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Sir,

It was with great interest that we read the paper written by Villa et al.,[1] which reported the results of a randomised trial included in the PREDO cohort study. Although the trial was underpowered, the results are in agreement with recent meta-analyses establishing that low-dose aspirin initiated in early pregnancy in high-risk women is associated with a reduction of pre-eclampsia, and more particularly with the disease's severe forms.[2]

We were, however, extremely surprised by the comment made by J. Thornton, published with the article.[1] From our perspective, Thornton's comment makes an unfair evaluation of an important study. Careful reading of the study's registration indicates that PREDO's first aim was the prediction of pre-eclampsia and not its prevention. The researchers recruited 942 women, having begun with an objective of 1000. Their second goal was to estimate the effect of low-dose aspirin in women who had risk factors for pre-eclampsia and abnormal uterine artery Doppler. The researchers reported a rate of 13% for severe pre-eclampsia in the placebo group and 5% in the aspirin group. From that pilot study, the sample size necessary to perform a large randomised trial that would combine first-trimester prediction of severe pre-eclampsia and its prevention using low-dose aspirin in high-risk women can be estimated. As far as we know: first-trimester uterine artery Doppler for the prediction of pre-eclampsia is not a standard of care in most developed countries; and the benefits of low-dose aspirin for the prevention of pre-eclampsia was still considered to be limited between 2005 and 2010.[3] Understood in this context, we submit that the ethical aspects of the researchers' study should not be questioned.

Until recently, major meta-analyses showed significant but modest benefits of low-dose aspirin in the prevention of pre-eclampsia.[3, 4] Askie et al.[3] observed a 10% reduction in the risk of pre-eclampsia with low-dose aspirin, but the meta-analysis included very few studies that recruited women ≤16 weeks. The Cochrane review observed an 18% reduction of pre-eclampsia with low-dose aspirin but had a significant heterogeneity (I2 = 46%, < 0.001).[4] Sensitivity and subgroup analyses based on specific disease's characteristics can often explain heterogeneity and discrepancies between trials. In the current case, a growing body of evidence suggests that failure of transformation of uterine spiral arteries is typically associated with the severe and early forms of pre-eclampsia; and both problems can be prevented through the administration of low-dose aspirin initiated in early gestation. Unfortunately, most large randomised trials only evaluated the effect of aspirin given in the second half of the pregnancy.

As recent studies demonstrate that most cases of severe and early-onset pre-eclampsia can be predicted using a combination of biochemical markers and first-trimester Doppler, the debate exists as to whether or not such predictive tests should be included in clinical practice. We believe that the study of Villa et al. sets the table for an adequately powered trial that would aim to demonstrate the benefits of first-trimester screening and adequate prophylactic measures in high-risk women.

References

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  2. References
  • 1
    Villa PM, Kajantie E, Raikkonen K, Pesonon AK, Hämäläinen E, Vainio M, et al. Aspirin in the prevention of pre-eclampsia in high-risk women: a randomised placebo-controlled PREDO trial and a meta-analysis of randomised trials. BJOG 2013;120:6474.
  • 2
    Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol 2010;116:40214.
  • 3
    Askie LM, Duley L, Henderson-Smart DJ, Stewart LA. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet 2007;369:17918.
  • 4
    Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev 2007;(2):CD004659.