Low dose aspirin in the prevention of recurrent spontaneous preterm labour – the APRIL study: a multicenter randomized placebo controlled trial

Laura Visser, Marjon A. de Boer, Christianne J. M. de Groot, Tobias A. J. Nijman, Marieke A. C. Hemels, Kitty W. M. Bloemenkamp, Judith E. Bosmans, Marjolein Kok, Judith O. van Laar, Marieke Sueters, Hubertina Scheepers, Joris van Drongelen, Maureen T. M. Franssen, J. Marko Sikkema, Hans J. J. Duvekot, Mireille N. Bekker, Joris A. M. van der Post, Christiana Naaktgeboren, Ben W. J. Mol, Martijn A. Oudijk

Preterm birth (birth before 37 weeks of gestation) is a major problem in obstetrics and affects an estimated 15 million pregnancies worldwide annually. A history of previous preterm birth is the strongest risk factor for preterm birth, and recurrent spontaneous preterm birth affects more than 2.5 million pregnancies each year. A recent meta-analysis showed possible benefits of the use of low dose aspirin in the prevention of recurrent spontaneous preterm birth. We will assess the (cost-)effectiveness of low dose aspirin in comparison with placebo in the prevention of recurrent spontaneous preterm birth in a randomized clinical trial. Women with a singleton pregnancy and a history of spontaneous preterm birth in a singleton pregnancy (22-37 weeks of gestation) will be asked to participate in a multicenter, randomized, double blinded, placebo controlled trial. Women will be randomized to low dose aspirin (80 mg once daily) or placebo, initiated from 8 to 16 weeks up to maximal 36 weeks of gestation. The primary outcome measure will be preterm birth, defined as birth at a gestational age (GA) < 37 weeks. Secondary outcomes will be a composite of adverse neonatal outcome and maternal outcomes, including subgroups of prematurity, as well as intrauterine growth restriction (IUGR) and costs from a healthcare perspective. Preterm birth will be analyzed as a group, as well as separately for spontaneous or indicated onset. Analysis will be performed by intention to treat. In total, 406 pregnant women have to be randomized to show a reduction of 35% in preterm birth from 36 to 23%. If aspirin is effective in preventing preterm birth, we expect that there will be cost savings, because of the low costs of aspirin. To evaluate this, a cost-effectiveness analysis will be performed comparing preventive treatment with aspirin with placebo. This trial will provide evidence as to whether or not low dose aspirin is (cost-) effective in reducing recurrence of spontaneous preterm birth. Clinical trial registration number of the Dutch Trial Register: NTR 5675 . EudraCT-registration number: 2015-003220-31.