Evaluation of low-dose aspirin in the prevention of recurrent spontaneous preterm labour (the APRIL study): A multicentre, randomised, double-blinded, placebo-controlled trial

Abstract

Background Preterm birth is the leading cause of neonatal morbidity and mortality. The recurrence rate of spontaneous preterm birth is high, and additional preventive measures are required. Our objective was to assess the effectiveness of low-dose aspirin compared to placebo in the prevention of preterm birth in women with a previous spontaneous preterm birth. Methods and findings We performed a parallel multicentre, randomised, double-blinded, placebo-controlled trial (the APRIL study). The study was performed in 8 tertiary and 26 secondary care hospitals in the Netherlands. We included women with a singleton pregnancy and a history of spontaneous preterm birth of a singleton between 22 and 37 weeks. Participants were randomly assigned to aspirin 80 mg daily or placebo initiated between 8 and 16 weeks of gestation and continued until 36 weeks or delivery. Randomisation was computer generated, with allocation concealment by using sequentially numbered medication containers. Participants, their healthcare providers, and researchers were blinded for treatment allocation. The primary outcome was preterm birth grade 1, intraventricular hemorrhage > grade 2, necrotising enterocolitis > stage 1, retinopathy of prematurity, culture proven sepsis, or perinatal death). Analyses were performed by intention to treat. From May 31, 2016 to June 13, 2019, 406 women were randomised to aspirin (n = 204) or placebo (n = 202). A total of 387 women (81.1% of white ethnic origin, mean age 32.5 ± SD 3.8) were included in the final analysis: 194 women were allocated to aspirin and 193 to placebo. Preterm birth Conclusions In this study, we observed that low-dose aspirin did not significantly reduce the preterm birth rate in women with a previous spontaneous preterm birth. However, a modest reduction of preterm birth with aspirin cannot be ruled out. Further research is required to determine a possible beneficial effect of low-dose aspirin for women with a previous spontaneous preterm birth. Trial registration Dutch Trial Register (NL5553, NTR5675) https://www.trialregister.nl/trial/5553. Anadeijda Landman and colleagues assess the effectiveness of low-dose aspirin in the prevention of preterm birth in women with a previous spontaneous preterm birth. Author summary Why was this study done? Complications of preterm birth are the leading cause of neonatal morbidity and mortality worldwide. As spontaneous preterm birth has a multifactorial etiology, different preventive measures, in addition to, e.g., progesterone, may be needed depending on the underlying cause in individual cases. Due to the partially similar pathophysiology of uteroplacental ischemia between spontaneous preterm birth and preeclampsia, it has been suggested that low-dose aspirin may also prevent spontaneous preterm birth. What did the researchers do and find? We performed a multicentre, randomised, double-blinded, placebo-controlled trial including 387 women with a singleton pregnancy and a previous spontaneous preterm birth of a singleton. Women were allocated to aspirin 80 mg or placebo starting between 8 and 16 weeks of gestation and continued until 36 weeks of gestation. The preterm birth rate was slightly lower in the aspirin group (21.2%) as compared to the placebo group (25.4%), especially among women with good adherence to medication (19.2% in the aspirin group versus 24.8% in the placebo group). These differences were not statistically significant. What do these findings mean? The study sample was too small to draw firm conclusions on the effectivity of low-dose aspirin for the prevention of spontaneous preterm birth, and, therefore, we do not recommend implementation of low-dose aspirin for this indication at this time. Further research is necessary to evaluate the possible beneficial effect of low-dose aspirin on the prevention of spontaneous preterm birth.