Fast track — ArticlesAntiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data
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
References (59)
- et al.
WHO analysis of causes of maternal death: a systematic review
Lancet
(2006) - et al.
Maternal mortality—a neglected tragedy. Where is the M in MCH?
Lancet
(1985) - et al.
Maternal vascular prostacyclin activity in pre-eclampsia
Lancet
(1980) Unraveling the mysteries of preeclampsia
Am J Obstet Gynecol
(2005)- et al.
Antioxidant supplementation in pre-eclampsia
Lancet
(2006) - et al.
Blood-pressure measurement and classification in pregnancy
Lancet
(2001) - et al.
A randomized controlled trial of aspirin in patients with abnormal uterine artery blood flow
Obstet Gynecol
(1996) - et al.
Prevention of fetal growth retardation with low-dose aspirin: findings of the EPREDA trial
Lancet
(1991) - et al.
Low dose acetylsalicylic acid in prevention of pregnancy-induced hypertension and intrauterine growth retardation in women with bilateral uterine artery notches
BJOG
(2002) - et al.
A small randomised trial of low dose aspirin in women at high risk of pre-eclampsia
Eur J Obstet Gynecol Reprod Biol
(2004)
A randomized controlled trial of low-dose aspirin in women at risk from pre-eclampsia
Int J Gynecol Obstet
Aspirin use during early pregnancy and the risk of congenital abnormalities: a population-based case-control study
Am J Obstet Gynecol
The classification and definition of the hypertensive disorders of pregnancy
Am J Obstet Gynecol
Geographic variation in the incidence of hypertension in pregnancy
Am J Obstet Gynecol
The safe motherhood initiative: a call to action
Lancet
Latest advances in understanding pre-eclampsia
Science
Early platelet consumption in pre-eclampsia
BMJ
Flow cytometric detection of activated platelets in pregnant women prior to the development of pre-eclampsia
Thromb Haemost
Differential inhibition of prostacyclin production and platelet aggregation by aspirin
Lancet
Prevention of preeclmapsia with low-dose aspirin in healthy, nulliparous pregnant women
N Engl J Med
CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women
Lancet
A randomised trial of low dose aspirin for primiparae in pregnancy
BJOG
Barbados Low Dose Aspirin Study in Pregnancy (BLASP): a randomised trial for the prevention of pre-eclampsia and its complications
BJOG
Low-dose aspirin to prevent preeclampsia in women at high risk
N Engl J Med
Antiplatelet agents for preventing pre-eclampsia and its complications
Cochrane Database Syst Rev
Antioxidants and the prevention of preeclampsia—unresolved issues
N Engl J Med
Antiplatelet agents for prevention of pre-eclampsia and its consequences: a systematic review and individual patient data meta-analysis
BMC Preg Childbirth
Measuring inconsistency in meta-analyses
BMJ
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