Dose based aspirin pharmacokinetics and pharmacodynamics in pregnancy and association with pregnancy outcomes - PROJECT SUMMARY Background: Aspirin is recommended in high risk pregnancies to reduce the risk of preeclampsia and preterm birth, but up to 20% will still have these adverse outcomes. Recommendations for aspirin dose range from 75mg-162mg daily. Gaps in knowledge regarding pregnancy specific aspirin pharmacology and relationship between aspirin response and pregnancy outcome limit optimal use of aspirin to prevent adverse perinatal outcomes. Objective: 1) Determine platelet inhibition in response to increased dosing of aspirin through gestation and factors impacting aspirin response. 2) Determine aspirin population pharmacokinetics (PK) and PK/PD (pharmacodynamic) relationship through gestation. 3) Determine association between aspirin response and perinatal outcomes. Methods: This is a randomized controlled trial of N=300 high risk singleton pregnancies randomized to either 81mg BID or 162mg daily of aspirin, initiated <16 weeks, and continued until 36 weeks gestation. Participants will have aspirin response assessed at baseline, 2-4 weeks after aspirin initiation and at 28-32 weeks gestation. Aspirin response will be assessed with PFA-100 epinephrine closure time (primary) and urine and serum thromboxane (secondary). A subset (N=50) will be enrolled in a PK study that involves 8-hour study visits in the 1st and 3rd trimester. Expected Results: Analyses for aims will include the two arms of the randomized trial along with a third arm of N=96 high risk singletons who took 81mg aspirin daily (already complete). Aim 1 will compare aspirin response between dosing groups and identify individual covariates that impact aspirin response. Aim 2 will develop a pregnancy model for aspirin PK and PK/PD. Aim 3 will examine the relationship between aspirin response and perinatal outcomes Impact: 1) Novel paradigm in clinical care, adjusting aspirin dosing based not only on the risk for preeclampsia/preterm birth, as currently suggested, but also on anticipated response to aspirin in pregnancy based on individual factors. 2) Inform development of a novel clinical paradigm with use of aspirin response to predict preterm birth, identifying patients who may benefit from dosing adjustment, adjunctive therapies, or additional monitoring. 3) Inform future clinical trials through computational modeling for rationale aspirin dose selection. 4) Inform novel research pathways of antiplatelet therapies in pregnancy through identification of relevant pharmacodynamic markers, individual covariates, and placental mechanisms of action. Ultimately, we will improve the management of high-risk pregnancies, leading to healthier mothers and babies.
