Pregnancy complicated by the antiphospholipid syndrome: outcomes with intravenous immunoglobulin therapy

Pregnancy Complicated by the Antiphospholipid Syndrome: Outcomes With Intravenous Immunoglobulin Therapy ANN L. CLARK, MD, D. WARE BRANCH, MD, ROBERT M. SILVER, MD, E. NIGEL HARRIS, MD, PhD, SILVIA PIERANGELI, PhD, AND JOSEPH A. SPINNATO, MD

Objective: To assess maternal and fetal outcomes in 15 patients with antiphospholipid syndrome (19 pregnancies) treated with intravenous immunoglobulin (IV Ig) during pregnancy. Methods: Monthly IV Ig therapy was initiated in the first or early second trimester of all pregnancies except two. Additional therapy consisted of low-dose aspirin and subcutaneous heparin. Six patients also received steroid therapy. Serial anticardiolipin IgG levels were measured in eight pregnancies. Results: The live-birth rate was 84% (16 of 19 live births), and there were three pregnancy losses. There were no cases of fetal growth restriction (FGR). Preeclampsia and nonreassuring fetal status were each diagnosed in 25% of the pregnancies. Seventy-five percent of the infants were delivered at 34 weeks’ gestation or later. Anticardiolipin IgG decreased throughout the course of therapy in seven pregnancies. Placental pathology was minimal. Conclusion: Pregnancy complications appear to be minimized with the use of IV Ig. Definitive recommendations regarding the use of IV Ig in pregnancy await the conclusion of randomized trials. If the combination of IV Ig, aspirin, and heparin significantly decreases the incidences of FGR and prematurity, it may be a cost-effective primary therapy for pregnancies complicated by the antiphospholipid syndrome. (Obstet Gynecol 1999;93:437– 41. © 1999 by The American College of Obstetricians and Gynecologists.)

The clinical and laboratory manifestations of the antiphospholipid syndrome have been well described.1 From the Department of Obstetrics and Gynecology, University of Louisville School of Medicine, Louisville, Kentucky; the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, Utah; and the Division of Rheumatology, Department of Medicine, Morehouse University School of Medicine, Atlanta, Georgia.

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The presence of anticardiolipin antibodies is clearly linked to recurrent pregnancy loss and fetal death. This relation has been established both clinically and through in vitro experiments in animal models.2,3 Treatment with steroids, low-dose aspirin, and heparin in various combinations improves live-birth rates2,4,5; however, both minor and serious adverse effects, such as gestational diabetes mellitus, preterm premature rupture of membranes, preeclampsia, osteoporosis, and thrombocytopenia, have been reported in association with these therapeutic interventions.2,4,6 These medications improve fetal survival, but women with antiphospholipid syndrome remain at high risk for serious pregnancy complications. Despite therapy with lowdose aspirin, heparin, or steroids, there remains a high incidence of fetal growth restriction (FGR) and preeclampsia (often severe). Preterm delivery is frequently required when these complications occur.2,7 Improved pregnancy outcomes with minimal complications have been reported after the use of intravenous immunoglobulin (IV Ig) for the treatment of antiphospholid syndrome.8 –11 Our group reported a series of five patients successfully treated with IV Ig.12 All five patients delivered healthy infants, and none of the patients experienced preeclampsia or recurrent thrombosis despite numerous episodes in previous pregnancies. There were no cases of FGR and only one case of fetal distress, which in retrospect may have been diagnosed incorrectly. Three of five patients had suppression of anticardiolipin IgG titers. The purpose of this descriptive study is to report our expanded experience with IV Ig in the treatment of 19 pregnancies complicated by antiphospholipid syndrome.

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Materials and Methods We reviewed the outcomes of 19 pregnancies (15 women with antiphospholipid syndrome) treated with IV Ig. All patients were cared for at the University of Louisville or the University of Utah. Five patients have been reported previously.12 Patients were considered eligible for treatment with IV Ig if they met criteria for the diagnosis of antiphospholipid syndrome as defined by Harris.13 Criteria for the diagnosis of antiphospholipid syndrome included at least one clinical manifestation of the disease (recurrent spontaneous abortion, thrombocytopenia, venous or arterial thrombosis) and at least one positive laboratory test (lupus anticoagulant and medium or high-positive anticardiolipin IgG).13 Anticardiolipin antibody titers were determined by enzyme-linked immunosorbent assay using serum standards from our antiphospholipid standardization laboratory. Anticardiolipin IgG results were reported as high positive (greater than 80 IgG binding units per milliliter), medium positive (20 – 80 IgG binding units per milliliter), and low positive (8 –19 IgG binding units per milliliter).14 Lupus anticoagulant activity was determined using the kaolin clotting time, activated partial thromboplastin time, and the Russell viper venom time.15 Intravenous Ig therapy was initiated in the first or early second trimester in all patients except two. The dose of IV Ig was 400 mg/kg/day for 5 days or 1 g/kg/day for 2 days each month. Two patients received slightly different treatments: One received her first dose of IV Ig at 21 weeks, and the other patient received only two 2-day courses during her pregnancy. Additional therapy included low-dose aspirin at 81 mg/day in 18 pregnancies and subcutaneous heparin at 5000 to 10,000 U twice daily in 15 pregnancies. Six patients were treated with prednisone. The indications for steroid therapy in three of these patients were Addison disease, herpes gestations, and exacerbations of systemic lupus. Gestational age at delivery was determined by menstrual dates, confirmed by either a first- or early secondtrimester ultrasound examination. Other outcomes reported include pregnancy complications of preeclampsia, FGR, recurrent thromboembolic events, and fetal distress. The diagnosis of preeclampsia was based on the ACOG classification,16 which requires the presence of blood pressure elevations and proteinuria. Blood pressure readings of greater than 140/90 mmHg or systolic and diastolic pressure increases of 30 and 15 mmHg, respectively, were required to satisfy the criteria. Proteinuria was defined as greater than 300 mg/dL in a 24-hour specimen or greater than 30 mg/dL in a random urine specimen (11 on dipstick). Fetal growth restriction was defined as a birth weight below the tenth

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percentile for estimated gestational age.17 Thromboembolic events were diagnosed by physical findings and were confirmed with either duplex ultrasound examination, venogram, or pulmonary arteriogram. Fetal distress was defined as a nonreassuring fetal heart rate (FHR) tracing prohibiting a trial of labor or further attempts at vaginal delivery. Fetal distress was diagnosed by the physician managing the patient. Neonatal outcomes included birth weight and Apgar scores. Placental pathology reports were available for 12 pregnancies.

Results The average age of the patients treated with IV Ig was 30.4 years (range 24 –39) and the average gravidity was 4.2 pregnancies (range one to 12). A review of the reproductive histories of these 15 patients revealed 66 previous pregnancies. One patient had no history of pregnancy losses and two had a history of only recurrent first-trimester losses. Ten patients had at least one previous second-trimester fetal death, and two had a history of third-trimester fetal death in addition to other pregnancy losses. Of the 63 fetal losses, 42 were firsttrimester spontaneous abortions and 19 and two were second- and third-trimester fetal deaths, respectively. Only three of the 66 previous pregnancies resulted in live births. These three infants required delivery at 27–28 weeks because of severe preeclampsia, and one suffered a neonatal death. Only ten of the 66 previous pregnancies progressed beyond 20 weeks, and six of these ten pregnancies were complicated by severe preeclampsia. Three patients had a history of systemic lupus erythematosus. Six patients had received some form of therapy for antiphospholipid syndrome (such as heparin, steroids, low-dose aspirin, or immunizations with paternal white blood cells) during seven previous pregnancies. Nine patients had a history of thrombosis, with a total of 23 thromboembolic events. These events included 13 deep vein thromboses and six cases of pulmonary emboli. The four arterial phenomena included an adrenal artery thrombosis resulting in Addison disease, one stroke, and two cases of amaurosis fugax. Table 1 summarizes the maternal and neonatal outcomes. Our 15 patients had a total of 19 pregnancies treated with IV Ig. Twelve patients had one pregnancy, two patients (E and O) had two pregnancies, and one patient (I) had three pregnancies. Sixteen of the 19 pregnancies resulted in a live birth. There were no cases of growth restriction in the live-born infants. Three of the 19 pregnancies resulted in fetal wastage (patients I-1, K, and L). Patient 1 was diagnosed with antiphospholipid syndrome in her first pregnancy at 21 weeks’

Obstetrics & Gynecology

Table 1. Pregnancy Outcomes After Treatment With Intravenous Immunoglobulin Apgar score

Patient

Outcome

Delivery EGA (wk)

No. of courses

Birth weight

1 min

5 min

A* B C* D†

LB LB LB LB

33.2 39.0 35.9 38.0

6 7 7 6

1786 2750 2778 3203

6 8 7 8

8 9 9 9

GDM, fetal distress None PPROM None

E-1 E-2 F*

LB LB LB

39.4 39.8 31.0

9 8 6

3459 3700 1871

8 9 6

9 9 8

G H

LB LB

40.0 35.4

9 8

3420 2100

7 5

9 8

I-1

FD

25.0

1

0

0

0

I-2

LB

39.0

7

2948

8

9

None None Lupus flare, severe preeclampsia, pulmonary embolus GDM, fetal distress Severe preeclampsia, fetal distress Severe FGR diagnosed at 21 wk EGA None

I-3 J K*† L*† M N*† O-1 O-2

LB LB FD FD LB LB LB LB

39.4 34.0 12.0 11.0 37.0 30.0 32.0 36.0

7 5‡ 1‡ 1 7 2 5 8‡

2977 2310 0 0 2690 1140 2098 2807

8 6 0 0 7 NA 6 8

9 8 0 0 8 NA 7 9

None Preterm labor FD FD None Severe preeclampsia Abruption, fetal distress Mild preeclampsia

Complications

Placental pathology Normal Intervillous fibrin Small focal infarction Fibrin plaques occupying ,5% of placental surface 5–10% infarction Normal Normal

Intervillous thrombus Focal fillous infarction Small placenta focal deciduitis Large placenta villous ischemic changes Normal NA NA NA NA NA NA NA

EGA 5 estimated gestational age; LB 5 live birth; GDM 5 gestational diabetes mellitus; PPROM 5 preterm premature rupture of membranes; FD 5 fetal death; FGR 5 fetal growth restriction. * Patients treated with prednisone. † Patients not treated with heparin. ‡ All patients received 400 mg/kg/d 3 5 d of intravenous immunoglobulin except for these; they received 1000 mg/kg/d 3 2 d.

gestation after the fetus was noted to have severe FGR and oligohydramnios. She received one 5-day course of IV Ig followed by 1 month of daily low-dose aspirin and heparin before the diagnosis of a fetal death at 25 weeks’ gestation. Subsequently, this patient received serial IV Ig infusions during pregnancies 2 and 3, experienced no pregnancy complications, and delivered two healthy term infants. Before the index pregnancies, patients K and L had histories of 12 and 11 previous early fetal losses, respectively. In the index pregnancies, IV Ig therapy was initiated at 6 and 11 weeks of gestation, respectively, in addition to low-dose aspirin and steroids. Neither patient received heparin therapy and both experienced recurrent fetal deaths at 12 and 11 weeks, respectively. Eight of the 16 live births occurred before 37 weeks’ gestation. Four of these infants were delivered between 30 and 33 weeks’ gestation. Severe preeclampsia (patients F and N) and fetal distress (patients A and O-1) were the indications for these four preterm deliveries. The remaining four preterm infants were delivered between 34 and 36 weeks’ gestation. Premature rupture of membranes (patient C), preeclampsia (patients H and

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O-2), and preterm labor (patient J) were the indications for these deliveries. Preeclampsia was diagnosed in four pregnancies (patients F, H, N, and O-2). Three pregnancies met the criteria for severe preeclampsia, and all resulted in preterm delivery. One of these patients received only two courses of IV Ig during her pregnancy, and two of the patients were receiving steroids during gestation. Mild preeclampsia was diagnosed in one patient at 36 weeks’ gestation. Four FHR tracings (patients A, G, H, and O-2) were interpreted as nonreassuring (nonreactive nonstress test or repeated late decelerations) and resulted in cesarean delivery. One patient (F) experienced an antepartum pulmonary embolus while receiving prophylactic heparin during a lupus flare, and soon thereafter required delivery for severe preeclampsia. Two cases of deep vein thrombosis were diagnosed at 4 and 5 weeks postpartum. Of these two patients, one (O-2) had a history of amaurosis fugax and was taking coumadin postpartum, and the other (G) had no history of thromboembolic disease and was being maintained on lowdose aspirin postpartum. Of the three patients with a

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history of systemic lupus, only one (F) experienced an exacerbation during the index pregnancy. There were two cases of gestational diabetes mellitus and no cases of clinically evident osteoporosis. Placental pathology is also described in Table 1. In six pregnancies, serial antiphospholipid antibody levels were not obtained (three were early fetal losses). Five pregnancies were characterized by both positive lupus anticoagulant activity and low to moderate levels of anticardiolipin IgG antibody. Serial assessments of anticardiolipin IgG in these pregnancies revealed no specific trends, and lupus anticoagulant activity was not measured routinely during gestation. Eight pregnancies were followed with serial anticardiolipin IgG titers. In all but one case, the initial anticardiolipin IgG titer was greater than 80 IgG binding units per milliliter. The anticardiolipin IgG levels decreased in seven pregnancies, all of which resulted in live births. One pregnancy (I-1) ended in fetal death. This patient had an initial level of 450 IgG binding units per milliliter at 21 weeks’ gestation, and 2 weeks before the diagnosis of fetal death, the level had increased to 1747 IgG binding units per milliliter after a single course of IV Ig.

Discussion The live-birth rate in this series of pregnancies treated with IV Ig was 84%. There were no cases of FGR. Seventy-five percent of the infants were delivered at or beyond 34 weeks’ gestation, and preeclampsia and fetal distress were diagnosed in 25% of the cases. Only one pregnancy (5%) was complicated by an antepartum thromboembolic event. The use of traditional therapy (low-dose aspirin, heparin, and steroids) results in live-birth rates of approximately 70%2,7; however, the incidence of pregnancy complications and maternal and neonatal morbidity remain high. In a series of 82 treated patients,2 almost 30% of the fetuses were diagnosed with FGR. Delivery before 32 weeks’ gestation occurred in approximately 40% of the pregnancies. Preeclampsia complicated 50% of the pregnancies and in 30% of these, the preeclampsia was classified as severe. Fifty percent of the pregnancies were complicated by fetal distress. Lima et al7 reported similar rates of obstetric complications in a series of 60 patients treated with low-dose aspirin and heparin. The rate of FGR was 31%. Premature delivery occurred in 43% of the patients, and hypertensive disorders were reported in 18%. Fetal distress was diagnosed in 50% of the pregnancies. In our series of 19 pregnancies treated with IV Ig, FGR, preterm delivery (birth before 34 weeks), preeclampsia, and FHR abnormalities occurred less frequently than in these two larger series.2,7 Valensise et

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al18 studied the outcomes of 14 pregnancies with antiphospholipid syndrome treated with IV Ig and similarly reported no cases of FGR or preterm delivery. In addition, there was only one case of gestational hypertension and placental abruption. Intravenous Ig therapy may offer an additional advantage over conventional therapy in that pregnancy complications such as FGR, preterm delivery, preeclampsia, and fetal distress may be minimized. Intravenous Ig is produced using pooled human sera and consists of at least 90% intact IgG.19 Improved pregnancy outcomes with the use of IV Ig preparations may result from increases in antiphospholipid antibody clearance mediated by anti-idiotype antibody. The addition of IV Ig (in vitro) to patient plasma inhibits the binding of anticardiolipin antibodies (idiotype) to cardiolipin-coated microtiter plates. Some investigators have demonstrated the formation of low-affinity idiotype–anti-idiotype complexes, with a resultant increase in the clearance of anticardiolipin antibodies.20 Although the mechanism of action of IV Ig is uncertain, the decrease in anticardiolipin IgG titers seen in our patients is consistent with the theory of increased antibody clearance. Additional mechanisms of action of IV Ig include anti-idiotype antibody–mediated decreases in anticardiolipin antibody production by interactions with B-cell antigen receptors, with subsequent receptor down-regulation.21 Finally, IV Ig may result in a decreased affinity of antiphospholipid antibodies for activated platelets through Fc receptor–mediated blockade.22,23 The relatively uncomplicated pregnancies reported in this series and that of Valensise et al18 support the use of IV Ig for the treatment of pregnancies complicated by antiphospholipid syndrome. In vitro and in vivo studies also support the clinical utility of this therapy.24 Intravenous Ig is an expensive therapy for antiphospholipid syndrome pregnancies compared with lowdose aspirin and subcutaneous heparin. However, the cost of IV Ig may be offset by a reduction in both maternal and neonatal morbidity. We acknowledge the drawbacks associated with a descriptive report of this nature, such as the use of historic controls, lack of uniform treatment, use of concurrent agents, and multiple pregnancies in some subjects. Although the outcomes of IV Ig-treated pregnancies appear to be improved compared with pregnancies treated with conventional therapy, definitive conclusions cannot be made until randomized trials are performed. A multicenter, randomized, blinded, placebo-controlled trial is under way to evaluate clinical outcomes in pregnancies with antiphospholipid syndrome treated with low-dose aspirin, heparin, and IV Ig compared with low-dose aspirin, heparin, and IV placebo (Branch W, Druzin M,

Obstetrics & Gynecology

Spinnato J, Harger J, Meis P, Peaceman A, et al. Randomized, placebo-controlled trial of intravenous immune globulin (IVIG) in antiphospholipid syndrome (APS) in pregnancy: A progress report [abstract]. Lupus 1996;5:553). Until the results of this trial are available, the use of IV Ig in pregnancies with antiphospholipid syndrome should be individualized. If the combination of IV Ig, low-dose aspirin, and heparin can be shown to significantly decrease the rates of FGR, preeclampsia, and subsequent prematurity, as we suspect, it may be a cost-effective primary therapy for pregnancies complicated by antiphospholipid syndrome.

References 1. Harris EN. Syndrome of the black swan. Br J Rheumatol 1987;26: 324 – 6. 2. Branch DW, Silver RM, Blackwell JL, Reading JC, Scott JR. Outcome of treated pregnancies in women with antiphospholipid syndrome: An update of the Utah experience. Obstet Gynecol 1992;4:614 –20. 3. Branch DW, Dudley DJ, Mitchell MD, Creighton KA, Abbott TM, Hammond EH, et al. Immunoglobulin G fractions from patients with antiphospholipid antibodies cause fetal death in Balb/c mice: A model for autoimmune fetal loss. Am J Obstet Gynecol 1990;163: 210 – 6. 4. Cowchock FS, Reece EA, Balaban D, Branch DW, Plouffe L. Repeated fetal losses associated with antiphospholipid antibodies: A collaborative randomized trial comparing prednisone to lowdose heparin treatment. Am J Obstet Gynecol 1992;166:1318 –23. 5. Rosove MH, Tabsh K, Wasserstrum N, Howard P, Hahn BH, Kalumian KC. Heparin therapy for pregnant women with lupus anticoagulant or anticardiolipin antibodies. Obstet Gynecol 1990; 75:630 – 4. 6. Dahlman T. Osteoporotic fractures and the recurrence of thromboembolism during pregnancy and the puerperium in 184 women undergoing thromboprophylaxis with heparin. Am J Obstet Gynecol 1993;168:1265–70. 7. Lima F, Khamashta MA, Buchanan NMM, Kerslake S, Hunt BJ, Hughes GRV. A study of sixty pregnancies in patients with the antiphospholipid syndrome. Clin Exp Rheumatol 1996;14:131– 6. 8. Francois A, Freund M, Daffos F, Remy P, Aiach M, Jacquot C. Repeated fetal losses and the lupus anticoagulant. Ann Intern Med 1988;109:993– 4. 9. Scott JR, Branch DW, Kochenour NK, Ward K. Intravenous immunoglobulin treatment of pregnant patients with recurrent pregnancy loss caused by antiphospholipid antibodies and Rh immunization. Am J Obstet Gynecol 1988;159:1055– 6. 10. Parks A, Maier D, Wilson D, Andresli J, Ballow M. Intravenous gamma globulin, antiphospholipid antibodies and pregnancy. Ann Intern Med 1989;110:495– 6. 11. Wapner RJ, Cowchock FS, Shapiro SS. Successful treatment in two women with antiphospholipid antibodies and refractory pregnancy losses with intravenous immunoglobulin infusions. Am J Obstet Gynecol 1989;161:1271–2.

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12. Spinnato JA, Clark AL, Pierangeli SS, Harris EN. Intravenous immunoglobulin therapy for the antiphospholipid syndrome in pregnancy. Am J Obstet Gynecol 1995;172:690 – 4. 13. Harris EN. Annotation: Antiphospholipid antibodies. Br J Haematol 1990;74:1–9. 14. Harris EN. The Second International Anti-cardiolipin Standardization Workshop/the Kingston Antiphospholipid Antibody Study (KAPS) group. Am J Clin Pathol 1990;94:476 – 84. 15. Triplett DA, Brandt JT, Kaczor D, Schaeffer J. Laboratory diagnosis of lupus inhibitors: A comparison of the tissue thromboplastin inhibition procedure with a new platelet neutralization procedure. Am J Clin Pathol 1983;79:678 – 82. 16. American College of Obstetricians and Gynecologists. Management of preeclampsia. ACOG technical bulletin no. 91. Washington DC: American College of Obstetricians and Gynecologists, 1986. 17. Usher R, McLean F. Intrauterine growth of live born caucasian infants at sea level. J Pediatr 1969;74:901–10. 18. Valensise H, Vaquero E, De Carolis C, Stipa E, Perrigone R, Arduinis D, et al. Normal fetal growth in women with antiphospholipid syndrome treated with high-dose intravenous immunoglobulin (IVIG). Prenat Diagn 1995;15:509 –17. 19. ASHP Commission on Therapeutics. ASHP therapeutic guidelines for intravenous immune globulin. Clin Pharm 1992;11:117–36. 20. Arnout J, Spitz B, Wittevrongel C, Vanrusselt M, Van Assche A, Vermylen J. High-dose intravenous immunoglobulin treatment of a pregnant patient with an antiphospholipid syndrome: Immunological changes associated with a successful outcome. Thromb Haemost 1994;71:741–7. 21. Anderson CL. Human IgG fc receptors. Clin Immunol Immunopathol 1989;53:563–71. 22. Arvieux J, Roussel B, Pouzol P, Columb MG. Platelet activating properties of murine monoclonal antibodies to beta 2-glycoprotein I. Thromb Haemost 1993;70:336 – 41. 23. Arnout J. The pathogenesis of the antiphospholipid syndrome: A hypothesis based on parallelisms with heparin-induced thrombocytopenia. Thromb Haemost 1996;75:536 – 41. 24. Bakimer R, Guilburd B, Zurgil N, Shoenfeld Y. The effect of intravenous gamma-globulin on the induction of experimental antiphospholipid syndrome. Clin Immunol Immunopathol 1993; 69:97–102.

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Ann L. Clark, MD Department of Obstetrics and Gynecology University of Louisville School of Medicine Louisville, KY 40292

Received May 4, 1998. Received in revised form August 28, 1998. Accepted September 3, 1998.

Copyright © 1999 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.

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