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  33. Branch, DW, Scott, JR, Kochenour, NK, et al. Obstetric complications associated with the lupus anticoagulant. N Engl J Med 1985; 313:1322.
  34. Branch, DW, Silver, RM, Blackwell, JL, et al. Outcome of treated pregnancies in women with antiphospholipid syndrome: An update of the Utah experience. Obstet Gynecol 1992; 80:614.
  35. Farguharson, RG, Pearson, JF, John, L. Lupus anticoagulant and intrauterine death in the absence of systemic lupus. Lancet 1984; 2:228.
  36. Joffe, AM, Hoskins, CF, Ghitter-Mannes, SC, Mant, MJ. Anticoagulant therapy for prevention of spontaneous abortion in a patient with lupus anticoagulant. Am J Hematol 1988; 29:56.
  37. Junger, P, Liote, F, Dautzenberg, F, et al. Lupus anticoagulant and thrombosis in systemic lupus erythematosus. Lancet 1984; 1:574.
  38. Lima, F, Khamashta, MA, Buchanan, NM, et al. A study of sixty pregnancies in patients with the antiphospholipid syndrome. Clin Exp Rheumatol 1996; 14:131.
  39. Ruffatti, A, Dalla Barba, B, Del Ross, T, et al. Outcome of fifty-five newborns of antiphospholipid antibody-positive mothers treated with calcium heparin during pregnancy. Clin Exp Rheumatol 1998; 16:605.

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