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aggregate data: more up-to-date information can be included risk of preeclampsia by 10% is probably closer to the truth
than was available at the time of the original trials publication; based on the current evidence.
analyses across studies are standardized; results of previously Our responsibility does not end here. As researchers, we
missing or poorly reported outcomes are incorporated; and must design studies that address the knowledge gaps. The
clinical decisions can be personalized by assessing different PARIS IPD meta-analysis has published a reanalysis of its data
treatment effects for subgroups, ensuring the optimal dose, 10 years after its conception, but the IPD has not been
timing, and delivery method of the interventions can be updated. The hypothesis that an earlier start is benecial and
studied.9 Meher et al7 also reached more statistical powerethey a high dose is better should be tested in trials directly
examined data from 9241 women to derive the RR of pre- comparing an early vs later start. We note with anticipation
eclampsia if aspirin was commenced <16 weeks and data from that the Aspirin for Evidence-based Preeclampsia Prevention
21,429 women to calculate the RR of preeclampsia if aspirin Trial is due to report its ndings soon.12 It is a study where
was started >16 weeks. In contrast, Roberge et al6 included nearly 30,000 women are being screened in the rst trimester
5130 participants who started aspirin 16 weeks and 15,779 for their risk of developing preeclampsia. Around 1700
participants who started aspirin >16 weeks. identied as high risk are then randomized to aspirin or
Apart from this increase in statistical power, the study of placebo. The quality and independence of systematic reviews
Meher et al7 is more protected against publication bias that may can be improved by complying with guidelines such as those
be present in the study by Roberge et al6 (see their funnel plot recommended by the Institutes of Medicine, and by following
[Figure 4, A] and the accompanying statistical analysis6). transparent protocols.13,14 Finally, we appeal to clinicians on
Also, it should be noted that there have been no clinical the ground to contribute to studies as part of their routine
trials that have randomized women to starting aspirin <16 practice. Currently, the costs of trial are in the millions
weeks gestation vs afterwards. Thus, there is no evidence and one of the main drivers is difcult recruitment, a
addressing this question in direct comparisons: both meta- responsibility that rests with all of us.
analyses have examined data generated from clinical trials, In the past decade and a half, the pace of discoveries in the
drawing their conclusions from indirect comparisons. eld of preeclampsia have accelerated and this has led to some
Turning to the possible biological mechanism of action new drug possibilities that could prove effective to treat or
does not really help us make our minds up whether aspirin prevent preeclampsia. The line of proposed new drugs are an
will work better, if started earlier in pregnancy. The enthu- eclectic mixesildenal,15 esomeprazole,16 metformin,17 and
siasts believing aspirin works better if commenced early even pravastatin.18,19 There may be others. Thus, it is possible
might refer to the long-standing belief that aspirin somehow that in coming years a drug will be proven in clinical trials to
facilitates early placental embedding,10 a process that is in fact be clearly better than aspirin at preventing preeclampsia and
poorly understood but is likely to be complete by 16 weeks other major complications. Lets hope soethat could nally
gestation. However, aspirin also increases prostacyclin draw to a close the circular debates over the timing, dose,
(vasodilator) and may also decrease endothelial (blood vessel) and the effectiveness of aspirin. -
dysfunction,11 actions that could make it effective in pre-
venting clinical preeclampsia well >20 weeks gestation.
So here we are in 2017, >23 trials and 30,000 women later, REFERENCES
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