Institute of Health Research, University of Exeter, Exeter, United Kingdom.
Harris Birthright Research Centre for Fetal Medicine, King's College, London, United Kingdom.
Am J Obstet Gynecol. 2019 Jun;220(6):580.e1-580.e6. doi: 10.1016/j.ajog.2019.02.034. Epub 2019 Feb 21.
In the Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention trial, risks of preterm preeclampsia were obtained from the competing risk model. Consenting women with risks of greater than 1 in 100 were randomized to treatment with aspirin or placebo. The trial showed strong evidence of an effect (odds ratio, 0.38, 95% confidence interval, 0.20-0.74) on the incidence of preterm preeclampsia, which was the primary outcome of Aspirin for Evidence-Based Preeclampsia Prevention. There was a small and insignificant effect on the incidence of term preeclampsia, which was a secondary outcomes (odds ratio, 0.95, 95% confidence interval, 0.64-1.39). These differential effects on term and preterm preeclampsia could reflect a mechanism in which the action of aspirin is to delay the delivery with preeclampsia, thereby converting what would be, without treatment, preterm preeclampsia to term preeclampsia.
The objective of the study was to examine the hypothesis that the effect of aspirin is to delay the time of delivery in women who have preeclampsia.
This was an unplanned exploratory analysis of data from the Aspirin for Evidence-Based Preeclampsia Prevention trial. The delay hypothesis predicts that in groups for which preterm preeclampsia, without aspirin, were infrequent relative to term preeclampsia, a reduction in term preeclampsia would be expected because few cases of preterm preeclampsia would be converted to term preeclampsia. In contrast, in groups for which preterm preeclampsia were frequent relative to term preeclampsia, the conversion of preterm preeclampsia to term preeclampsia by aspirin would reduce or even reverse any effect on the incidence term preeclampsia. This is examined using the Aspirin for Evidence-Based Preeclampsia Prevention trial data by analysis of the effect of aspirin on the incidence of term preeclampsia stratified according to the risk of preterm preeclampsia at randomization. Given that women were included in Aspirin for Evidence-Based Preeclampsia Prevention with risks of preterm preeclampsia >1 in 100, a risk cutoff 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 Aspirin for Evidence-Based Preeclampsia Prevention trial data and the consistency of the predictions from this model with the observed incidence was demonstrated.
In the lower-risk group (<1 in 50), there was a reduction in the incidence of term preeclampsia (odds ratio, 0.62, 95% confidence interval, 0.29-1.30). In contrast, in the higher risk group (≥1 in 50) there was a small increase in the incidence of term- preeclampsia (odds ratio 1.11, 95% confidence interval, 0.71- .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 preeclampsia by an estimated 4.4 weeks (95% confidence interval, 1.4-7.1 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% confidence interval, 0.021-0.40 weeks) for each week of gestation so that at 40 weeks, the estimated delay was by 0.8 weeks (95% confidence interval, -0.03 to 1.7 weeks).
The Aspirin for Evidence-Based Preeclampsia Prevention trial data are consistent with the hypothesis that aspirin delays the gestational age at delivery with preeclampsia.
在联合多标志物筛查和随机患者阿司匹林治疗证据预防子痫前期试验中，早产子痫前期的风险是从竞争风险模型中获得的。风险大于 1/100 的有意愿的妇女被随机分配接受阿司匹林或安慰剂治疗。试验表明，阿司匹林对早产子痫前期的发生率有很强的影响（比值比，0.38，95%置信区间，0.20-0.74），这是证据预防子痫前期阿司匹林的主要结局。对足月子痫前期的发生率有较小且无统计学意义的影响，这是次要结局之一（比值比，0.95，95%置信区间，0.64-1.39）。这些对足月和早产子痫前期的不同影响可能反映了一种机制，即阿司匹林的作用是延迟子痫前期的分娩时间，从而将未经治疗的早产子痫前期转化为足月子痫前期。
本研究旨在检验阿司匹林的作用是延迟子痫前期妇女分娩时间的假设。
这是对证据预防子痫前期阿司匹林试验数据的一项计划外探索性分析。延迟假设预测，如果没有阿司匹林，早产子痫前期在各组中相对足月子痫前期不常见，则由于早产子痫前期病例很少转化为足月子痫前期，预计会减少足月子痫前期的发生。相比之下，如果早产子痫前期在各组中相对足月子痫前期常见，则阿司匹林将早产子痫前期转化为足月子痫前期的情况会减少甚至逆转阿司匹林对足月子痫前期发生率的影响。这是通过根据随机分组时早产子痫前期的风险对证据预防子痫前期阿司匹林试验数据进行分析来检验的，将阿司匹林对足月子痫前期发生率的影响分层。鉴于有意愿的妇女被纳入证据预防子痫前期阿司匹林试验，其早产子痫前期的风险大于 1/100，因此使用风险截止值 1/50 来定义高风险和低风险组。拟合了一个模型，该模型假设阿司匹林的作用是延迟子痫前期的分娩孕周，并用该模型对证据预防子痫前期阿司匹林试验数据进行拟合，并证明了该模型预测与观察到的发病率之间的一致性。
在低风险组（<1/50），足月子痫前期的发生率降低（比值比，0.62，95%置信区间，0.29-1.30）。相比之下，在高风险组（≥1/50），足月子痫前期的发生率略有增加（比值比 1.11，95%置信区间，0.71-0.75）。尽管这些效果没有达到统计学意义，但它们与延迟假设一致。在阿司匹林相关的延迟假设框架内，阿司匹林将子痫前期的分娩孕周延迟了估计 4.4 周（95%置信区间，1.4-7.1 周），对于那些在安慰剂组中会在 24 周分娩的妇女，而随着妊娠周数的增加，预计的延迟减少了 0.23 周（95%置信区间，0.021-0.40 周），因此在 40 周时，预计的延迟为 0.8 周（95%置信区间，-0.03 至 1.7 周）。
证据预防子痫前期阿司匹林试验的数据与阿司匹林延迟子痫前期分娩时间的假设一致。
