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Successful treatment in two women with antiphospholipid antibodies and refractory pregnancy losses with intravenous immunoglobulin infusions
Successful treatment in two women with antiphospholipid antibodies and refractory pregnancy losses with intravenous immunoglobulin infusions RonaldJ. Wapner, MD: F. Susan Cowchock, MD,b and Sandor S. Shapiro, MDc Philadelphia, Pennsylvanza In two women with anti phospholipid antibodies and recurrent fetal losses refractory to usual treatments, therapy consisting of aspirin, heparin, and intravenous 'V-globulin infusions was successful. Production of anti phospholipid antibodies was not suppressed. The transient decrease in anticoagulant activity noted in one case was not reproduced in vitro and was probably not physiologically important. (AM J OBSTET GVNECOL 1989;161:1271-2.)
Key words: Antiphospholipid antibodies, intravenous immunoglobulin therapy, lupus anticoagulant, repeated abortion The use of intravenous immunoglobulin infusions, alone or with anticlotting drugs, for treatment of antiphospholipid antibody-associated pregnancy losses refractory to usual therapy has been described in single case reports. I. 2 We report normal pregnancy outcomes in two such women treated with low-dose aspirin, heparin, and monthly intravenous infusions of "'(-globulins. Case reports Case 1. A 29-year-old woman had a history of amaurosis fugax and two second-trimester pregnancy losses associated with eclampsia, fetal growth retardation, and placental infarction. A lupus anticoagulant was demonstrated by a prolonged dilute Russell's viper venom time, which did not correct with the addition of freshfrozen plasma. Only M-class immunoglobulin binding was demonstrated on enzyme-linked immunosorbent assay for antiphospholipid antibodies. Anticlotting treatment was planned in her next pregnancy, and she was treated with 80 mg aspirin daily. However, a blighted gestational sac was demonstrated at 7 weeks. She was treated in her fourth pregnancy with 80 mg aspirin daily and 20 mg prednisone twice daily, but this pregnancy also ended in fetal death at 21 weeks with signs of preeclampsia, placental infarction, and abrup-
From the DzvlSion of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology: the Divisions of Medical Genetzes and Endocrinology, Departments of MedIcine and Obstetncs and Gynecology/ and the Division of Hematology, Department of MediCine, and the Cardeza Foundation,' jefferson Medical College. ThIS work was supported in part by NatIOnal Institutes of Health grant 1 R01 HD21657-01A1. Recezved for pubbcatlOn Apnl 19, 1989; reVISed May 24, 1989; accepted june 1, 1989. Repnnt requests: F. Susan Cowchock MD, SUIte 400,1100 Walnut St., jefferson MedIcal College, Philadelphia, PA 10107.
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tio placentae. In her fifth pregnancy she was treated with 80 mg aspirin and heparin every 12 hours adjusted to obtain activated partial thromboplastin times in the normal range 6 hours after a dose (adjusted low-dose heparin). Intravenous "'(-globulin (Sandoglobulin) was added at a dose of 1 gm/kg in a single 6% infusion at monthly intervals from 9 weeks through 34 weeks of pregnancy. She was spontaneously delivered of a 3490 gm female infant at 40 weeks without complications. Case 2. A 35-year-old woman had a history of two electively terminated pregnancies and two secondtrimester losses complicated by hypertension, falsepositive rapid plasma reagin test results, and fetal growth retardation. Testing for anti phospholipid antibodies by enzyme-linked immunosorbent assay demonstrated binding of both G- and M-class immunoglobulins, and lupus anticoagulant was present by prolonged dilute Russell's viper venom time. She was treated in her next pregnancy with 80 mg aspirin daily and 20 mg prednisone twice daily. The prednisone was tapered to 15 mg twice daily in the second trimester because of euphoria and sleeplessness. An 1800 gm male infant was delivered at 32 weeks by cesarean section. The pregnancy was complicated by preeclampsia, oligohydramnios, and placental infarction. Since the outcome in this pregnancy was unsatisfactory, anticlotting treatment was planned. She was given 80 mg aspirin daily but miscarried the next two pregnancies at 5 and 7 weeks, even though adjusted low-dose heparin and supplemental progesterone were added early in ',the course of the second pregnancy. In her sixth pregnancy she was treated with the same doses of aspirin :and heparin plus intravenous "'(-globulin (Sandoglob:ulin) at a dose of 1 gm/kg given as a single 6% infusion monthly from 10 to 33 weeks of pregnancy. Labor was induced at 37 weeks because of nonreassuring results of fetal monitoring. She was delivered vaginally of a 2700 gm male infant. Total maternal serum levels of 1271
1272 Wapner, Cowchock, and Shapiro
,),-globulins were still elevated >4 weeks after infusion treatment, as was total ,),-globulin in a cord blood sample. Cord blood levels of M and A immunogloublins were normal. After discharge the infant was readmitted for observation because of an episode of bradycardia associated with a small subarachnoid hemorrhage. Results of neonatal coagulation studies were normal, and the infant recovered in a few days without further treatment. Further studies. Serial blood specimens were drawn from both patients before and after intravenous ,),-globulin infusion for lupus anticoagulant testing and measurement of anti phospholipid antibody levels. Heparin was withheld the day of infusion. We have previously demonstrated that neither heparin nor aspirin interferes with enzyme-linked immunosorbent as say measurements of anticardiolipin antibodies, but addition of the 6% solution of intravenous ,),-globulin in dilutions of up to I: 1000 did produce elevations of apparent nonspecific immunoglobulin G binding in this assay. When ,),-globulin was added to patient or control plasma in concentrations equivalent to those achieved after infusion, Russells' viper venom times were actually prolonged at high levels and unchanged by lower dilutions. Anticoagulant levels in case I increased through the second trimester, while levels of antiphospholipid antibodies by either enzyme-linked immunosorbent assay or Russell's viper venom time measurements were essentially unchanged throughout pregnancy in case 2. Very prolonged Russell's viper venom times fell immediately after infusion in case I, but this effect was not sustained. Placentas in both cases demonstrated deciduitis, severe villitis, and multifocal avascular villi. Two parabasal infarcts of 0.7 and 2.5 em were noted in case 1, and extensive infiltration of the decidua with plasma cells occurred in case 2. Despite the relatively severe inflammatory changes in decidua and villi, neither patient had a positive antinuclear antibody test result, antibodies to deoxyribonucleic acid
November 1989
Am J Obslel Gynecol
or Ro antigen, or clinical signs suggesting systemic lupus erythematosus.
Comment The mechanisms for the efficacy of intravenous ')'globulin infusions in the treatment of pregnant women with anti phospholipid antibodies are still speculative. Our studies did not suggest decreased antibody production. In vitro addition of the immunoglobulins to plasma from the woman in whom lupus anticoagulant decreased immediately after infusion did not reproduce this effect, confirming a previous report. The decrease in anticoagulant activity was probably not of physiologic importance, since the effect was transient and not observed in both patients. It seems most likely that the immunoglobulins block antibody binding to receptors of endothelial and other cells, similar to the reported block in monocyte Fe receptor binding, thus prohibiting local antibody effects. Determination of treatment intervals was empiric, since phospholipid antibody tests did not appear to be useful for monitoring therapy. For this reason our patients were also treated with low-dose heparin and aspirin. Intravenous ,),-globulin appears to be a useful adjunct to treatment of women with anti phospholipid antibodies, but infusion treatments are costly and we would recommend their use only after conventional therapies have failed . We thank the Jefferson Home Infusion Program members who assisted in patient care.
REFERENCES 1. Carreras LO, Perez GN, Vega HR, Casavilla F. Lupus anticoagulant and recurrent fetal loss: successful treatment with gammaglobulin. Lancet 1988;2:393. 2. Parke A, Maier D, Wilson D, Andreoli], Ballow M. Intravenous gamma-globulin, anti phospholipid antibodies, and pregnancy. Ann Intern Med 199; 110:495-6.
Key words: Antiphospholipid antibodies, intravenous immunoglobulin therapy, lupus anticoagulant, repeated abortion The use of intravenous immunoglobulin infusions, alone or with anticlotting drugs, for treatment of antiphospholipid antibody-associated pregnancy losses refractory to usual therapy has been described in single case reports. I. 2 We report normal pregnancy outcomes in two such women treated with low-dose aspirin, heparin, and monthly intravenous infusions of "'(-globulins. Case reports Case 1. A 29-year-old woman had a history of amaurosis fugax and two second-trimester pregnancy losses associated with eclampsia, fetal growth retardation, and placental infarction. A lupus anticoagulant was demonstrated by a prolonged dilute Russell's viper venom time, which did not correct with the addition of freshfrozen plasma. Only M-class immunoglobulin binding was demonstrated on enzyme-linked immunosorbent assay for antiphospholipid antibodies. Anticlotting treatment was planned in her next pregnancy, and she was treated with 80 mg aspirin daily. However, a blighted gestational sac was demonstrated at 7 weeks. She was treated in her fourth pregnancy with 80 mg aspirin daily and 20 mg prednisone twice daily, but this pregnancy also ended in fetal death at 21 weeks with signs of preeclampsia, placental infarction, and abrup-
From the DzvlSion of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology: the Divisions of Medical Genetzes and Endocrinology, Departments of MedIcine and Obstetncs and Gynecology/ and the Division of Hematology, Department of MediCine, and the Cardeza Foundation,' jefferson Medical College. ThIS work was supported in part by NatIOnal Institutes of Health grant 1 R01 HD21657-01A1. Recezved for pubbcatlOn Apnl 19, 1989; reVISed May 24, 1989; accepted june 1, 1989. Repnnt requests: F. Susan Cowchock MD, SUIte 400,1100 Walnut St., jefferson MedIcal College, Philadelphia, PA 10107.
6/1/14476
tio placentae. In her fifth pregnancy she was treated with 80 mg aspirin and heparin every 12 hours adjusted to obtain activated partial thromboplastin times in the normal range 6 hours after a dose (adjusted low-dose heparin). Intravenous "'(-globulin (Sandoglobulin) was added at a dose of 1 gm/kg in a single 6% infusion at monthly intervals from 9 weeks through 34 weeks of pregnancy. She was spontaneously delivered of a 3490 gm female infant at 40 weeks without complications. Case 2. A 35-year-old woman had a history of two electively terminated pregnancies and two secondtrimester losses complicated by hypertension, falsepositive rapid plasma reagin test results, and fetal growth retardation. Testing for anti phospholipid antibodies by enzyme-linked immunosorbent assay demonstrated binding of both G- and M-class immunoglobulins, and lupus anticoagulant was present by prolonged dilute Russell's viper venom time. She was treated in her next pregnancy with 80 mg aspirin daily and 20 mg prednisone twice daily. The prednisone was tapered to 15 mg twice daily in the second trimester because of euphoria and sleeplessness. An 1800 gm male infant was delivered at 32 weeks by cesarean section. The pregnancy was complicated by preeclampsia, oligohydramnios, and placental infarction. Since the outcome in this pregnancy was unsatisfactory, anticlotting treatment was planned. She was given 80 mg aspirin daily but miscarried the next two pregnancies at 5 and 7 weeks, even though adjusted low-dose heparin and supplemental progesterone were added early in ',the course of the second pregnancy. In her sixth pregnancy she was treated with the same doses of aspirin :and heparin plus intravenous "'(-globulin (Sandoglob:ulin) at a dose of 1 gm/kg given as a single 6% infusion monthly from 10 to 33 weeks of pregnancy. Labor was induced at 37 weeks because of nonreassuring results of fetal monitoring. She was delivered vaginally of a 2700 gm male infant. Total maternal serum levels of 1271
1272 Wapner, Cowchock, and Shapiro
,),-globulins were still elevated >4 weeks after infusion treatment, as was total ,),-globulin in a cord blood sample. Cord blood levels of M and A immunogloublins were normal. After discharge the infant was readmitted for observation because of an episode of bradycardia associated with a small subarachnoid hemorrhage. Results of neonatal coagulation studies were normal, and the infant recovered in a few days without further treatment. Further studies. Serial blood specimens were drawn from both patients before and after intravenous ,),-globulin infusion for lupus anticoagulant testing and measurement of anti phospholipid antibody levels. Heparin was withheld the day of infusion. We have previously demonstrated that neither heparin nor aspirin interferes with enzyme-linked immunosorbent as say measurements of anticardiolipin antibodies, but addition of the 6% solution of intravenous ,),-globulin in dilutions of up to I: 1000 did produce elevations of apparent nonspecific immunoglobulin G binding in this assay. When ,),-globulin was added to patient or control plasma in concentrations equivalent to those achieved after infusion, Russells' viper venom times were actually prolonged at high levels and unchanged by lower dilutions. Anticoagulant levels in case I increased through the second trimester, while levels of antiphospholipid antibodies by either enzyme-linked immunosorbent assay or Russell's viper venom time measurements were essentially unchanged throughout pregnancy in case 2. Very prolonged Russell's viper venom times fell immediately after infusion in case I, but this effect was not sustained. Placentas in both cases demonstrated deciduitis, severe villitis, and multifocal avascular villi. Two parabasal infarcts of 0.7 and 2.5 em were noted in case 1, and extensive infiltration of the decidua with plasma cells occurred in case 2. Despite the relatively severe inflammatory changes in decidua and villi, neither patient had a positive antinuclear antibody test result, antibodies to deoxyribonucleic acid
November 1989
Am J Obslel Gynecol
or Ro antigen, or clinical signs suggesting systemic lupus erythematosus.
Comment The mechanisms for the efficacy of intravenous ')'globulin infusions in the treatment of pregnant women with anti phospholipid antibodies are still speculative. Our studies did not suggest decreased antibody production. In vitro addition of the immunoglobulins to plasma from the woman in whom lupus anticoagulant decreased immediately after infusion did not reproduce this effect, confirming a previous report. The decrease in anticoagulant activity was probably not of physiologic importance, since the effect was transient and not observed in both patients. It seems most likely that the immunoglobulins block antibody binding to receptors of endothelial and other cells, similar to the reported block in monocyte Fe receptor binding, thus prohibiting local antibody effects. Determination of treatment intervals was empiric, since phospholipid antibody tests did not appear to be useful for monitoring therapy. For this reason our patients were also treated with low-dose heparin and aspirin. Intravenous ,),-globulin appears to be a useful adjunct to treatment of women with anti phospholipid antibodies, but infusion treatments are costly and we would recommend their use only after conventional therapies have failed . We thank the Jefferson Home Infusion Program members who assisted in patient care.
REFERENCES 1. Carreras LO, Perez GN, Vega HR, Casavilla F. Lupus anticoagulant and recurrent fetal loss: successful treatment with gammaglobulin. Lancet 1988;2:393. 2. Parke A, Maier D, Wilson D, Andreoli], Ballow M. Intravenous gamma-globulin, anti phospholipid antibodies, and pregnancy. Ann Intern Med 199; 110:495-6.