Abstract
INTRODUCTION: Pre-eclampsia (PEC) is a morbid and potentially lethal complication of pregnancy and is more common in women with risk factors such as hypertension, diabetes, autoimmune disease, kidney disease or multifetal pregnancies. Low dose aspirin (ASA) is currently the only prophylactic therapy known to decrease PEC in this patient population. However, currently, there is no prospective literature comparing various low-dose ASA formulations in the risk reduction of PEC. In the USA, the currently available low-dose ASA is over-the-counter and found in 81 mg tablets. Therefore, when clinicians initiate low-dose ASA therapy, they may prescribe one or two tablets of 81 mg per day without comparative evidence to guide their decision. Our objective is to prospectively compare pregnant patients on 81 mg vs 162 mg of ASA and determine a possible dose response in the prevention of PEC. METHODS AND ANALYSIS: We designed a pragmatic phase 3 prospective randomised open label blinded-end point clinical trial with parallel assignment between two groups of pregnant people at high risk for PEC, as defined by the US Preventive Services Task Force and American College of Obstetricians and Gynecologists (ACOG). The primary outcome is the incidence of preterm (<37 weeks' gestation) PEC and PEC with severe features. Secondary outcomes include adherence to therapy, maternal and fetal complications of PEC, and time-to-event development of PEC across the two treatment groups. Participants are recruited from a tertiary care academic institution and its affiliated community hospital and clinics if they present for prenatal care at <16 weeks' gestation. Women are randomised and accordingly instructed to either take one or two tablets of 81 mg ASA daily. Participants are followed from recruitment until 6 weeks postpartum, with adherence questionnaires collected at 18-22 weeks, 24-28 weeks and 34-38 weeks gestation via a Simple Medication Adherence Questionnaire. After the first 100 pregnancies are completed, a prespecified interim analysis is performed to assess feasibility, tailor power calculations, and ensure safety. The second stage comprises the continuation of recruitment and randomisation to the accrual ceiling as determined by the first stage. Analysis will be completed in an intention-to-treat manner. ETHICS AND DISSEMINATION: Our research protocol and safety monitoring protocol have been approved by the Weill Cornell Medicine institutional review board (IRB) and the Office of Human Research Protection. Evaluation for adverse events will be monitored throughout the study period. Adverse events will be assessed at each study visit. TRIAL REGISTRATION NUMBER: NCT04070573.