Chronotherapy with low-dose aspirin for prevention of complications in pregnancy

Preeclampsia and gestational hypertension are major contributors to perinatal morbidity and mortality. Several studies aimed to test the effects of low-dose aspirin (ASA) in the prevention of preeclampsia concluded that the beneficial effects of such treatment outweigh adverse ones. Such benefits have not been fully corroborated by larger randomized trials usually carried out in low-risk women, testing a dose of 60 mg/d ASA presumably ingested in the morning, and including women randomized as late as at 26-32 wks of gestation. The authors conducted a prospective, randomized, double-blind, placebo-controlled, chronotherapy trial on 350 high-risk pregnant women (183 nulliparous), 30.7 ± 5.3 (mean ± SD) yrs of age, and 13.5 ± 1.4 wks of gestation at the time of recruitment. Women were randomly assigned to one of six groups, defined according to treatment (placebo or ASA, 100 mg/d) and time of treatment: upon awakening, 8 h after awakening, or at bedtime. Intervention started at 12-16 wks of gestation and continued until delivery. Blood pressure (BP) was measured by ambulatory monitoring (ABPM) for 48-h at baseline, every 4 wks until the 7th month of gestation, every 2 wks thereafter until delivery, and at puerperium. The effects of ASA on ambulatory BP were markedly dependent on administration time: there was no effect on BP, compared with placebo, when ASA was ingested upon awakening, but the BP reduction was highly statistically significant when low-dose ASA was ingested 8 h after awakening and, to a greater extent, at bedtime (p < .001). At puerperium, 6-8 wks after discontinuation of treatment, there was no statistically significant difference in 24-h BP means between the groups of women who ingested ASA at different circadian times. Women ingesting low-dose ASA, compared with placebo, evidenced a significantly lower hazard ratio (HR) of serious adverse outcomes, a composite of preeclampsia, preterm delivery, intrauterine growth retardation (IUGR), and stillbirth (.35, 95% confidence interval [CI]: .22-.56; p < .001). The HR of individual outcome variables, i.e., preeclampsia, preterm delivery, IUGR, and gestational hypertension, were also significantly lower with ASA versus placebo (p always < .041). There were small and nonsignificant differences in outcomes between placebo and low-dose ASA ingested upon awakening. These four groups combined showed highly significant greater event rate of serious adverse outcomes than women ingesting ASA either in the evening or at bedtime (HR: .19, 95% CI: .10-.39; p < .001). There was no increased risk of hemorrhage, either before or after delivery, with low-dose ASA relative to placebo (HR: .57, 95% CI: .25-1.33; p = .194). Results indicate that (i) 100 mg/d ASA should be the recommended minimum dose for prevention of complications in pregnancy; (ii) ingestion of low-dose ASA should start at ≤16 wks of gestation; and (iii) low-dose ASA ingested at bedtime, but not upon awakening, significantly regulates ambulatory BP and reduces the incidence of preeclampsia, gestational hypertension, preterm delivery, and IUGR. ABPM evaluation at the first trimester of pregnancy provides sensitive endpoints for identification of women at high risk for preeclampsia who might benefit most from the cost-effective preventive intervention with timed low-dose ASA.