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. 1999 Jul 31;319(7205):316.

Low dose aspirin for preventing and treating pre-eclampsia

Author of editorial did not criticise studies’ methodology

J Emeagi 1,2, S Patni 1,2, H M Tikum 1,2, A M Mander 1,2
PMCID: PMC1126945  PMID: 10426756

Editor—In her editorial discussing the value or otherwise of aspirin for preventing and treating pre-eclampsia Duley wonders why the small trials have such different results from the large trials.1 We suggest the following answer.

Evidence based medicine means integrating individual skill with the best available evidence from systematic research. Duley’s conclusions, based on several multicentre studies, seem to rely on the conclusions of these studies without her making criticisms of the methodology used.

Firstly, the timing of the start of treatment with low dose aspirin is important. The studies consistently fail to show the percentage of women who were <16 weeks pregnant, the crucial time when maximum trophoblastic invasion is taking place (table). This issue was raised by de Swiet in Bower’s news article2 and by Beaufilis et al.3

Secondly, the dose of aspirin used in the later large trials is low. A meta-analysis by Leitich et al (not quoted in the editorial) shows that aspirin was more effective at higher doses (100-150 mg/day) than at lower doses (50-80 mg/day).4 It seems that these large studies have looked at the wrong dose of aspirin used at the wrong time of pregnancy.

The editorial’s conclusions are based on trials with flawed methodology. The question of whether aspirin given in early pregnancy in an appropriate dose is effective in preventing pre-eclampsia remains unanswered.

Table.

Studies of low dose aspirin in pregnancy: dose used and gestational age at time treatment was started

Study and year Dose used (mg) Gestational age when treatment started (weeks) % of pregnancies for which treatment was started at:
<16 weeks <20 weeks
CLASP, 19945 60 12-32 Unknown 62
Italian study, 19936 50 16-32 Unknown 49
BLASP, 19987 60 12-32 Unknown 53
ECPPA, 19968 60 12-32 Unknown 4
JLASP, 19989 60 12-32 Unknown 24
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References

  • 1.Duley L. Aspirin for preventing and treating pre-eclampsia. BMJ. 1999;318:751–752. doi: 10.1136/bmj.318.7186.751. . (20 March.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Bower H. Studies reject aspirin for prevention of pre-eclampsia. BMJ. 1998;316:885. [Google Scholar]
  • 3.Beaufils M, Uzan S, Donsimoni R, Colau JC. Prevention of pre-eclampsia by early antiplatelet therapy. Lancet. 1985;1(8443):840–842. doi: 10.1016/s0140-6736(85)92207-x. [DOI] [PubMed] [Google Scholar]
  • 4.Leitich H, Egarter C, Hussein P, Schemoer M. A meta-analysis of low dose aspirin for the prevention of intrauterine growth retardation. Br J Obstet Gynaecol. 1997;104:450–459. doi: 10.1111/j.1471-0528.1997.tb11497.x. [DOI] [PubMed] [Google Scholar]
  • 5.Collaborative Low-dose Aspirin Study in Pregnancy (CLASP) Collaborative Group. A randomised trial of low dose asprin for prevention and treatment of pre-eclampsia among 9364 pregnant women. Lancet. 1994;343:619–629. [PubMed] [Google Scholar]
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BMJ. 1999 Jul 31;319(7205):316.

Author’s reply

Lelia Duley 1

Editor—I agree that conclusions about the role of low dose aspirin during pregnancy should be based on a systematic review. This review should, however, address a well formulated and clinically relevant question. Here the important question is not whether low dose aspirin prevents pre-eclampsia but whether it has worthwhile benefits for the woman or her child, or both.

As I pointed out, aspirin does reduce the risk of pre-eclampsia, by 10-15%, but this is not reflected in any more substantive benefit, such as a reduction in perinatal death or intrauterine growth restriction. Provisional results from a systematic review in preparation for the Cochrane Library support the conclusions in my editorial. This review includes 38 trials involving 30 000 women. The review by Leitich et al was based on 13 trials involving <14 000 women.1-1

If influencing trophoblast invasion was the crucial factor for preventing pre-eclampsia, aspirin would need to be started early in the first trimester, probably before 12 weeks. Although data have largely been reported for women randomised before or after 20 weeks’ gestation, some trend towards a greater effect for women randomised during the first half of pregnancy would be expected if the trophoblast hypothesis was correct.

A higher dose of aspirin may have greater benefits, but the evidence to support this argument is not strong. Fewer than 900 women have been entered into trials evaluating the higher doses. Results of these trials do suggest a greater reduction in the risk of pre-eclampsia, but there is insufficient evidence for any reliable conclusions about the effects on perinatal death or intrauterine growth restriction. Also, reassurance about the safety of aspirin comes from studies in which low dose aspirin (50-60 mg) was started after 12 weeks. This reassurance cannot automatically be extended to include earlier treatment with higher doses.

Many of the questions about low dose aspirin have now been answered, and it is clear that aspirin does not have the kind of widespread benefits that were once hoped for. Nevertheless, as Emeagi et al point out, a few issues remain controversial.

References

  • 1-1.Leitich H, Egarter C, Hussein P, Schemoer M. A meta-analysis of low dose aspirin for the prevention of intrauterine growth retardation. Br J Obstet Gynaecol. 1997;104:450–459. doi: 10.1111/j.1471-0528.1997.tb11497.x. [DOI] [PubMed] [Google Scholar]
BMJ. 1999 Jul 31;319(7205):316.

Trials are needed to determine when treatment should be started

Mark Sullivan 1, Michael de Swiet 1, Murdoch Elder 1

Editor—Duley correctly reports that most large studies of the efficacy of aspirin for preventing and treating pre-eclampsia are disappointing in that aspirin has little beneficial effect.2-1 There may be three main reasons for this.

Firstly, most patients in these trials are recruited in the second and third trimesters of pregnancy. Trophoblast invasion occurs mainly in the first and second trimesters and is most active in the first, and the defects in trophoblast invasion associated with pre-eclampsia are certainly present from about 16 weeks’ gestation. It therefore seems that most patients were recruited after the primary pathology developed, which may explain the limited impact of aspirin.

We have started low dose aspirin in the first trimester and have found that antiplatelet treatment started then has much stronger positive effects than the same treatment started in the second trimester.2-2 Indeed, we found that antiplatelet treatment was of limited benefit in the second group of patients, which is consistent with the results of large trials. There were no differences in history between the groups of patients, so this would not account for the difference in data obtained.

A second consideration is that maternal platelets may “escape” from antiplatelet treatment, such that a given treatment becomes less effective. In the same study we used stepped increases of aspirin (up to 75 mg twice daily), in combination with dipyridamole (from 100 mg three times daily up to 200 mg four times daily) if necessary2-2; this may also have contributed to the good outcomes observed.

Finally, several of the large trials included women at low risk of the disorder, whereas our study concentrated on patients with a high risk of complications of pregnancy. This would also limit the overall efficacy of the treatments used in the trials.

As Duley stated in the editorial, low dose aspirin treatment seems to be safe. The timing and dose of such treatment may make a critical difference in patients at high risk of pre-eclampsia. Appropriate trials are needed to address these questions, as the small studies that generally report positive findings are inadequate for such purposes.

References

  • 2-1.Duley L. Aspirin for preventing and treating pre-eclampsia. BMJ. 1999;318:751–752. doi: 10.1136/bmj.318.7186.751. . (20 March.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2-2.Sullivan MHF, Clark NAC, de Swiet M, Nelson-Piercy C, Elder MG. Titration of anti-platelet treatment in pregnant women at risk of pre-eclampsia. Thromb Haemost. 1998;79:743–746. [PubMed] [Google Scholar]

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