Empirical use of aspirin to prevent myocardial infarction dates back to 1950.1 It would take another 20 years for Sir John Vane to describe aspirin’s primary mechanism of action, inhibition of cyclooxygenase, for which he shared a Nobel Prize.2 In 1975 aspirin’s inhibitory effect on platelet-induced arterial thrombosis was described by Weiss and associates.3 Later studies showed that this antithrombotic property was mediated by inhibition of the synthesis of platelet thromboxane A2 (TXA2), a potent platelet aggregator and vasoconstrictor.
Drawing on these anti-platelet effects, in 1978 Dr Bob Goodlin and colleagues were the first to report the use of aspirin to prevent preeclampsia.4 They treated a thrombocytopenic patient with a history of recurrent early–onset severe preeclampsia using high doses of aspirin starting at 15 weeks, and reported that she delivered a live-born, although growth-restricted, infant at 34 weeks gestation. Eleven years later, Schiff and colleagues conducted the first randomized, placebo-controlled clinical trial of low-dose aspirin for the prevention of preeclampsia in high-risk women.5 The authors screened 791 high-risk pregnant women with a rollover test at 28 to 29 weeks gestation. Among 65 patients with a positive test, 34 were randomized to a daily dose of 100 mg of aspirin and 31 to placebo. They reported a substantially lower incidence of preeclampsia among aspirin recipients (2.9% vs 22.6%; P = 0.019) and noted that treated patients had decreased ratios of serum TXA2 to prostacyclin (PGI2), a platelet aggregation inhibitor and vasodilator. Several other small studies yielded similar results.6,7
It seemed we were on the cusp of a potential cure for this ancient, though poorly understood, scourge of mothers and babies. However, as so often happens in the era of evidenced-based medicine, subsequent studies yielded marginal or contradictory results, leaving clinicians confused and discouraged.
A brief history of randomized trials of aspirin to prevent preeclampsia
In 1993, the National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units reported the effects of low-dose aspirin on the occurrence of preeclampsia in normotensive nulliparous women.8 Patients were randomized at 13 to 26 weeks to either 60 mg of aspirin per day (n=1485) or placebo (n=1500). The authors noted a modest reduction in the occurrence of preeclampsia in the aspirin group (4.6%) compared with placebo (6.3%) (relative risk [RR] of 0.7; 95% CI: 0.6 to 1.0). Greater relative reductions were observed among patients with initially elevated systolic pressures. However, they observed no significant differences in birth weight, the incidence of fetal growth restriction (FGR) or either maternal or neonatal bleeding episodes, and the occurrence of placental abruption was slightly higher in aspirin recipients (1.3% vs 0.4%).
Subsequently, Subtil and colleagues conducted a large multicenter, randomized, double-blinded placebo-controlled trial of aspirin (100 mg) vs placebo beginning at 14 to 20 weeks among more than over 3000 nulliparous women.9 They found no differences in the incidence of preeclampsia between treated and control patients (1.7% vs 1.6%; RR 1.08; 95% CI: 0.64-1.83). Moreover, no differences were found in the occurrence of hypertension, HELLP (hemolysis, elevated liver enzyme levels, and low platelet levels) syndrome, placental abruption, perinatal deaths, or FGR, and, of concern, mothers receiving aspirin had a significantly higher rate of hemorrhage.
By 2007, more than 32,000 pregnant women at varying risk for preeclampsia had been enrolled in 31 randomized control trials (RCTs) testing the efficacy of various doses of aspirin or other antiplatelet agents (eg, dipyridamole) initiated at differing gestational ages for the prevention of preeclampsia. A meta-analysis of these studies found that antiplatelet agents conferred a modest reduction in preeclampsia (RR 0.90; 95% CI: 0.84-0.97), and preterm births (PTB) before 34 weeks (RR 0.90; 95% CI: 0.83-0.98), but had no effect on stillbirth, FGR, or maternal or fetal bleeding.10 In 2014, after pooling all available studies, many of which were small and of lower quality, the US Preventive Services Task Force (USPSTF) concluded that aspirin was associated with absolute risk reductions in preeclampsia of 2% to 5% (RR 0.76; 95% CI: 0.62 to 0.95), as well as 1% to 5% reductions in FGR (RR 0.80; 95% CI: 0.65 to 0.99), and 2% to 4% reductions in PTB (RR 0.86; 95% CI: 0.76 to 0.98).11 The USPSTF ultimately recommended low-dose aspirin as a preventive medication after 12 weeks gestation in women who had 1 or more high-risk factor(s) and consideration of such treatment in patients with “several” moderate-risk factors (see Table).12 No specific dosage was recommended but use of 81 mg tablets was considered “reasonable” and a wide gestational age range (12 to 28 weeks) was provided for initiating therapy.
However, in view of the mix of negative and positive trials, heterogeneous populations studied, and variable methodological designs employed, controversies were generated about the magnitude of putative benefits, the optimal dose of aspirin to use, and the ideal gestational age at which to start treatment. Answers to these nagging questions were sought in 2 recent studies.