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Low-dose aspirin is recommended for pregnant individuals at high-risk of developing preeclampsia, but less is known about those that develop preeclampsia even while using prophylactic aspirin for preeclampsia prevention as the best course of treatment. The objective of this study is to investigate the risk factors with the highest risk of developing preeclampsia among pregnant individuals already using aspirin from high-risk obstetrical centers across five countries. This is a secondary analysis of pregnant individuals from the Folic Acid Clinical Trial (FACT) who were using prophylactic aspirin before 16 weeks gestation. The FACT randomized control trial took place in 70 high risk obstetrical centers in Canada, United Kingdom, Australia, Jamaica, and Argentina between 2011–2015. Participants were included if they had any of the risk factors for preeclampsia: diabetes, chronic hypertension, twin pregnancy, history of preeclampsia, and/or obesity (Body Mass Index ≥35). The outcomes of interest were preeclampsia and preterm preeclampsia (&lt;37 weeks). Log binomial regressions assessed factors significantly associated with any preeclampsia or preterm-preeclampsia (&lt;37 weeks) using adjusted risk ratios (ARR) and 95% confidence intervals (CI). There were 2296 pregnant individuals with complete information on aspirin included in this study. At baseline, all patients were at high risk of preeclampsia and were eligible for aspirin prophylaxis, however, only 660 (28.7%) were taking aspirin. Among the 660 pregnant individuals taking aspirin, 132 (20%) developed preeclampsia and 60 (9.09%) preterm preeclampsia. Among pregnant individuals using aspirin, the risks of preeclampsia were highest for twins (ARR:2.62, 95% CI: 1.68–4.11), history of preeclampsia (ARR: 2.42, 95% CI: 1.74–3.38), and hypertension (ARR:1.92, 95% CI: 1.37–2.69). Similar trends were found for preterm-preeclampsia for twins (ARR:4.10, 95% CI:2.15–7.82), history of preeclampsia (ARR:2.75, 95% CI:1.62–4.67), and hypertension (ARR:2.18, 95% CI:1.28–3.72). No significant differences were found for obesity or diabetes. These findings suggest that individuals with twin pregnancies, a history of preeclampsia, or hypertension may not benefit from aspirin to the same extent as those with other complications such as obesity or diabetes. Careful clinical monitoring for these risks factors is recommended and future research into the effectiveness in these populations would increase our understanding of the current best practice of prophylactic aspirin use to prevent preeclampsia.  TRIAL REGISTRATION:  Current Controlled Trials ISRCTN23781770 and ClinicalTrials.gov NCT01355159

Persisting risk factors for preeclampsia among high-risk pregnancies already using prophylactic aspirin: a multi-country retrospective investigation