A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy,☆☆,

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Abstract

Objective: Treatment with heparin and low-dose aspirin improves fetal survival among women with antiphospholipid syndrome. Despite treatment, however, these pregnancies are frequently complicated by preeclampsia, fetal growth restriction, and placental insufficiency, often with the result of preterm birth. Small case series suggest that intravenous immune globulin may reduce the rates of these obstetric complications, but the efficacy of this treatment remains unproven. This pilot study was undertaken to determine the feasibility of a multicenter trial of intravenous immune globulin and to assess the impact on obstetric and neonatal outcomes among women with antiphospholipid syndrome of the addition of intravenous immune globulin to a heparin and low-dose aspirin regimen. Study Design: This multicenter, randomized, double-blind pilot study compared treatment with heparin and low-dose aspirin plus intravenous immune globulin with heparin and low-dose aspirin plus placebo in a group of women who met strict criteria for antiphospholipid syndrome. All patients had lupus anticoagulant, medium to high levels of immunoglobulin G anticardiolipin antibodies, or both. Patients with a single live intrauterine fetus at ≤12 weeks’ gestation were randomly assigned to receive either intravenous immune globulin (1 g/kg body weight) or an identical-appearing placebo for 2 consecutive days each month until 36 weeks’ gestation in addition to a heparin and low-dose aspirin regimen. Maternal characteristics, obstetric complications, and neonatal outcomes were compared with the Student t test and the Fisher exact test as appropriate. Results: Sixteen women were enrolled during a 2-year period; 7 received intravenous immune globulin and 9 were given placebo. The groups were similar with respect to age, gravidity, number of previous pregnancy losses, and gestational age at the initiation of treatment. Obstetric outcomes were excellent in both groups, with all women being delivered of live-born infants after 32 weeks’ gestation. The rates of antepartum complications such as preeclampsia, fetal growth restriction, and placental insufficiency (as manifested by fetal growth restriction or fetal distress) were similar between the 2 groups. Gestational age at delivery (intravenous immune globulin group, 34.6 ± 1.1 weeks; placebo group, 36.7 ± 2.1 weeks) and birth weights (intravenous immune globulin group, 2249.7 ± 186.1 g; placebo group; 2604.4 ± 868.9 g) were similar between the 2 groups. There were fewer cases of fetal growth restriction (intravenous immune globulin group, 0%; placebo group, 33%) and neonatal intensive care unit admission (intravenous immune globulin group, 20%; placebo group, 44%) among the infants in the intravenous immune globulin group than those in the placebo group, but these differences were not significant. Conclusion: A multicenter treatment trial of intravenous immune globulin is feasible. In this pilot study intravenous immune globulin did not improve obstetric or neonatal outcomes beyond those achieved with a heparin and low-dose aspirin regimen. Although not statistically significant, the findings of fewer cases of fetal growth restriction and neonatal intensive care unit admissions among the intravenous immune globulin–treated pregnancies may warrant expansion of the study. (Am J Obstet Gynecol 2000;182:122-7.)

Section snippets

Methods

We performed a randomized, double-blind, placebo-controlled pilot trial. Women with antiphospholipid antibodies who were at high risk for pregnancy loss were recruited for inclusion in the study at 6 university medical centers through currently existing referral and consultation networks. Women with a single live conceptus who were at ≤12 weeks’ gestation could enroll in the study. Eligibility criteria included the following: (1) the presence of ≥20 immunoglobulin G phospholipid-binding (GPL)

Results

We identified 30 women as candidates for enrollment during the 2-year period from 1995 to 1997. Among these, 14 women were not eligible for enrollment for the following reasons: 3 were not pregnant, 5 declined to enroll, 1 was identified after 12 weeks’ gestation, and 5 did not have appropriate levels of antiphospholipid antibodies when tested in the central laboratory. The remaining 16 women were randomly assigned to receive either intravenous immune globulin (n = 7) or placebo (n = 9). All

Comment

Intravenous immune globulin therapy has been used for the successful treatment of several autoimmune conditions, including Kawasaki disease14 and systemic lupus erythematosus.15 Its mechanism of action is thought to include solubilizing immune complexes or anti-idiotypic down-regulation of autoantibody production. Indeed, Spinnato et al10 showed that immune globulin treatment during pregnancy resulted in a decline in anticardiolipin antibody levels in a group of women with antiphospholipid

Acknowledgements

We thank the Bayer Corporation, West Haven, Conn, for the donation of the Gamimune-N.

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Supported by the Bayer Corporation, West Haven, Connecticut.

☆☆

Reprint requests: D. Ware Branch, MD, Rm 2B200, Department of Obstetrics and Gynecology, University of Utah School of Medicine, 50 N Medical Dr, Salt Lake City, UT 84132.

0002-9378/2000 $12.00 + 06/1/103091

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