Determinants of preterm pre-eclampsia following low-dose aspirin prophylaxis: evidence from stepped-wedge cluster randomized trial in Asia.

OBJECTIVES: To identify potential risk factors - among maternal factors, pre-eclampsia (PE)-specific biomarkers and estimated risks derived from the first-trimester Fetal Medicine Foundation (FMF) triple test - that are associated with the subsequent development of preterm PE, and to evaluate predictors of any-onset PE using time-to-event analysis, in high-risk women receiving low-dose aspirin prophylaxis. METHODS: This was a secondary analysis of a multicenter stepped-wedge cluster randomized trial, including 18 maternity/diagnostic units from 10 regions in Asia between August 2019 and February 2022. The study population comprised women with a singleton pregnancy identified as being at high risk for preterm PE (estimated risk ≥ 1:100) according to the first-trimester FMF triple test, who subsequently received low-dose aspirin prophylaxis. A locally estimated scatterplot smoothing (LOESS) curve was applied initially to explore the relationship between the incidence of preterm PE and the estimated risk. Based on the trend observed in the LOESS curve, participants were categorized into five estimated risk groups: 1:2 to 1:5, 1:6 to 1:10, 1:11 to 1:20, 1:21 to 1:50 and 1:51 to 1:100. Logistic and Cox regression analyses were performed to identify independent predictors of preterm PE and to evaluate the risk of delivery with PE, respectively. RESULTS: Among 2919 high-risk pregnant women receiving aspirin prophylaxis, 280 (9.6%) developed PE, including 107 (3.7%) who developed preterm PE. Chronic hypertension (adjusted odds ratio (aOR), 1.835 (95% CI, 1.070-3.146)), mean arterial pressure (MAP) multiples of the median (MoM) > 1.149 (aOR, 2.162 (95% CI, 1.434-3.261)) and higher estimated risk were associated with higher odds of preterm PE. Compared to women with an estimated risk of 1:51 to 1:100, those with estimated risks of 1:2 to 1:5, 1:6 to 1:10 and 1:11 to 1:20 had a 16-fold (aOR, 15.845 (95% CI, 8.166-30.746)), eight-fold (aOR, 7.674 (95% CI, 3.925-15.004)) and three-fold (aOR, 3.454 (95% CI, 1.802-6.622)) higher odds of developing preterm PE, respectively, whereas no significant difference was observed in those with an estimated risk of 1:21 to 1:50 (aOR, 1.343 (95% CI, 0.722-2.499)). On Cox regression analysis, chronic hypertension was associated with a three-fold higher risk of delivering with PE (adjusted hazard ratio (aHR), 2.979 (95% CI, 2.154-4.120)), while MAP MoM > 1.149 increased the risk by 66% (aHR, 1.659 (95% CI, 1.304-2.111)). Compared with the reference group (estimated risk of 1:51 to 1:100), the risk of delivering with PE increased progressively across estimated risk groups, with aHRs of 1.435 (95% CI, 1.051-1.959), 2.408 (95% CI, 1.653-3.508), 4.058 (95% CI, 2.658-6.197) and 7.053 (95% CI, 4.588-10.841) for the 1:21 to 1:50, 1:11 to 1:20, 1:6 to 1:10, and 1:2 to 1:5 estimated risk groups, respectively. CONCLUSIONS: Chronic hypertension, elevated MAP and higher estimated risk are associated with the earlier development of PE in women identified as high risk by the first-trimester FMF triple test, despite low-dose aspirin prophylaxis. Incorporating these factors into the risk stratification framework may improve the detection of residual risk in first-trimester screening and prevention strategies, thereby supporting the development of more effective preventive measures. © 2026 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.