EAGeR Trial - The Effects of Aspirin in Gestation and Reproduction Trial

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The EAGeR trial was a multi-center, block-randomized, double-blind, placebo-controlled trial conducted across four medical centers in the U.S. from 2007 to 2012. A total of 1228 women ages 18-40 years with up to two documented prior miscarriages and who planned to become pregnant again were randomized for this trial, making the EAGeR trial the largest preconception trial of LDA. Each woman was randomly assigned to 81 mg aspirin daily or placebo beginning prior to conception and continued to 36 weeks gestation in women achieving pregnancy. Participants were block randomized by study center and eligibility stratum, defined based on specific eligibility qualifications: 1) original stratum, women with exactly one documented pregnancy loss <20 weeks gestation during the preceding 12 months; and 2) expanded stratum, women not meeting all criteria for the original stratum, and having 1 or 2 prior pregnancy losses of any gestational age at any time in the past. Participants attended two study visits per menstrual cycle for the first two cycles attempting pregnancy and once per cycle thereafter, which included spot urine and blood sample collection. Follow-up ended after six menstrual cycles attempting pregnancy or, in women becoming pregnant, throughout pregnancy. EAGeR recruitment started in June 2007 and ended in July 2011. Since the completion of EAGeR, Dr. Schisterman and the EAGeR team have completed analysis of the primary (live birth) and secondary trial outcomes (pregnancy rates and pregnancy outcomes, including losses), and examined several ancillary study questions. The primary findings of the trial were published in 2014, reporting that daily LDA did not significantly affect live birth (RR 1.10, 95%CI 0.98, 1.22) or pregnancy loss rates overall. However, among the prespecified original stratum (those with a single recent loss, specifically only one prior pregnancy loss <20 weeks gestation in the previous year) live birth rate was higher in the LDA compared with placebo group (62% LDA vs. 53% placebo; RR 1.17, 95%CI 1.01, 1.37). The pathway through which this effect was evident was not an effect of reducing pregnancy loss, but rather through an increased fecundability (i.e., a shorter time to pregnancy) in this group. Similarly, preterm birth was lower in the LDA group of the original stratum (3.8% LDA vs. 9.7% placebo; RR 0.39, 95%CI 0.16, 0.94). These collective findings lend support to the notion that low-dose aspirin could have favorable effects on fecundity as opposed to reducing pregnancy loss risk after pregnancy is diagnosed, but precise factors to indicate which women may receive benefit remained unclear. Secondary outcomes explored from the EAGeR trial included evaluation of adverse events, anovulation, and offspring sex ratio. Multiple other reports were also published or are in-progress examining different etiologic and clinical questions. In addition, another crucial next phase in examining mechanisms impacted by LDA will include the study of placental specimens collected from a subset of term deliveries in the trial. To this end, a pilot study was conducted 2014-2016 to plan use of the frozen specimens. This pilot effort was composed of experiments aimed at determining the effects of storage and collection methods that were unique to this trial to accomplish large scale, clinical tissue collection, on levels of inflammatory and angiogenic analytes. These data will provide important validation information, as well of laboratory processing standard operating procedures, to conduct analyses on the stored EAGeR specimens and compare our work with previously reported data.