Aspirin delays the development of preeclampsia

Abstract

BACKGROUND: In the Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention (ASPRE) trial risks of preterm preeclampsia (PE) were obtained from the competing risk model. Consenting women with risks of greater than 1 in 100 were randomised to treatment with aspirin or placebo. The trial showed strong evidence of an effect (odds ratio 0.38, 95% confidence interval 0.20 to 0.74) on the incidence of preterm-PE, which was the primary outcome of ASPRE. There was a small and insignificant effect on the incidence of term-PE which was one of the secondary outcomes (odds ratio 0.95, 95% CI 0.64 to 1.39). These differential effects on term and preterm-PE could reflect a mechanism in which the action of aspirin is to delay the delivery with PE thereby converting what would, without treatment, be preterm-PE to term-PE. OBJECTIVE: To examine the hypothesis that the effect of aspirin is to delay the time of delivery with PE. STUDY DESIGN: This was an unplanned exploratory analysis of data from the ASPRE trial. The delay hypothesis predicts that in groups for which preterm-PE, without aspirin, were infrequent relative to term-PE, a reduction in term-PE would be expected because few cases of preterm-PE would be converted to term-PE. In contrast, in groups for which preterm-PE were frequent relative to term-PE, the conversion of preterm-PE to term-PE by aspirin would reduce or even reverse any effect on the incidence term-PE. This is examined using the ASPRE trial data by analysis of the effect of aspirin on the incidence of term-PE stratified according to the risk of preterm-PE at randomization. Given that women were included in ASPRE with risks of preterm PE > 1 in 100, a risk cut-off if 1 in 50 was used to define higher risk and lower risk strata. A statistical model in which the effect of aspirin is to delay the gestational age at delivery was fitted to the ASPRE trial data and the consistency of the predictions from this model with the observed incidence was demonstrated. RESULTS: In the lower risk group (<1 in 50), there was a reduction in the incidence of term-PE (odds ratio 0.62, 95% confidence interval 0.29 to 1.30). In contrast, in the higher risk group (≥1 in 50) there was a small increase in the incidence of term-PE (odds ratio 1.11, 95% confidence interval 0.71 to 1.75). Although these effects fail to achieve significance, they are consistent with the delay hypothesis. Within the framework of the aspirin-related delay hypothesis, the effect of aspirin was to delay the gestational age at delivery with PE by an estimated 4.4 weeks (95% CI 1.4 to 7.1 weeks) for those that in the placebo group would be delivered at 24 weeks and the effect decreased by an estimated 0.23 weeks (95% CI 0.021 to 0.40 weeks) for each week of gestation so that at 40+0 weeks the estimated delay was by 0.8 weeks (95% confidence interval -0.03 to 1.7 weeks). CONCLUSIONS: The ASPRE trial data are consistent with the hypothesis that aspirin delays the gestational age at delivery with PE.