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Antiphospholipid Syndrome in Pregnancy: A Randomized, Controlled Trial of Treatment

From the Department of Obstetrics and Gynaecology, Liverpool Women’s Hospital, Liverpool, United Kingdom; Department of Obstetrics and Gynaecology, University of Liverpool, Liverpool Women’s Hospital, Liverpool, United Kingdom; and Department of Medicine and Therapeutics, University of Aberdeen Medical School, Aberdeen, United Kingdom.

Address reprint requests to: Roy G. Farquharson, MD, FRCOG, Liverpool Women’s Hospital, Department of Obstetrics and Gynaecology, Crown Street, Liverpool, L8 7SS, United Kingdom; E-mail: roy.farquharson{at}lwh-tr.nwest.nhs.uk.

	ABSTRACT

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OBJECTIVE: To compare the efficacy of low-dose aspirin alone versus low-dose aspirin plus low molecular weight heparin in pregnant women with antiphospholipid syndrome and recurrent miscarriage as prophylaxis against pregnancy loss.

METHODS: From a regional miscarriage clinic, 119 consecutive women with persistently positive tests for lupus anticoagulant and/or anticardiolipin immunoglobulin G and M antibody were invited to participate in a randomized, controlled trial between 1997 and 2000. After ethical approval and adherence to a written protocol, 12 women were unwilling to participate, five failed exclusion/inclusion criteria, and four were nonpregnant. Laboratory analysis was performed by Sheffield University Coagulation Department, electronically generated randomization by Manchester University Centre for Cancer Epidemiology, and data collection and analysis by a research officer at Leeds University. Viability ultrasound every 2 weeks was provided until 12 weeks’ gestation before transfer to the pregnancy support antenatal clinic.

RESULTS: Ninety-eight women were randomized before 12 weeks’ gestation. Forty-seven received low-dose aspirin 75 mg daily (group A), and 51 received low-dose aspirin plus low molecular weight heparin 5000 U subcutaneously daily (group B) throughout pregnancy. There were 13 pregnancy losses and 34 live births in group A and 11 losses and 40 live births in group B. The live-birth rate was 72% in group A and 78% in group B (odds ratio 1.39, 95% confidence interval 0.55, 3.47). There were no cases of maternal thrombosis in either group.

CONCLUSION: A high success rate is achieved when low-dose aspirin is used for antiphospholipid syndrome in pregnancy. The addition of low molecular weight heparin does not significantly improve pregnancy outcome.

Antiphospholipid syndrome is strongly associated with recurrent miscarriage and less frequently, maternal thrombosis during pregnancy.¹ As a procoagulant state, the pathogenesis of antiphospholipid syndrome-associated pregnancy loss is thought to be linked to placental thrombosis,² although a recent study has cast doubt on this theory.³

Many centers have adopted treatment using thrombo-prophylaxis in the form of low-dose aspirin and/or heparin. Clear consensus for evidence-based practice has been absent⁴ as several authorities dispute the combination of low-dose aspirin plus heparin being superior to low-dose aspirin alone.

We undertook a randomized, controlled trial to assess whether the combination of low-dose aspirin plus low molecular weight heparin was superior to low-dose aspirin alone in the prevention of miscarriage in a group of women with a history of recurrent pregnancy loss and positive diagnostic tests for antiphospholipid syndrome.

	MATERIALS AND METHODS

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The local research ethics committee approved the trial, and women were recruited from the miscarriage clinic from January 1997 to January 2000. The planned trial population consisted of women aged 18–41 years who had suffered at least three consecutive pregnancy losses or two consecutive losses with proven fetal death after 10 weeks’ gestation. The diagnosis of antiphospholipid syndrome was made on the basis of two positive tests for antiphospholipid antibody more than 6 weeks apart. Lupus anticoagulant activity was determined by prolongation of the dilute Russell viper venom time ratio greater than 1.09 with at least 20% correction by washed, frozen/thawed platelets, consistent with contemporaneous UK national guidelines.⁵ An in-house enzyme-linked immunosorbent assay was used for the determination of anticardiolipin titer. International standards were employed, and after construction of a normal range by calculation of the mean values and three standard deviations above the mean in a healthy population, levels of immunoglobulin G and M anticardiolipin of more than 9 anticardiolipin U/mL and more than 5 anticardiolipin U/mL, respectively, were considered positive. Blood sampling and storage followed optimal preparation using double-spin centrifugation for plasma and storage at -70C within 2 hours for plasma and serum. Samples were sent for analysis to the Coagulation Department, University of Sheffield.

Parental chromosomal abnormality, uterine anomaly, previous arterial or venous thrombosis, use of steroids during pregnancy, systemic lupus erythematosus requiring medication or complicated by nephritis, and other thrombophilia such as activated protein C resistance or protein C/S deficiency.

The aim was to assess the efficacy of low molecular weight heparin in the treatment of antiphospholipid syndrome during pregnancy by comparing low molecular weight heparin combined with low-dose aspirin against low-dose aspirin alone in women suffering pregnancy loss. Before 12 weeks’ gestation, women were randomized to group A (low-dose aspirin tablets 75 mg daily until delivery) or to group B (low-dose aspirin 75 mg daily plus low molecular weight heparin 5000 U subcutaneously daily until delivery).

The type of pregnancy loss was classified as an embryo loss where no visible crown rump length or fetal heart activity could be visualized within the sac on weekly ultrasound assessment starting at 5 completed weeks’ gestation. After viability was confirmed, a fetal loss was diagnosed when fetal heart activity disappeared after clear identification on previous ultrasound scan.

For a trial with 80% power and significance at the 5% level, using an anticipated baseline of 50% live-birth rate (aspirin group A) with an expected improvement to 60% live-birth rate with treatment (aspirin and heparin group B), a power calculation required 110 women in each treatment arm (n = 220). This was considered to be a cautious prediction of power. For example, a power calculation based on the study of Rai et al,⁶ the only pre-existing randomized, controlled trial indicated a requirement to recruit 54 patients. On this basis and in consideration of the high success rate observed in the aspirin group, an interim analysis was performed.

All analyses were completed on an intention-to-treat basis. Twenty-four women did not follow the protocol (nonadherent group). In group A, 11 women randomized to aspirin alone wished heparin as well. In group B, 13 women took aspirin only and did not wish heparin. Demographic and clinical data were compared between the two groups. Comparisons between groups were expressed as odds ratios (OR) and 95% confidence intervals (CI). The ² test was used for statistical analysis of discrete and continuous variables, and a P value of <.05 was taken as statistically significant.

Compliance with low molecular weight heparin was recorded by longitudinal inspection of injection sites, which were clearly demarcated. Aspirin compliance could not be accurately assessed except by repeat prescription request and patient enquiry.

Individual women were randomly allocated to group A or B by telephone randomization to the Trials Unit at the Centre for Cancer Epidemiology at the University of Manchester, which generated the random allocation sequence using a computer. The unit of randomization was the individual patient. Randomization was stratified in blocks of 20 to provide a 1:1 balance between intervention and control groups. Each subject was given a unique study number. At the time of enrollment by the authors, details of patient identification using hospital number and date of birth were given, followed by number of pregnancy losses and antiphospholipid status. Allocation to treatment group was concealed until a full checklist of inclusion/exclusion criteria was completed after which randomization was made. Of 119 patients invited to participate, 12 declined randomization, five failed inclusion/exclusion criteria, and four were nonpregnant (Figure 1).

View larger version (19K): [in this window] [in a new window]   Figure 1. Consensus Statement for Reporting Randomized Trials diagram of patients and events during the trial. Farquharson. Antiphospholipid Syndrome in Pregnancy Trial. Obstet Gynecol 2002.

Data analysis was undertaken by a research officer (CC) and communicated to the authors.

	RESULTS

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We recruited 98 women: 47 to group A (low-dose aspirin alone) and 51 to group B (low-dose aspirin plus low molecular weight heparin). There were no significant differences between groups in respect of maternal age, number of previous consecutive miscarriages, or gestation at time of randomization (Table 1). In addition, there was no significant variation in the type or level of positive laboratory criteria for diagnosis of antiphospholipid syndrome (Table 2). Of the 98 patients, there were four patients with serological markers for systemic lupus erythematosus when investigated for joint discomfort. None had other clinical evidence of systemic lupus erythematosus nor had they received immunosuppressive therapy.

Of 13 pregnancy losses in group A, there were nine embryo losses before 10 weeks’ gestation and four fetal deaths at 7, 8, 10, and 30 weeks’ gestation. Of 11 pregnancy losses in group B, there were three embryo losses before 10 weeks’ gestation and eight fetal deaths at 7, 8, 8, 8, 9, 12, 22, and 23 weeks’ gestation.

Analyses for the adherent group (n = 74) and the nonadherent group (n = 24) are given separately. Within the subset of 24 women who altered their allocated treatment (nonadherent group), the outcomes for fetal loss type (OR 0.38, 95% CI 0.03, 4.81, P = .45) and obstetric outcome (live-birth OR 3.14, 95% CI 0.45, 21.9, P = .25) were not significantly different either from the whole group (n = 98) or from the adherent group (n = 74).

Within the adherent group (n = 74), the outcomes were not significantly different (live-birth OR 1.07, 95% CI 0.37, 3.11, P = .89), although an increased number of fetal losses was observed in the heparin/aspirin arm (OR 3.83, 95% CI 0.74, 19.9, P = .11).

	DISCUSSION

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This study demonstrates no significant difference between the two treatment arms whether on intention-to-treat analysis or adherent group analysis. The combination of low molecular weight heparin with low-dose aspirin in the prevention of miscarriage in women with antiphospholipid syndrome and recurrent pregnancy loss has not been clearly demonstrated to be superior to low-dose aspirin alone. Although the study number was small, the sample size represents the largest recruitment population to date. The prospective fetal death rate in the groups varied between 10% (four of 38) in group A and 16% (eight of 48) in group B. The higher fetal loss rate with heparin is similar to that previously reported,^6,7 where a 20% loss rate was found. The success rate for aspirin alone is compatible with reported retrospective studies.^8,9 A recent and smaller randomized, controlled trial has shown that aspirin alone is associated with an 80% success rate but interestingly reported a significant placebo effect.¹⁰ As a result, the practice of routine heparin use during pregnancy with antiphospholipid syndrome becomes more questionable as the fetal survival rate is similar for all treatment arms. Furthermore, no case of de novo maternal thrombosis has been reported from a prospective randomized trial.

Previously, there has been inconsistency in the diagnosis of antiphospholipid syndrome, both clinically and in relation to laboratory parameters. Persistent positivity in tests for lupus anticoagulant and/or anticardiolipin antibody using carefully validated techniques in a subject with the appropriate clinical history is considered to be necessary. In relation to pregnancy complications, the clinical criteria are:

• three or more consecutive spontaneous losses before the 10th week of gestation
  
• one or more premature births before 34 weeks for severe preeclampsia or impaired fetal growth
  
• one or more unexplained intrauterine deaths beyond 10 weeks’ gestation¹¹
  

These criteria were adhered to during recruitment. In addition to prepregnancy testing, recent evidence suggests that a first-trimester test is beneficial in excluding antiphospholipid syndrome, as antiphospholipid syndrome activity is most prominent within the first 12 weeks of pregnancy.¹²

The association of recurrent pregnancy loss with antiphospholipid syndrome has become increasingly accepted since the first description of apparently successful intervention in 1983.^13,14 Although our results are in apparent conflict with some other studies, this may be due to superior study design with less potential for bias. Previously reported treatment trials have lacked formal randomization,⁶ defined miscarriage without evidence of past fetal death,^15,16 and included patients without antiphospholipid syndrome.¹⁷ It is noteworthy that, in the absence of antiphospholipid syndrome, the live-birth rate for a prospectively observed group with idiopathic recurrent miscarriage is 75%, with a 20% embryo loss and 5% fetal loss rate.¹⁸ We used low molecular weight heparin, in contrast to the study of Rai et al,⁷ where unfractionated heparin was reported to provide an 80% success rate compared with a 40% success with aspirin alone. Although there are pharmacokinetic differences between heparin preparations, this is unlikely to explain the different outcomes as we found a relatively high success rate in women treated with aspirin alone. Patient preference for aspirin alone in women with fetal loss history (five of 13) compared with the heparin preference group (one of 11) serves to highlight the state of patient equipoise for randomization without deleterious effect.

Historically, the proposed pathogenesis has focused on placental thrombosis and end-stage infarction, associated with the known procoagulant state, causing fetal demise. Early in vitro studies showed decreased prostacyclin production from vascular endothelial cells incubated with affected patient serum.¹⁹ Recent work casts doubt on a thrombotic pathogenesis of pregnancy failure in antiphospholipid syndrome by suggesting direct inhibition of trophoblast cell proliferation.³ The common appearance of sudden fetal death with antiphospholipid syndrome especially between 12 and 24 weeks has been considered to result from interference with spiral artery remodeling during secondary trophoblast invasion in the second trimester. If treatment intervention is to improve the established excess fetal death rate with antiphospholipid syndrome, further avenues of research need to be explored to elucidate a clearer pathogenesis. Whether aspirin can have a beneficial effect on these processes is not known.

In conclusion, in a randomized, controlled trial of women with pregnancy failure and antiphospholipid antibodies, we have demonstrated a high rate of success using low-dose aspirin, with no apparent benefit achieved through addition of low molecular heparin. Our data suggest that first-line treatment in women with antiphospholipid syndrome and recurrent pregnancy failure should be with low-dose aspirin. Whether addition of heparin may be effective in the minority of women in whom aspirin alone is ineffective remains to be determined.

	Footnotes

 
The authors wish to thank LUPUS UK and NHS R&D (NWEST) for grant support and the following people (in alphabetical order) who helped with the study: Leanne Bricker, Caron Brookfield, Claire Conlon, Craig Cowan, Paolo Dey, Andrew Drakeley, Ann-Maria Hughes, Bob Malia, Kathryn Moore, James Neilson, and Joanne Topping.

PII S0029-7844(02)02165-8

Received December 28, 2001. Received in revised form March 7, 2002. Accepted March 14, 2002.

	REFERENCES

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3. Chamley LW, Duncalf AM, Mitchell MD, Johnson PM. Action of anticardiolipin antibodies to beta-2 glycoprotein-1 on trophoblast proliferation as a mechanism for fetal death. Lancet 1998;352:1037–8.[Medline]

4. Ruiz-Irastorza G, Khamashta MA, Castellino G, Hughes GRV. Systemic lupus erythematosus. Lancet 2001;357: 1027–32.[Medline]

5. Machin SJ, Giddings JC, Greaves M. Guidelines on testing for lupus anticoagulant. J Clin Pathol 1991;44:885–9.[Free Full Text]

6. Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin plus heparin in pregnant women with recurring miscarriage associated with antiphospholipid antibodies. BMJ 1997;314:253–7.[Abstract/Free Full Text]

7. Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss: Treatment with heparin and low dose aspirin is superior to low dose aspirin alone. Am J Obstet Gynecol 1996;174:1584–9.[Medline]

8. Granger K, Farquharson RG. Obstetric outcome in antiphospholipid syndrome. Lupus 1997;6:509–13.[Abstract/Free Full Text]

9. Silver RK, Macgregor SM, Sholl JS, Hobart JM, Neerhof MG, Ragin A. Comparative trial of prednisone plus aspirin versus aspirin alone in the treatment of ACA positive obstetric patients. Am J Obstet Gynecol 1993;169:1411–7.[Medline]

10. Pattison NS, Chamley LW, Birdsall M, Zanderigo AM, Liddell HS, McDougall J. Does aspirin have a role in improving pregnancy outcome for women with antiphospholipid syndrome? A randomised controlled trial. Am J Obstet Gynecol 2000;183:1008–12.[Medline]

11. Wilson WA, Gharavi AE, Kolke T, Lockshin MD, Branch DW, Plette JC. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: Report of an internal workshop. Arthritis Rheum 1999;42:1309–11.[Medline]

12. Topping J, Quenby S, Farquharson RG, Malia R, Greaves M. Marked variation in antiphospholipid antibodies during pregnancy; relationship to pregnancy outcome. Hum Reprod 1999;14:224–8.[Abstract/Free Full Text]

13. Lubbe W, Palmer SJ, Butler WS, Liggins GC. Fetal survival after prednisone suppression of maternal lupus anticoagulant. Lancet 1983;1:1361–3.[Medline]

14. Cowchock S, Reece E, Balaban D, Branch W, Plouffe L. Repeated fetal losses associated with antiphospholipid syndrome: A collaborative randomised trial comparing prednisone with low dose heparin treatment. Am J Obstet Gynecol 1992;166:1318–23.[Medline]

15. Cowchock S, Reece EA. Do low-risk pregnant women with antiphospholipid antibodies need to be treated? Am J Obstet Gynecol 1997;176:1099–100.[Medline]

16. Silver RK, MacGregor SN, Sholl JS, Hobart JM, Neerhof MG, Ragin A. Comparative trial of prednisone plus aspirin versus aspirin alone in the treatment of anticardiolipin antibody positive obstetric patients. Am J Obstet Gynecol 1993;169:1411–7.

17. Laskin CA, Bombardier C, Hannah ME, Mandel FP, Ritchie JW, Farewell V, et al. Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. N Engl J Med 1997;337:148–53.[Abstract/Free Full Text]

18. Brigham S, Conlon C, Farquharson RG. A longitudinal study of pregnancy outcome following idiopathic recurring miscarriage. Hum Reprod 1999;14:2868–71.[Abstract/Free Full Text]

19. Carreras LO, Machin SJ, Deman R. Arterial thrombosis, intrauterine death and lupus anticoagulant detection of immunoglobulin interfering with prostacyclin production. Lancet 1981;1:244–6.[Medline]

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This Article Abstract Full Text (PDF) Erratum (v100,p1361) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Farquharson, R. G. Articles by Greaves, M. Search for Related Content PubMed PubMed Citation Articles by Farquharson, R. G. Articles by Greaves, M.