Elsevier

The Lancet

Volume 369, Issue 9575, 26 May–1 June 2007, Pages 1791-1798
The Lancet

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Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data

https://doi.org/10.1016/S0140-6736(07)60712-0Get rights and content

Summary

Background

Pre-eclampsia is a major cause of mortality and morbidity during pregnancy and childbirth. Antiplatelet agents, especially low-dose aspirin, might prevent or delay pre-eclampsia, and thereby improve outcome. Our aim was to assess the use of antiplatelet agents for the primary prevention of pre-eclampsia, and to explore which women are likely to benefit most.

Methods

We did a meta-analysis of individual patient data from 32 217 women, and their 32 819 babies, recruited to 31 randomised trials of pre-eclampsia primary prevention.

Findings

For women assigned to receive antiplatelet agents rather than control, the relative risk of developing pre-eclampsia was 0·90 (95% CI 0·84–0·97), of delivering before 34 weeks was 0·90 (0·83–0·98), and of having a pregnancy with a serious adverse outcome was 0·90 (0·85–0·96). Antiplatelet agents had no significant effect on the risk of death of the fetus or baby, having a small for gestational age infant, or bleeding events for either the women or their babies. No particular subgroup of women was substantially more or less likely to benefit from antiplatelet agents than any other.

Interpretation

Antiplatelet agents during pregnancy are associated with moderate but consistent reductions in the relative risk of pre-eclampsia, of birth before 34 weeks' gestation, and of having a pregnancy with a serious adverse outcome.

Introduction

Pre-eclampsia is a multisystem disorder of pregnancy that is usually associated with hypertension and proteinuria. The condition complicates 2–8% of pregnancies,1 and can lead to liver and renal problems, convulsions (eclampsia), and abnormalities of the clotting system. Since the condition adversely affects the placenta, risks for the baby include poor intrauterine growth and premature birth. Worldwide, 10–15% of the half million maternal deaths that occur every year are associated with hypertensive disorders of pregnancy, mainly pre-eclampsia and eclampsia;2 99% of these occur in low-resource countries.3, 4

The cause of pre-eclampsia remains unclear. Nevertheless, disordered trophoblast invasion of the maternal spiral arteries in early pregnancy is known to lead to underperfusion of the placenta and, ultimately, placental ischaemia and infarction.5 The resultant placental damage is thought to lead to activation of platelets and the clotting system6, 7 and to an imbalance between prostacyclin, a vasodilator, and thromboxane, a vasoconstrictor and stimulant of platelet aggregation.8, 9 The hypothesis that antiplatelet agents might prevent or delay pre-eclampsia has been widely tested in randomised trials. The optimism following early trials was later dashed by the results of larger studies.10, 11, 12, 13, 14 Although systematic reviews of aggregate data show modest reductions in the relative risk of pre-eclampsia, preterm birth, and baby death associated with antiplatelet agent use,15 controversy remains.16, 17

Recent enthusiasm that antioxidants—particularly the combination of vitamins C and E—might prevent pre-eclampsia has been dampened, because once again the promising results of a small trial were not supported by subsequent larger studies.18 Although results of further trials are awaited, it now seems unlikely that antioxidants will offer major benefit for women at risk of pre-eclampsia. Thus, better understanding of the effects of antiplatelet agents currently offers the best potential for improving outcomes for women at risk of pre-eclampsia. The PARIS (Perinatal Antiplatelet Review of International Studies) Collaboration was formed to do a systematic review and meta-analysis based on individual patient data to assess the use of antiplatelet agents for the primary prevention of pre-eclampsia and to explore which women are most likely to benefit from such treatment.19

Section snippets

Search strategy and selection criteria

We searched the comprehensive register of trials developed and maintained by the Cochrane Pregnancy and Childbirth Review Group. Details of how this register is maintained are available elsewhere,20 but it involves extensive searching of bibliographic databases such as Medline, the database of randomised controlled trials in the Cochrane Library, and searching relevant journals by hand. PARIS trialists were also asked if they knew of any further studies. The search was last updated in December,

Results

115 trials were identified as potentially eligible for our review. Of these, 50 were ineligible, for several reasons, including an absence of a comparison group or because they recruited women with established pre-eclampsia only. Two further trials were excluded from the analysis after data collection because they were found to have used quasirandom methods of treatment allocation. A full list of ineligible trials is available on request. Thus, 63 trials (with 38 026 women) were eligible for

Discussion

Our results show that antiplatelet agents produce moderate but consistent reductions in the relative risk of pre-eclampsia, preterm birth before 34 weeks' gestation, and having a pregnancy with serious adverse outcome. There is no clear evidence that these agents are any more or less effective in reducing the relative risk for any particular subgroup of women. The effect of antiplatelet agents on pre-eclampsia seen here was much the same as that in the largest individual trial (7974 primary

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