Incremental predictive value of first-trimester biomarkers beyond maternal and biophysical risk factors for pre-eclampsia: a systematic review of prediction model studies

Abstract

Pre-eclampsia remains associated with substantial maternal and perinatal morbidity, and first-trimester risk assessment may support timely prevention and surveillance. This systematic review evaluated whether biochemical biomarkers measured in the first trimester add predictive performance beyond maternal characteristics and biophysical markers. On 8 September 2026, seven structured searches were performed in an academic literature index without date or language restrictions. Seventy records were identified; after removing 17 duplicates or overlapping versions, 53 unique records were screened, 14 were examined in depth, and 10 primary studies were included in the qualitative synthesis. No meta-analysis was performed because of heterogeneity in model architecture, outcomes, thresholds, metrics, and possible cohort overlap. Included studies were published from 2015 to 2025 and ranged from 226 to 61,174 pregnancies; an overall participant total was not calculated to avoid double counting. Placental growth factor (PlGF), when measured at 11–13+6 weeks and combined with maternal characteristics, mean arterial pressure, and uterine artery pulsatility index, showed the most consistent incremental value for preterm or early-onset pre-eclampsia. First-trimester sFlt-1 did not consistently improve prediction, while PAPP-A added limited information when PlGF was already included. Machine-learning approaches did not clearly outperform the Fetal Medicine Foundation model when the same predictors were used. Overall, the evidence supports multiparametric models including PlGF at 11–13+6 weeks, although confidence is constrained by heterogeneity and limited external validation in part of the evidence base.