Intravenous immunoglobulin therapy for the antiphospholipid syndrome in pregnancy

February 1995 An1J Obstet Gynecol

Spinnato et al.

REFERENCES

1. Bishop EH. Pelvic scoring for elective induction. Obstet Gynecol 1964;24:266. 2. Garret WJ. Prognostic signs of surgical induction of labor. Med J Aust 1960;49:29. 3. Calder AA, Embrey MP, Tait T. Ripening of the cervix with extra-amniotic prostaglandin E9 in viscous gel before induction of labor. Br J Obstet Gynaecol 1977;84:264-8. 4. Trofatter KF. Cervical ripening. Clin Obstet Gynecol 1992;35:476-85. 5. Keirse MJNC. Prostaglandins in preinduction cervical ripening: meta-analysis of worldwide clinical experience. J Reprod Med 1993;38:89-100. 6. Embrey MP, MoUison BC. The unfavorable cervix and the induction of labor using a cervical balloon. J Obstet Gynaecol Br Commonw 1967;74:44-8. 7. Ezimokhai M, NwabineliJM. The use of Foley's catheter in r!pening the unfavorable cervix prior to induction of labour. Br J Obstet Gynaecol 1980;87:281-6.

8. Hackett GA, Reginald P, Paintin DB. Comparison of the foley catheter and dinoprostone pessary for cervical preparation before second trimester abortion. Br J Obstet Gynaecol 1989;96:1432-4. 9. Thomas IL, ChenowethJN, Tronc GN, Johnson ]R. Preparation for induction of labor of the unfavorable cervix with foley catheter compared with vaginal prostaglandin. Aust N Z J Obstet Gynecol 1986;26:30-5. 10. Atad J, Bornstein J, Calderon I, Petrikovsky BM, Sorokin Y, Abramovici H. Nonpharmaceutical ripening of the unfavorable cervix and induction of labor by a novel double balloon device. Obstet Gynecol 1991;77:146-52. 11. Sanchez-Ramos L, Kaunitz AM, Connor PM. Hygroscopic cervical dilators and prostaglandin E2 gel for preinduction cervical ripening. J Reprod Med 1992;37:355-9. 12. Mahomed K. Foley catheter under traction versus extraamniotic prostaglandin gel in pretreatment in unripe cervix-a randomized controlled trial. Cent Mr J Med 1988;34:98-102.

Intravenous immunoglobulin therapy for the antiphospholipid syndrome in pregnancy Joseph A. Spinnato, MD," Ann L. Clark, MD," Silvia S. Pierangeli, PhD, b and E. Nigel Harris, MD b Louisville, Kentucky OBJECTIVE: Our purpose was to study the influence of intravenous immunoglobulin on pregnancy

outcome. STUDY DESIGN: Pregnancy outcomes were evaluated in five patients with 17 unsuccessful previous

pregnancies. Each patient received 400 mg/kg immunoglobulin for 5 days monthly beginning in the first or early second trimester. Four patients with previous thromboembolic events were treated with concomitant heparin prophylaxis. Four patients received 81 mg of aspirin daily. RESULTS: Short- and long-term decreases of anticardiolipin immunoglobulin G were noted in three patients. Four patients were delivered of healthy infants at term, one at 32 weeks' gestation with a diagnosis of fetal distress. Neither preeclampsia nor fetal intrauterine growth retardation were observed. The immunoglobulin therapy was not associated with major side effects. Significant placental histologic anomalies were not identified. CONCLUSIONS: The observations suggest that immunoglobulin therapy may improve pregnancy outcomes beyond that observed with heparin and aspirin. A prospective trial is encouraged. (AM J OBSTET GYNECOL1995;172:690-4.)

Key words: Immunoglobulin therapy, antiphospholipid syndrome, pregnancy wastage

The antiphospholipid syndrome is described as the presence of anticardiolipin antibodies or lupus antico-

From the Departments of Obstetrics and Gynecologyc~and Rheumatology,b University of Louisville School of Medicine. Received for publication May 16, 1994; revised June 29, 1994; acceptedJuly 21, 1994. Reprint requests:J.A. Spinnato, MD, Department of Obstetrics and Gynecology, University of Louisville, Louisville, KY 40292. Copyright © 1995 by Mosby-Year Book, Inc. 0002-9378/95 $3.00 + 0 6/1/59394 690

agulant in combination with one of the following: recurrent pregnancy loss, recurrent thrombosis, or thrombocytopenia?-4 A high incidence of fetal distress, prematurity, and thrombotic events has been reported in pregnancies complicated by the syndrome? Treatment options for pregnant women with this disease have evolved over the past 10 years yet have remained controversial. Previous reports have suggested that treatment with low-dose aspirin and prednisone 6s or aspirin and heparin 9 is beneficial in preventing preg-

Volume 172, Number 2, Part 1 AmJ Obstet Gynecol

nancy loss and complications. Other studies have refuted these conclusions ~° or found no difference s in efficacy when treatment regimens were compared. All reported series are small and differed in patient selection criteria. Recent case reports have suggested that intravenous immunoglobulin is efficacious in preventing pregnancy loss and in suppressing anticardiolipin and lupus anticoagulant titers. '~-'4 In this study we examined the influence of intravenous immunoglobulin on pregnancy outcome and anticardiolipin antibody levels in five patients with antiphospholipid syndrome and recurrent pregnancy loss. We chose to use intravenous immunoglobulin because of the severity of the antiphospholipid syndrome in the selected patients, the previous failure of other therapies in two patients, and the possibility that outcomes could be improved beyond that reported with other therapies. Material and methods Since 1990 five pregnant women with the diagnosis of antiphospholipid syndrome were treated with intravenous immunoglobulin. All patients were managed by the authors at a University of Louisville-affiliated hospital. Past medical and obstetric histories were obtained from hospital and clinic charts. The diagnosis of antiphospholipid syndrome was based on accepted criteria. 1Treatment with intravenous immunoglobulin began in the first or early second trimester and was administered at a dose of 400 mg/kg for 5 days each month. This largely empiric dosing schedule was chosen after a general review of the literature regarding therapeutic intravenous immunoglobulin. Four patients received 81 mg of aspirin daily (patient 1 was allergic). Four patients received subcutaneous heparin at doses of 5000 to 7500 U twice daily. Prophylactic (vs therapeutic) heparin therapy was chosen because of the prolonged interval to prior thrombotic events (> 1 year in each case) and a postulated reduction of thrombotic risk provided by the immunoglobulin G (lgG) therapy itself. Patient 5 was initially treated with heparin, but it was discontinued because of a marked allergic reaction unresponsive to a change of manufacturer. A switch was made to intravenous immunoglobulin at 16 weeks' gestation for this patient. Two patients were treated with steroids because of separate diagnoses. Patient 1 was diagnosed with herpes gestationis at 18 weeks' gestation, and prednisone was prescribed. Patient 2 had a history of Addison's disease and was treated with hydrocortisone throughout her pregnancy. Anticardiolipin IgG and immunoglobulin M (IgM) antibody titers were measured at the University of Louisville Rheumatology Laboratory by enzyme-linked immunosorbent assay (ELISA) 15 with serum standards from our antiphospholipid standardization labora-

Spinnato et al. 691

t o r y . 16 Results were reported as high positive ( > 80 GPL units/ml or > 80 MPL units/ml), medium positive (20 to 80 GPL units/rill or 20 to 80 MPL units/ml), or low positive (8 to 19 GPL units/ml or 10 to 19 MPL units/ml). Patients had IgG and IgM anticardiolipin determinations before each intravenous immunoglobulin treatment was initiated and at the completion of each treatment cycle. Lupus anticoagulant activity was determined by measuring the kaolin clotting time, activated partial thromboplastin time, and the Russell viper venom time. 17 The diagnosis of systemic lupus erythematosus was based on criteria used by the American Rheumatism Association. 18 Antenatal testing was begun at 28 weeks' estimated gestational age, and sonograms to assess growth were obtained as clinically indicated. The standard 1-hour glucose tolerance test was taken by each patient at approximately 28 weeks' estimated gestational age. All placentas were sent for histopathologic evaluation.

Results Seventeen previous pregnancies had failed to result in a live birth. Of these pregnancies, 12 were firsttrimester spontaneous abortions, three were secondtrimester deaths in utero, and two were third-trimester deaths in utero. A total of 12 previous thromboembolic events were noted in patients 1 through 4. Patient 1 had experienced five deep venous thrombosis and two pulmonary emboli. Patient 2 had a history of adrenal artery thromboembolism and amaurosis fugax. Two previous pulmonary emboli has been noted in patient 3 and two deep venous thromboses in patient 4. Patient 5 had no history of thromboembolic events. Both patients 1 (chronic hypertension, lupus cerebritis) and 3 were previously diagnosed with systemic lupus erythomatosus and had preeclampsia in previous pregnancies. Patients 4 and 5 had positive lupus anticoagulant activity. Patient 1 had received heparin therapy in three previous pregnancies, and patient 2 was treated with hydrocortisone combined with aspirin. In the five IgG-treated pregnancies there were no maternal thromboembolic events and preeclampsia did not occur. Five healthy infants were delivered without evidence of intrauterine growth retardation. All infants were delivered at term except for patient 1, who was delivered at 32 weeks' gestation because of decreased fetal movement and fetal distress. Preterm premature rupture of the membranes occurred at 36 weeks' gestation in patient 2. Gestational diabetes occurred in patient 1, who was treated with steroids for herpes gestationis. Placental histopathologic features appeared to be minimal. There were no flares of lupus activity. See Table I for delivery data.

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February 1995 AmJ Obstet Gynecol

Table I. Patient summary Patient No.

1 Parity

Gravida 4, para 0-1-2-0 EGA at delivery (wk) 33 Age (yr) 29 Delivery Primary LTCS Indication Fetal distress

A p g ascore r

1 min 5 min Weight (gm) Placental pathologic study results

6 8 1786 No abruptio placentae, no infarction

2

3

4

5

Gravida 3, para 0-0-2-0 36 29 Primary LTCS PPROM, footling breech, labor

Gravida 2, para 0-1-0-0 39 28 SVD Elective induction

Gravida 8, para 0-0-7-0 39 28 SVD Spontaneous labor

Gravida 5, para 0-1-3-0 38 39 Primary LTCS Breech

7 9 2799 Small focal infarction

8 9 2750 Intervillous fibrin deposition

8 9 3459 5% to 10% placental infarction

8 9 3224 Fibrin plaques < 5% of surface area

EGA, Estimated gestational age; LTCS, low transverse cesarean section; SVD, spontaneous vaginal delivery; PPROM, preterm premature rupture of membranes.

A reduction of IgG anticardiolipin was demonstrated in patients 1 through 3. All had IgG anticardiolipin titers in the high-positive range before the onset of treatment with intravenous immunoglobulin. Patient 1 had an initial IgG of 85.9 GPL units, which decreased to 44.7 GPL units after 5 days of intravenous immunoglobulin. This trend continued during each treatment, and a nadir of 20.2 GPL units was reached at 28 weeks' estimated gestational age. Patient 2 had an initial IgG titer of 92.0 GPL units and showed a gradual decrease in titers throughout her pregnancy. The lowest value was 12.0 GPL units at 32 weeks' estimated gestational age. In patient 3 an initial IgG titer of 507 GPL units decreased to 22.0 GPL units, followed by increased values. At delivery the patient's IgG titer was 70.0 GPL units. Fig. 1 plots the value observed at the beginning of each treatment cycle. Anticardiolipin IgG determinations selectively performed at the end of therapy demonstrated an approximate 50% reduction in antibody level. Patients 4 and 5 had IgG anticardiolipin titers in the low-positive range throughout the course of their pregnancies. Both had positive lupus anticoagulant tests before the initiation of treatment. Treatment with heparin precluded monitoring of lupus anticoagulant activity in patient 4 and was noted to intermittently revert to negative in patient 5. Anticardiolipin IgM levels in all patients were usually negative but occasionally in the low-positive range and failed to show any specific trends with treatment. Only minimal side effects of intravenous immunoglobulin therapy were noted; they included infrequent low-grade temperature elevation and headache which occurred during the infusions and which responded to acetaminophen. One Rh-negative patient was noted to have a 1 : 2 anti-Rh(D) antibody titer that was presumed to be related to the therapy. Rh immunoprophylaxis was administered at

28 weeks' gestation and post partum. Six months post partum anti-Rh(D) antibody was not detected. Comment The presence of anticardiolipin antibody has been found to be a sensitive indicator of fetal death and distress. 19 Studies have shown that higher titers of IgG anticardiolipin are associated with more frequent episodes of those p h e n o m e n a characteristic of the antiphospholipid syndrome?' 2o Ishii et al. 21 demonstrated that persistently positive IgG anticardiolipin in patients with systemic lupus erythematosus, irrespective of disease activity, was associated with a much higher spontaneous abortion rate compared with those patients who had elevated IgG titers only during times of increased lupus activity. The presumed mechanism for fetal loss is placental thrombosis, 22 although there are instances where placental thrombosis and infarction are insufficient to explain fetal loss/9 Speculation exists as to whether the IgG anticardiolipin antibody is directly responsible for thrombosis or whether it is merely an e p i p h e n o m e n o n of the thrombogenic process. 23 Branch et al. 23 demonstrated that fetal loss could be mediated in BALB/c mice injected with purified IgG anticardiolipin antibody from patients with antiphospholipid syndrome. Similar findings were r e p o r t e d by Blank et al. 24 Also of note was the observation by Branch et al. 23 that severe decidual necrosis was present in 82% of the mice experiencing fetal loss. Immunofluorescent studies were performed on the IgG anticardiolipin, which showed a pattern consistent with placental intravascular staining, lending evidence to the presumption that IgG anticardiolipin is the direct cause of fetal loss and that attempts to reduce titers might be fruitful. Treatment protocols have used prednisone, aspirin, heparin, or various combinations of these drugs in

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Spinnato et al. 693

,o4

IgG (GPL)

200- ..... C ~ - - - ~ , ::

PATIENT1 -¢~ PATIENT2 e PATIENT3

/

150-

\

10050-

--a.. -..,

08

12

16

20

24

28

32

36

40

Gestational age (weeks) Fig. 1. Anticardiolipin IgG levels before each treatment week among patients with elevated titers.

attempts to prevent pregnancy loss in women with antiphospholipid syndrome. 5' 8, 9, 20 Prednisone therapy has been linked with a high incidence of preterm premature rupture of the membranes, preterm delivery, preeclampsia, and gestational diabetes. 5' 90steoporotic fractures have been noted in pregnant women treated with heparin prophylaxis. 25 The overall treatment failure with the combinations of aspirin and prednisone, heparin and aspirin, and a combination of all three is approximately 30%. 5 Although none of our patients experienced fractures, one patient receiving prednisone had gestational diabetes and the other had preterm premature rupture of the membranes. Decreased fetal movement prompted early delivery for our first patient. In retrospect, the fetus may not have been in jeopardy. The number of patients treated with intravenous immunoglobulin in our study is small, thus prompting cautious interpretation of our encouraging results. We cannot draw clear conclusions regarding the apparent success of intravenous immunoglobulin therapy or the correctness of the selected dosing schedule. Indeed, three of our patients whose pregnancies were not previously treated for antiphospholipid syndrome may have experienced good outcomes with heparin and low-dose aspirin without intravenous immunoglobulin. However, all our patients had well-defined antiphospholipid syndrome, unlike study subjects in other reports, and the potential for maternal complications was very high, given the patients' histories. Previous case reports have included one to three patients, and standardized schedules and doses of intravenous immunoglobulin have not been followed, n We are intrigued by the virtual absence of significant placental pathologic features and encouraged by the possible IgG suppression observed, the infrequency of pregnancy complications (particularly preeclampsia, intrauterine growth

retardation, and gestational diabetes), and the healthy infants delivered. If IgG anticardiolipin is the direct mediator of placental thrombosis and fetal loss and if the observed decreases of anticardiolipin IgG represent responses to intravenous immunoglobulin, then suppressing IgG titers with intravenous immunoglobulin would seem prudent. It is tempting to speculate that concurrent heparin prophylaxis might be unnecessary in some patients so treated (patient 5). Indeed, IgG therapy, by its own influence on thrombotic risk, may obviate heparin therapy for these patients, regardless of past thromboembolic events. An influence of intravenous immunoglobulin on the frequency of lupus flares cannot be determined, but none occurred. If fetal loss or the need for indicated preterm delivery because of preeclampsia, intrauterine growth retardation, or fetal distress can be reduced by intravenous immunoglobulin to a greater extent than with heparin or other therapies, the possible benefit in reduced nursery costs and perinatal morbidity or mortality may offset the cost ($4000 to $5000 per month) of intravenous immunoglobulin therapy. A randomized prospective trial will be required, and is encouraged, to determine the efficacy of intravenous immunoglobulin compared with standard treatments. REFERENCES

1. Harris EN. Syndrome of the black swan. Br J Rheumatol 1987;26:324-6. 2. Lockshin MD, Qamar T, Druzin ML, Goei S. Antibody to cardiolipin, lupus anticoagulant, and fetal death. J Rheumatol 1987;14:259-62. 3. Harris EN, Chan JK, Asherson RA, Aber VR, Gharavi AE, Hughes GR. Thombosis, recurrent fetal loss, and thrombocytopenia. Arch Intern Med 1986;146:2153-6. 4. Alarcon-Segovia D, Deleze M, Oria CV, et aL Antiphospholipid antibodies and the antiphospholipid syndrome in systemic lupus erythematosus: a prospective analysis of 500 consecutive patients. Medicine 1990;68:353-65. 5. Branch WD, Silver RM, BlackwellJL, ReadingJC, Scott JR.

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Outcome of treated pregnancies in women with antiphospholipid syndrome: an update of the Utah experience. Obstet Gynecol 1992;80:614-20. Lubbe WF, Liggins GC. Role of lupus anticoagulant and autoimmunity in recurrent pregnancy loss. Semin Reprod Endocrinol 1988;2:181-90. Lubbe WE Butler WS, Palmer SJ, Liggins GC. Lupus anticoagulant in pregnancy. Br J Obstet Gynaecol 1984; 91:357-63. Lubbe WF, Palmer SJ, Butler WS, Liggins GC. Fetal survival after prednisone suppression of maternal lupusanticoagulant. Lancet 1983;1:1361-3. Cowchock SF, Reece AE, Balaban D, Branch WD, Plouffe L. Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment. AMJ OBSTET GYNECOL1992;166:1318-23. Lockshin MD, Druzin ML, Qamar T. Prednisone does not prevent recurrent fetal death in women with antiphospholipid antibody. AMJ OBSTZTGVNECOI~1989;160:439-43. Kaja R, Julkunen H, Ammala P, Palosuo T, Kurki P. Intravenous immunoglobulin treatment of pregnant patients with recurrent pregnancy losses associated with antiphospholipid antibodies. Acta Obstet Gynecol Scand 1993;72:63-6. Katz VL, Thorp JM, Watson WJ, Fowler L, Heine PR. Human immunoglobulin therapy of preeclampsia associated with lupus anticoagulant and antiphospholipid antibody. Obstet Gynecol 1990;76:986-7. McVerry BA, Spearing R, Smith A. SLE anticoagulant: transient inhibition by high dose immunoglobulin infusions. BrJ Haematol 1985;61:579-80. Parke A, Maier D, Wilson D, Andreoli J, Ballow M. Intravenous gamma-globulin, antiphospholipid antibodies, and pregnancy. Ann Intern Med 1989;110:495-6. Harris EN. Serological detection of antiphospholipid antibodies. Stroke 1992;23:3-6.

February 1995 Am J Obstet Gynecol

16. Harris EN. The second international anti-cardiolipin standardization workshop/the Kingston antiphospholipid antibody study (KAPS) group. Am J Clin Pathol 1990;94: 476-84. 17. Triplen DA, Bran& JT, Kaczor D, et al. Laboratory" diagnosis of lupus inhibitors: a comparison of the tissue thromboplastin inhibition procedure with a new platelet neutralization procedure. Am J Clin Pathol 1983;79:678-72. 18. Tan EM, Cohen AS, Fries JL, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271-7. 19. Lockshin MD, Druzin ML, Goei S, et al. Antibody to cardiolipin as a. predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus. N EnglJ Med 1985;313:152-6. 20. Loizou S, Byron MA, Englert HR, Walport MJ, Hughes GRV. Association of quantitative anti-cardiolipin antibody levels with fetal loss. Q J Med 1988;68:525-31. 21. Ishii Y, Nagasawa K, Mayumi T, Niho Y. Clinical importance of persistence of anticardiolipin antibodies in systemic lupus erythematosus. J Rheum Dis 1990;49:387-90. 22. Abramowsky CR, Vegas ME, Swinehart G, Gyves MT. Decidual vasculopathy in the placenta in lupus erythematosus. N Engl J Med 1980;303:668-72. 23. Branch WD, Dudley DJ, Mitchell MD. Immunoglobulin G fractions from patients with antiphospholipid syndrome cause fetal death in balb/c mice: a model for autoimmune fetal loss. AM J OBST~TGVNECOL1990;163:210-6. 24. Blank M, Cohen J, Toder V, Shoenfeld Y. Induction of antiphospholipid syndrome in naive mice with mouse lupus monoclonal and human polyclonal anticardiolipin antibodies. Proc Natl Acad Sci USA 1991;88:3069-73. 25. Dahlman T. Osteoporotic fractures and the recurrence of thromboembolism ,during pregnancy and the puerperium in 184 women undergoing thromboprophylaxis with heparin. AM J OBSTETGYNECOL1993;168:1265-70.

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