Preterm birth is the leading cause of perinatal mortality worldwide. Surviving neonates are at increased risk for short- and long term morbidities. Approximately 65% of all preterm births has a spontaneous onset following the onset of contractions or rupture of the membranes. Spontaneous preterm birth has a multifactorial etiology and different preventive measures are needed depending on the underlying cause. An increasing body of evidence shows that uteroplacental ischaemia is one of the possible underlying mechanisms, similar to described in preeclampsia. As low-dose aspirin is effective for the prevention of preterm preeclampsia, we hypothesized aspirin could also be effective in the prevention of spontaneous preterm birth.

To evaluate the effect of low-dose aspirin for the prevention of spontaneous preterm birth, we performed a multicentre, double-blind, placebo-controlled, randomised trial in 8 tertiary and 26 secondary care hospitals in the Netherlands within the NVOG Consortium. We recruited women with a singleton pregnancy and a history of spontaneous preterm birth of a singleton between 22 and 37 weeks of gestation. Participants were randomly assigned to daily aspirin (80 mg) or placebo initiated between 8 and 16 weeks of gestation and continued until 36 weeks or delivery. The primary outcome was preterm birth before 37 weeks of gestation. We performed analyses by intention-to-treat. For the primary outcome, we performed a pre-specified sensitivity analysis including women with ≥80% compliance with medication.

A total of 387 women were included in the analysis: 194 women in the aspirin group and 193 in the placebo group. Preterm birth <37 weeks occurred in 41 (21.2%) women in the aspirin group and 49 (25.4%) in the placebo group (Relative Risk (RR) 0.83, 95% CI 0.58-1.20, p=0.32). In women with ≥80% medication adherence, preterm birth occurred in 24 (19.2%) versus 30 (24.8%) women (RR 0.77, 95% CI 0.48-1.25, p=0.29). Furthermore, we found significant effect modification based on the gestational age of the previous spontaneous preterm birth (p=0.042). In women with a previous preterm birth <30 weeks of gestation, preterm birth occurred in 19.2% (15/78) of those allocated to aspirin and 32.6% (28/86) of those allocated to placebo (RR 0.59, 95% CI 0.23-1.02, p=0.059). There were no significant differences between treatment groups among women with a previous preterm birth at 30 weeks of gestation or later. The rate of the composite of poor neonatal outcome was 4.6% (n=9) versus 2.6% (n=5) (RR 1.79, 95% CI 0.61 to 5.25, p=0.29).

We observed trend towards less preterm birth in women with a previous spontaneous preterm birth. Unfortunately, the study was underpowered due to a lower than expected recurrence rate of preterm birth. Interestingly, the significant effect modification we found in the APRIL trial indicated that women with a previous spontaneous preterm birth <30 weeks of gestation may benefit more from aspirin than women with a previous spontaneous preterm birth ≥30 weeks. This might be a reflection of variations in underlying etiologies in different gestational age groups. In conclusion, a small beneficial effect of low-dose aspirin, or an effect in a subset of women with certain underlying etiologies (e.g. uteroplacental insufficiency or inflammation) cannot be excluded. Considering the global burden of preterm birth, even a small reduction would be of great importance.