Antiphospholipid antibody–associated recurrent pregnancy loss: Treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone

Antiphospholipid antibody-associated recurrent pregnancy loss: Treatment with heparin and low.dose aspirin is superior to low-dose aspirin alone William H. Kutteh, MD, Phi) Dallas, Texas OBJECTIVE: The purpose of this study was to compare the use of low-dose aspirin alone with heparin and low-dose aspirin in the treatment of the antiphospholipid antibody syndrome. STUDY DEESI(IN: A prospective, single-center trial included 50 patients who were alternately assigned to treatment. Each patient had at least three consecutive spontaneous pregnancy losses, positive antiphospholipid antibodies on two occasions, and a complete evaluation. Data were compared by Z2 analysis and Fisher's exact test. RESULTS; Viable infants were delivered of 11 of 25 (44%) women treated with aspirin and 20 of 25 (80%) women treated with heparin and aspirin (p < 0.05). There were no significant differences between the low-dose aspirin and the heparin plus low-dose aspirin groups with respect to gestational age at delivery (37.8 + 2.1 vs 37.2 + 3.4 weeks), number of cesarean sections (18% vs 20%), or complications. CONCLUSION: Heparin plus low-dose aspirin provides a significantly better pregnancy outcome than low-dose aspirin alone does for antiphospholipid antibody-associated recurrent pregnancy loss. (AMJ 08STET GYNECOL1996;174:1584-9.)

Key words: Recurrent pregnancy loss, antiphospholipid antibodies, heparin, low-dose aspirin

Antiphospholipid antibodies (APAs) are acquired autoantibodies to negatively charged phospholipids found in approximately 15% of patients diagnosed with recurrent pregnancy loss) The generally proposed mechanism of obstetric complications related to APAs includes placental thrombosis, which can lead to fetal death. High levels of APAs have also been associated with other medical disorders such as thromboembolic events, stroke, and thrombocytopenia. 2 APAs are thought to cause these thrombotic events either by (1) binding and decreasing the function ofantithrombin III, 3' 4 (2) enhancing thromboxane release, which leads to platelet aggregation, or (3) decreasing the activation of protein C, which is needed to inactivate the clotting process) The APA syndrome is diagnosed in the presence of both clinical and laboratory criteria. These strict criteria require a history of thrombosis or recurrent pregnancy loss in addition to a positive test for lupus anticoagulant From the Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas. Presented at theForty-secondAnnual Meeting of The American Collegeof Obstetricians and Gynecologists, Orlando, Florida, May 9-12, 1994. Receivedfor publicationJuly 14, 1995; revised October6, 1995; accepted October 10, 1995. Reprint requests: William H. Kutteh, MD, PhD, Division of Reproductive Immunology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Cent~ 5323 Harry Hines Blvd., Dallas, TX 75235-9032. Copyright 9 1996 by Mosby-Year Book, Inc. 0002-9378/96 $5.00+ 0 6/1/69803 1584

or positive levels of immunoglobulin G (IgG) (or immunoglobulin M [IgM]) anticardiolipin antibodies (>20 phospholipid units).6 Several investigators have proposed various treatments for the APA syndrome during pregnancy including low-dose aspirin, prednisone, heparin, and intravenous "f-globulin treatments." ~-9 These treatments are thought to affect both the immune and coagulation systems to counteract the adverse actions of APAs. The rationale for heparin use has been that the anticoagulant activity overrides the thrombotic events caused by APAs binding to phospholipidz or other cross-reactive substances?' 4 Moreover, it was recently shown that the addition of heparin to APA-positive serum from women with recurrent pregnancy loss caused a dose-dependent decrease in IgG binding to cardiolipin and phosphatidylserine in an enzyme-linked immunosorbent assay (ELISA).10, 1i Thus heparin may have multiple mechanisms of action in the APA syndrome. Because of my interest in women with recurrent pregnancy loss and my preliminary data supporting the use of heparin for the treatment of patients with the APA syndrome, this study was initiated in 1991 to establish whether the addition of heparin to low-dose aspirin enhanced the chances for a successful pregnancy outcome in women with the APA syndrome. This controlled, prospective study of women with three or more pregnancy losses and positive APA indicates a significant advantage with heparin and aspirin treatment compared with lowdose aspirin alone.

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Material and methods Subjects. All women were patients at the Southwestern Fertility Associates of the University of Texas Southwestern Medical Center. More than 600 women with recurrent pregnancy loss were evaluated before 50 women with the APA syndrome who consented to participate in this study were identified. This diagnosis was based on a welldocumented history of at least three spontaneous consecutive miscarriages and APA levels that were ->27 IgG or >23 IgM phospholipid units (>2.5 multiples of the median) on two separate occasions. 12All women with recurrent pregnancy loss were interviewed and had a complete evaluation that included a history and physical e x a m i n a tion, karyotypes on both partners, hysterosalpingogram or hysteroscopy, midlnteal progesterone or late-luteal endometrial biopsy, prolactin, thyroid-stimulating hormone, lupus anticoagulant (partial thromboplastin time [PTT], dilute Russell viper venom time, and platelet neutralization), IgG and IgM anticardiolipin and antiphosphatidylserine antibodies, and cervical cultures for mycoplasma, ureaplasma, and chlamydia. Patients with medium to high levels of APAs and a history of recurrent pregnancy loss were started on low-dose aspirin (81 mg/day) and prenatal vitamins before conception. All patients were instructed to have quantitative h u m a n chorionic gonadotropin-~ tests with any missed period. Conception was a random event, and women were alternatively assigned to continue on aspirin only (81 mg/day) or to add twice daily subcutaneous injections of heparin 5000 units at the first confirmed pregnancy test (mean 5.3 +-1.1 gestational weeks). This study was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center. Entry criteria included women who desired to have a pregnancy, agreed to have a complete evaluation, had at least three documented pregnancy losses, had positive APAS on at least two occasions, and agreed to be alternatively assigned to low-dose aspirin or low-dose aspirin plus heparin. Exclusion criteria included women who had systemic lupus erythematosus, were positive for lupus anticoagulant, had another abnormal test result that was not corrected either medically or surgically, had an aspirin allergy, had another reason for anticoagulation duri n g pregnancy, or refused treatment or assignment to treatment. ELISA. All of the women selected were evaluated for the presence of APAs by the ELISA method, as described by Harris. 6 Briefly, individual 96-well microtiter plates (Immulon-2, Dynatech, Chantilly, Va.) were coated with 30 pl of either cardiolipin or phosphatidylserine at a concentration of 50 p g / m l (Sigma, St. Louis). The plates were air-dried overnight, blocked with 200 pl of 10% fetal calf serum (Gibco, Long Island, N.Y.) in l x phosphatebuffered saline solution (Gibco), and then incubated at 37 ~ C for 2 hours with 50 pl of patients' sera diluted 1 : 50

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in 10% fetal calf serum in phosphate-buffered saline solution. The plates were then washed to remove unb o u n d antibody and proteins, and a secondary antibody, either alkaline phosphatase-conjugated antihuman IgG (Caltag, South San Francisco) or alkaline phosphataseconjugated antihuman IgM (Tago, Burlingame, Calif.) was added to the plate. After incubation and washing, p-nitrophenyl phosphate substrate (Sigma 104) was used to measure indirectly the level of APAs in a patient's serum. The optical density of the samples, caused by the cleavage of the substrate by the enzyme, was determined at 405 n m by a BioRad platereader model 450 (Bi0Rad, Richmond, Calif.) and was used to quantitate the amount of APAs in the sera. Referenced standards for anticardiolipin antibodies (Louisville APL Diagnostics, Louisville, Ky.) and known negative and positive sera were used on every plate. The results of both anticardiolipin and antiphosphatidylserine antibodies were read from these standards and defined in phospholipid units for IgG or IgM as follows: <10, negative; 10 to 19, borderline; 20 to 80, positive; and >80, high positive. Background absorbances obtained from wells prepared without the coating phospholipid were subtracted before a value was determined to be positive. Patient monitoring. Subcutaneous heparin (10,000 or 20,000 units/ml) was administered every 12 hours. Platelets and PTT were obtained 6 hours after injecting heparin after the initiation of heparin therapy and 1 week after any adjustment in heparin dosage. Heparin dosages were adjusted to maintain 1.2 to 1.5 times the baseline PTT and were increased by 1000 units per dose weekly until the desired range was achieved. Thereafter platelets and PTT were checked at least every other week, and the heparin dosage was adjusted if necessary. Supplementation with calcium carbonate to achieve a total daily intake of 1.5 gm/day was recommended for all patients. 13 Each pregnancy was documented by transvaginal ultrasonography at approximately 7 weeks of gestation for the determination of fetal heart rate. Additional ultrasonography was performed as indicated, but generally baseline sonograms were obtained at 20 weeks. Antenatal testing was initiated at 28 to 30 weeks when indicated. Heparin was continued until term and was discontinued when the patient initiated spontaneous labor. The evening heparin dose was not given before a planned amniocentesis or a scheduled operative delivery. Heparin was reinitiated post partum at two thirds the predelivery dosage and incrementally decreased over 2 to 3 weeks before discontinuation. Statistical analyses and data collection. Statistical analyses were performed by Z2 analysis and Fisher's exact test. Assumptions made from the start of the study were (1) the estimated variance of the paired differences was 25%, (2) the certainty that the difference detected was not due to chance was 0.05 (e.g., significance level or 0~= 0.05),

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Table I. Comparison of study patients in each treatment group Heparin and aspirin (n = 25)

Aspirin alone (n = 25)

33.2 + 4.2 4.6 _+1.5 0.7 + 0.5 3.9 _+1.4 9.2 + 6.6

33.5 -+ 5.8 4.3 + 1.0 0.5 + 0.7 3.7 -+ 1.0 10.4 _+5.1

79.1 12.2 8.7 41.7 + 25.2 6/25 (24%)

76.6 11.9 11.5 51.4 + 19.7 5/25 (20%)

Age at entry (yr) Total prior pregnancies/patient Total prior live births/patient Total prior miscarriages/patient EGA at prior losses (wk) Prior losses (%) <12 wk 13-19 wk >20 wk APA (phospholipid units) IgM only antibodies

No significant differences were present between groups. Numbers represent mean + SD. EGA, Estimated gestational age.

Table II. O u t c o m e data from w o m e n with live births in each treatment group Heparin and aspirin (n = 25)

Aspirin alone (n = 25)

20 (80%)* 3712 + 3.4 2922 + 716 16 (80%) 36.9 + 4.1 4 (20%) 37.5 _+1.3

11 (44%)* 37.8 + 2.1 3064 -+ 628 9 (82%) 37.5 + 2.4 2 (18%) 38.0 _+0.5

No. of live births EGA at birth (wk) Birth weight (gin) No. of SVD EGA at SVD (wk) No. of cesarean sections EGA at cesarean section (wk)

EGA, Estimated gestational age; SVD, spontaneous vaginal deliveries.

*Differences were significant at p < 0.05. (3) and the certainty that a difference as small as 0.25 could be detected was 0.8 (e.g., power or 1 - 13= 0.80). The Academic C o m p u t i n g Services of the University of Texas Southwestern Medical Center at Dallas were used. Each patient was interviewed, and medical records were reviewed to confirm pregnancy histories. O u t c o m e data included maternal and obstetric complications. Preterm birth included deliveries before 37 c o m p l e t e d menstrual weeks. Gestational diabetes included w o m e n who demonstrated glucose intolerance requiring dietary or medical control. Minor bleeding included hematuria, nosebleeds, g u m bleeding, and bleeding at the injection site. T h r o m b o c y t o p e n i a was defined as platelet counts <100,000 m l ? Preeclampsia was diagnosed on the basis of hypertension plus proteinuria or e d e m a or both. 14 Intrauterine growth restriction (IUGR) was diagnosed when birth weight was <10th percentile for gestational age. Major bleeding included abruptio placentae, blood losses at delivery requiring transfusion, or any bleeding episode requiring hospitalization during pregnancy.

Results Patient population. Fifty w o m e n with the APA synd r o m e were sequentially assigned to treatment with aspirin alone or with heparin plus aspirin after a confirmed pregnancy test. As shown in Table I, there were no significant differences in the patient age at entry, total n u m b e r of prior pregnancies, prior live births or miscarriages, gestational age at loss, or percentage of losses that o c -

curred before 12 weeks, between 13 to 19 weeks, or after 20 weeks of gestation. Each w o m a n had an APA level of at least 27 phospholipid units of IgG or 23 phospholipid units of IgM; however, the average levels of APA were higher in both treatment groups (Table I). A patient was considered positive if either anticardiolipin or antiphosphatidylserine or both were positive. The highest level of IgG or IgM anticardiolipin or antlphosphatidylserine was selected for the data summation in Table I. O u t c o m e data. T h e r e were 20 viable infants born to the 25 w o m e n who were treated with heparin plus low-dose aspirin (80%) c o m p a r e d with 11 viable infants from the 25 w o m e n who were treated with low-dose aspirin only (44%). These differences in live births were significant (p < 0.05). As shown in Table II, there were no differences between the two groups in the estimated gestational age at birth, birth weight, or percentage of vaginal deliveries versus cesarean sections. H e p a r i n treatment parameters. Heparin treatment was initiated at 5.3 + 1.1 weeks in the 20 w o m e n who had successful deliveries. The initial dosage of 5000 units given subcutaneously twice daily was increased over the n e x t few weeks until the PTT value was 1.2 to 1.5 times baseline. The m e a n dosages of heparin used t h r o u g h o u t pregnancy are shown in Fig. 1. The average m a x i m u m dosage was 13,500 units twice daily with a range of 8000 to 20,000 units twice daily. T h e n u m b e r of weeks of treatm e n t averaged 31.4 _+ 3.2. Platelet counts r e m a i n e d stable t h r o u g h o u t pregnancy, as shown in Fig. t.

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Complications of treatment. The differences in the incidence of complications in the two treatment groups were n o t statistically significant. As shown in Table III, there were no differences in p r e t e r m births, gestafional diabetes, m i n o r b l e e d i n g episodes (nosebleeds, hematuria, b l e e d i n g at injection sites), thrombocytopenia (platelets <100,000), preeclampsia, or IUGR. T h e r e were no episodes of major bleeding, thrombosis, or fractures in either t r e a t m e n t group. O u t c o m e of w o m e n with losses. Five w o m e n treated with h e p a r i n PlUs aspirin a n d 14 w o m e n treated with aspirin only had a r e c u r r e n t loss after e n r o l l m e n t in this study (Table W). The estimated gestational age at the time of loss o n the basis of the last menstrual period was n o t different in tile two groups (7.8 + 0.8 weeks vs 7.3 + 0.5 weeks). Although karyotypes were n o t obtained after each miscarriage, there were n o differences in the incidence of blighted ovum or absent fetal heart m o t i o n at initial ultrasonography (Table IV). Comment R e c u r r e n t p r e g n a n c y loss, defined as three or m o r e s p o n t a n e o u s consecutive abortions, affects approximately 1% to 2% of reproductive-aged w o m e n in the U n i t e d States. 1 Various causes of r e c u r r e n t p r e g n a n c y loss include genetic, anatomic, endocrinologic, immunologic, microbiologic, a n d as yet u n k n o w n factors. O f the i m m u n o l o g i c causes, several investigators have correlated increased levels of APAs a n d the presence of lupus anticoagulant with increased obstetric complications i n c l u d i n g [UGR, pregn a n c y - i n d u c e d hypertension, a n d stillbirth.l' 5,6,15

Cardiolipin a n d phosphatidylserine have received the most attention as the phospholipids of primary importance in r e c u r r e n t pregnancy loss) +' 17 Several regimens have b e e n proposed for the t r e a t m e n t of APA syndrome, i n c l u d i n g aspirin alone, p r e d n i s o n e a n d aspirin, h e p a r i n a n d aspirin, a n d more recently intravenous i m m u n o g l o b ulin.7-1~ 15It has b e e n suggested t h a t w o m e n with r e c u r r e n t pregnancy loss a n d APAs who r e m a i n u n t r e a t e d have a 25% to 35% chance of having a successful pregnancy. 2' 15,18 There has b e e n a tendency to treat w o m e n with a history of pregnancy loss a n d APAs with a single "baby" aspirin per day because of ease of treatment, low cost, a n d safety. 19 Recent studies have suggested that h e p a r i n with or without aspirin may be superior to p r e d n i s o n e a n d aspirin for the t r e a t m e n t of APA-associated r e c u r r e n t pregnancy loss. 7-1~ 15, a+ Because we a n d others have suggested that the use of h e p a r i n a n d aspirin is preferred to p r e d n i s o n e a n d aspirin in these women, 1~7, 10,1~a prospecfive study to d e t e r m i n e the efficacy of h e p a r i n a n d aspirin versus aspirin alone was initiated in 1991. This series of subsequent pregnancies in w o m e n with well-characterized APA syndrome is the largest single-center t r e a t m e n t trial that has b e e n reported to date. O n the basis of the U.S. Preventive Services Task Force, the quality of evidence from this study is type II-1 (evidence obtained from a well-designed controlled trial without randomization). This study used n o n r a n d o m alternating assignment of t r e a t m e n t when patients had a positive p r e g n a n c y test result. This m e t h o d of t r e a t m e n t assignment eliminated infertility as a study variable a n d avoided the n e e d to exclude patients because of a pro-

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Table III. Obstetric and medical complications of patients in each treatment group with live births

Obstetric Pretermbirth IUGR Maternal Gestational diabetes Minor bleeding Thrombocytopenia Preeclampsia Major bleeding

Heparin and aspirin (n = 20)

Aspirin alone (n = 11)

3 (15%) 3 (15%)

1 (9%) 1 (9%)

2 (10%) 3 (15%) 0 2 (10%) 0

1 (9%) 1 (9%) 0 1 (9%) 0

All differences between groups were nonsignificant.

longed interval to conception. Therefore this study is n o t a prospective randomized trial. However, the patient demographic data presented in Table I confirm that there were n o significant differences in treatment groups at the time of entry into this study. There are a n u m b e r of i m p o r t a n t observations that can be made from this study. First, the APA syndrome may n o t be restricted to losses a n d complications that occur in the late second and third trimesters of pregnancy, as has b e e n reported in the pastil ~ In these 50 women who all had at least three well-documented pregnancy losses and positive levels of APAs o n at least two separate occasions, the average gestational age at the time of previous loss was 9 to 10 weeks. In addition, <25% of these losses occurred after 13 gestational weeks. These differences may reflect various referral patterns. Subspecialists who customarily deal with obstetric complications may see patients with APAs associated with later pregnancy losses or pregnancy complications (thrombosis, systemic lupus erythematosus, etc.), whereas those who customarily deal with fertility difficulties may predominantly see patients with early pregnancy losses. Overall, the maternal complications of patients in each treatment group were low. There were n o cases of thrombosis d u r i n g pregnancy or in the immediate 6 weeks post partum. Generally, the patients tolerated the heparin well, and there were no serious bleeding problems, episodes of thrombocytopenia, or osteoporotic fractures. All patients in this study received supplementation to achieve a daily intake of 1.5 gm of calcium carbonate. This has b e e n reported to b l u n t the osteoporotic effect of heparin when daily doses are _>15,000 units. 13 In addition, to reduce local h e m a t o m a formation, patients were instructed to apply ice to the injection site for several minutes before a n d after the injection and to rotate the injection site on the a b d o m e n daily. The obstetric complications observed in each treatm e n t group were low. Preterm delivery, IUGR, and preeclampsia were present in <15% of these women. These data are in a g r e e m e n t with reports of a lower incidence of complications of APA-positive women treated with heparin compared with APA-positive women treated with

Table IV. Outcome data from recurrent losses

Miscarriages (%) EGA at loss (wk) Blighted ovum No fetal heartbeat

Heparin and aspirin (n = 25)

Aspirin alone (n = 25)

5 (20%)* 7.8 -+0.8 1/5 (20%) 2/5 (40%)

14 (56%)* 7.3 _+0.5 3/14 (21.4%) 5/14 (35.7%)

EGA, Estimated gestational age.

*Differences were significant at p < 0.05.

prednisone.7. 8 These findings suggest that some of the adverse obstetric outcomes that have b e e n attributed to APAs may be exacerbated by treatment with prednisone.lS The findings reported here are in contrast to those of other investigators who reported preeclampsia in 41%, small-for-gestational-age infants in 20%, and fetal distress in 60% of women treated with heparin for APAs. 1< 19 It is important to emphasize that at the time of entry, their patient profiles differed significantly from those in this study. Specifically, a prior diagnosis of systemic lupus erythematosus (32%), thromboembolic disease (41%), transient ischemic attacks (24%), thrombocytopenia (22%), chronic hypertension (7%), or other autoimm u n e disease (17%) was made in patients included in the report of Branch et al) ~ W o m e n with a diagnosis of systemic lupus erythematosus or a prior thromboembolic event were specifically excluded from entry in this study. These differences in patient population and referral patterns emphasize that the APA syndrome may have different presentations. 2' 6 Previous investigators have reported successful outcomes ranging from 75% to 93% in w o m e n with APAs who were treated with heparin. 7' 8, 10, 1~ Rosove et al. 8 reported on 14 women with positive APAs who were treated with heparin. Half their patients had only one pregnancy loss and did n o t meet the strict criteria for APA syndrome. Five women had systemic lupus erythematosus a n d five had lupus anticoagulant; both of these diagnoses were excluded from our study. In addition, all women were treated with heparin, and there were no treatment options. T r e a t m e n t with heparin was initiated at a m e a n of 10.3 _+4.0 gestational weeks. Cowchock et a17 reported on 20 women with a history of at least two pregnancy losses a n d positive APAs who were randomized to treatm e n t with prednisone a n d aspirin versus heparin and aspirin. Nine of 12 women treated with heparin were delivered of viable infants. T r e a t m e n t was started after d o c u m e n t a t i o n of fetal heart motion in their study. Branch et al. 15 reported o n 19 women with well-characterized APA syndrome who were treated with heparin and aspirin. This was a n o n r a n d o m i z e d study, a n d treatment decisions by outside referring physicians may have b e e n influenced by a prior history of thromboembolic disease. Furthermore, treatment was initiated at a m e d i a n of 8 gestational weeks (range 5 to 25 weeks). It has previously been reported that the majority of w o m e n with r e c u r r e n t

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pregnancy loss who have fetal heart m o t i o n d e t e c t e d at 7 gestational weeks will be delivered of a viable infant, regardless o f etiology. 21 To eliminate selection bias in this study, t r e a t m e n t was initiated at the first d o c u m e n t e d p r e g n a n c y test (mean 5.3 _+ 1.1 weeks). In conclusion, the data r e p o r t e d h e r e indicate that h e p a r i n plus low-dose aspirin is a safe and effective treatm e n t for w o m e n with r e c u r r e n t p r e g n a n c y loss associated with APAs. T h e m a t e r n a l and obstetric complications were low, and the patients tolerated the t r e a t m e n t well. A study is currently underway to d e t e r m i n e w h e t h e r lowerdose h e p a r i n may be as effective a t r e a t m e n t as higherdose heparin in these women. I thank the following physicians who h e l p e d care for patients d u r i n g their pregnancies: A. A h m e d , J. Arias, B. A x m a n n , S. Bakos, K. Bradshaw, M. Cane, J. Cornwell, B. Crockett, U. Crosby, M. Davis, K.M. Doody, J. Dorsett, R. Dowling, C. Edman, J. Gilbertson, J. Goss, A. Guerami, S. H o f f m a n , E. H u n t , A. Johns, J. Kapsos, C. Kinney, C. Kutteh, W. Maxwell, T. Neel, J. NelsOn, M. Read, R. R e i n m u n d , K. Reisler, E. Silverstein, B. Stettler, S. Stone, L. Tatum, G. Theilen, K. Trimmer, L. Umholtz, M. Whitaker, L. Word, a n d J . Zavaleta. T h e assistance of Cristy Bennett, RN, clinical nurse coordinator; Rebecca M. Wester and LeAnn D. Ermel, research assistants; and Gladys Phipps, administrative secretary; is gratefully acknowledged.

REFERENCES

1. Kutteh WH, Pasquarette M. Recurrent pregnancy loss. In: Rock, JA, ed. Advances in obstetrics and gynecology. St. Louis: Mosby-Year Book, 1995;2:147-77. 2. Triplett DA. Antiphospholipid antibodies and recurrent pregnancy loss. Am J Reprod Immunol 1989;20:52-67. 3. Chamley LW, McKay EJ, Pattison NS. Inhibition of heparin/antithrombin III cofactor activity by anticardiolipin antibodies: a mechanism for thrombosis. Thromb Res 1993; 71:103-11. 4. Shibata S, Harpel P, Bona C, Filit H. Monoclonal antibodies to heparin sulfate inhibit the formation of thrombin-antithrombin III complexes. Clin Immunol Immunopathol 1993;67:264-72. 5. Rote NS. Pregnancy-associated immunological disorders. Curr Opin Immunol 1989;1:1165-72. 6. Harris EN. Annotation: antiphospholipid antibodies. Br J Haematol 1990;74:1-9. 7. Cowchock FS, Reece EA, Balaban D, Branch DW, Plouffe L. Repeated fetal losses associated with antiphospholipid

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antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment. AMJ OBST~T G~NEcoL 1992;155:1318-23. 8. Rosove MH, Tabsh K, Wasserstrum N, Howard R Hahn BH, Kalunian KC. Heparin therapy for pregnant women with lupus anticoagulant or anticardiolipin antibodies. Obstet Gynecol 1990;75:6304. 9. Coulam CB, SternJJ, Bustillo M. Ultrasonographic findings of pregnancy losses after treatment for recurrent pregnancy loss: intravenous immunoglobulin versus placebo. Fertil Steril 1994;61:248-51. 10. Ermel LD, Marshburn PB, Kutteh WH. Interaction ofheparin with antiphospholipid antibodies (APA) from the sera of women with recurrent pregnancy loss (RPL). Am J Reprod Immunol 1995;33:14-20. 11. McIntyreJA, Taylor CG, Torry DS, Wagenknecht DR, Wilson J, Faulk WP. Heparin and pregnancy in women with a history of repeated miscarriages. Haemostasis 1993;23(suppl 1):202-11. 12. Kutteh WH, Wester RM. Multiples of the median: an alternate method for reporting antiphospholipid antibodies in women with recurrent pregnancy loss. Obstet Gynecol 1994; 84:811-5. 13. Dahhnan T, Sj6berg HE, Ringertz H. Bone mineral density during long-term prophylaxis with heparin in pregnancy. AM J OBSTETGYNECOL1994;170:1315-20. 14. Cunningham FG, MacDonald PC, Gant NF, Leveno KJ, Gilstrap LC. Hypertensive disorders in pregnancy. In: Cunningham FG, MacDonald PC, Gant NF, Leveno KJ, Gilstrap CC, eds. Williams' obstetrics. 19th ed. Norwalk, Connecticut: Appleton & Lange, 1993:763-817. 15. Branch DW, Silver RM, Blackwell JL, Reading JC, Scott JR. Outcome of treated pregnancies in women with antiphosphoiipid syndrome: an update of the Utah experience. Obstet Gynecol 1992;80:614-20. 16.' Branch DW, Rote NS, Dostal DA, Scott JR. Association of lupus anticoagulant with antibody against phosphatidylserine. Clin Immunol Immunopathol 1987;42:63-75. 17. Rote NS, Dostal-Johnson DA, Branch DW. Antiphospholipid antibodies and recurrent pregnancy loss: Correlation between the activated partial thromboplastin time and antibodies against phosphatidylserine and cardiolipin. AM J OBST~TGWECOL1990;163:575-84. 18. Lockshin MD, Druzin ML, Qamar T. Prednisone does not prevent recurrent fetal death in women with antiphospholipid antibody. AMJ OBSTETG~ECOL 1989;160:439-43. 19. HauthJC, Goldenberg RL, Parker CR, Cutter GR, Cliver SE Low-dose aspirin: lack of association with an increase in abruptio placenta or perinatal mortality. Obstet Gynecol 1995;85:1055-8. 20. Branch DW, Scott JR. Clinical implication of antiphospholipid antibodies: the Utah experience. In: Harris EN, Exner T, Hughes GRU, Asherson RA, eds. Phospholipid-binding antibodies. Boca Raton, Florida: CRC, 1990:355-46. 21. Laufer MR, EckerJC, HilIJA. Pregnancy outcome following ultrasound-detected fetal cardiac activity in women with a history of multiple spontaneous abortions. J Soc Gynecol Invest 1994;1:138-42.