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

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The EAGeR Study is a multi-site, prospective, double-blind, block-randomized trial designed to assess the effects of low-dose aspirin on implantation and pregnancy outcomes. In this trial, 1,228 regularly menstruating women aged 18-40 years with a history of one or two miscarriages and attempting pregnancy again were block-randomized to receive either daily low dose aspirin (81mg) or placebo. Treatment or placebo began before conception and continued for 6 months of trying or through week 36 of pregnancy among women who became pregnant. Participants were stratified into two groups: 1) original: women with one documented pregnancy loss at <20 weeks gestation during the past 12 months; and 2) expanded: women with 1-2 prior pregnancy losses, regardless of gestational age of the loss or time since the loss. Women used fertility monitors to time intercourse and used home pregnancy tests to detect pregnancy. Primary outcomes of the EAGeR trial were published in 2014 (Schisterman et al. Lancet 2014), with additional secondary outcomes published in 2015-2017. Overall, daily low-dose aspirin was not found to prevent subsequent pregnancy loss among women with a history of 1-2 prior losses (Schisterman et al. Lancet 2014; Mumford et al. Human Reproduction 2016). More recently, the EAGeR team continued the story of discovery from the EAGeR cohort identifying that low grade inflammation was associated with fewer spontaneous conceptions, which was ameliorated by treatment with daily low dose aspirin. We identified that LDA was most effective in increasing pregnancy and birth rate in women with no or few components of the metabolic syndrome, as opposed to those who may be plagued by greater inflammatory and metabolic burden not amenable to aspirins effects (Nobles et al. Epidemiol 2019). Addressing an important motivation for the EAGeR trial to investigate low-cost interventions to improve reproductive outcomes despite level of resources or insurance coverage, the effectiveness of LDA for increasing live birth rate stratified by markers of socioeconomic status was also investigated. Findings stratified by income and education indicated that LDA increased hCG and clinical pregnancy rates in women with the combination of either low education/low income or high income/high education. However, no effects of LDA were observed among middle education/income women. Different underlying mechanisms may enable a greater effectiveness of daily preconception LDA therapy for women at either end of the socioeconomic spectrum. The specific underpinnings of these differential effects remain unclear but likely involve differences in medication compliance and underlying health and healthcare differences (Agrawala et. al. PLoS One 2019). We also examined multiple potential preconception factors related to fecundability and pregnancy loss in this novel cohort. For example, to better understand the potential neuroendocrine mechanisms by which obese or overweight women are at increased risk for subfertility and infertility, the team examined serum leptin in relation to fecundability. Higher leptin was linked to poorer fecundability, which was nullified after adjustment for BMI but not when adjusted for a different adiposity measure of waist to hip ratio. Although there may not be a singular or simple surrogate for adiposity and its associated milieu, the need to understand the pathways in which leptin and obesity decreases female fecundability remain an important research priority (Plowden et. al. J Endocr Soc 2019). Also, stress being a commonly cited factor in a variety of health complications but with a dearth of available evidence, the team identified that women reporting higher stress also experienced 30% poorer fecundability compared to women reporting the lowest stress level (Schliep et. al. Epidemiol 2019). In relation to dietary factors, fatty acids (FAs) are known to be important for reproductive processes, including steroidogenesis, and pose a potentially modifiable dietary factor that may influence a womans fecundity. In the EAGeR cohort, we observed that monounsaturated fatty acids were associated with increased fecundability, whereas polyunsaturated fatty acids were associated with decreased fecundability. Interestingly, these observed associations only remained significant after false discovery rate adjustment among women with normal BMI, but not those with overweight or obesity. Saturated FA and trans FA were not associated with fecundability. These findings can help inform the potential utility of future interventional studies of diet or dietary supplements (Kim et. al. Epidemiol 2019). Lastly, given the increasing concentrations of circulating folate observed in women living in high resource settings, largely attributable to folate fortification of food and supplementation in prenatal vitamins, the team investigated folate and homocysteine status of women in the EAGeR trial, identifying greater risks of pregnancy loss with great plasma homocysteine concentrations, though only among women with two rather than one previous pregnancy loss. Reassuringly, no relationship were found between serum folate and reproductive outcomes (DeVilbiss et. al. Am J Obstet Gynecol 2019).