Maternal cell-free RNA versus combined screening for first-trimester prediction of early-onset preeclampsia: a nested case-control study

@misc{satorresperez2026maternal,
  title = {{Maternal cell-free RNA versus combined screening for first-trimester prediction of early-onset preeclampsia: a nested case-control study}},
  author = {E. Satorres-Perez and N. Castillo-Marco and M. Igual and T. Cordero and I. Munoz-Blat and R. Monfort-Ortiz and B. Marcos-Puig and C. Simon and T. Garrido-Gomez and A. Perales-Marin},
  howpublished = {medRxiv},
  year = {2026},
  month = aug,
  doi = {10.64898/2026.08.28.26361628},
  url = {https://www.medrxiv.org/content/10.64898/2026.08.28.26361628v1},
  note = {CC BY-NC-ND},
}

TY  - UNPB
TI  - Maternal cell-free RNA versus combined screening for first-trimester prediction of early-onset preeclampsia: a nested case-control study
AU  - E. Satorres-Perez
AU  - N. Castillo-Marco
AU  - M. Igual
AU  - T. Cordero
AU  - I. Munoz-Blat
AU  - R. Monfort-Ortiz
AU  - B. Marcos-Puig
AU  - C. Simon
AU  - T. Garrido-Gomez
AU  - A. Perales-Marin
PY  - 2026
DA  - 2026/08/28
PB  - medRxiv
DO  - 10.64898/2026.08.28.26361628
UR  - https://www.medrxiv.org/content/10.64898/2026.08.28.26361628v1
AB  - BackgroundIn Europe, first-trimester combined screening with the Fetal Medicine Foundation (FMF) algorithm identifies women at increased risk of preeclampsia who may benefit from personalized aspirin prophylaxis. However, a substantial proportion of early-onset preeclampsia (EOPE) remains undetected at clinically acceptable specificity.  ObjectiveTo evaluate the first-trimester performance of MaiRa for early-onset preeclampsia (EOPE) risk stratification by benchmarking it against FMF screening in the same women, characterizing discordant patient-level classification profiles and exploring potential implementation strategies.  Study DesignThis secondary case-control analysis was nested within the prospective, multicentre PREMOM cohort [NCT04990141], which enrolled women with singleton pregnancies across 14 tertiary hospitals in Spain. First-trimester MaiRa and FMF risk estimates were evaluated in the same 126 pregnant women, comprising 99 uncomplicated controls and 27 EOPE cases, defined by disease onset before 34 weeks. Discrimination was compared using a stratified paired bootstrap analysis of the areas under the receiver-operating-characteristic curves. Performance was assessed at prespecified clinical thresholds, and detection rates were evaluated at fixed false-positive rates. Universal and contingent MaiRa implementation strategies were also evaluated.  ResultsMaiRa showed greater first-trimester discrimination for EOPE than FMF combined screening (AUC, 0.974 vs 0.900; P=.040) and consistently achieved higher detection rates across fixed false-positive rates. At false-positive rates of 5% and 10%, MaiRa detected 85.2% and 92.6% of EOPE cases, compared with 44.4% and 70.4% for FMF, respectively. Patient-level analysis demonstrated that MaiRa identified 12 of 27 EOPE cases (44.4%) classified as low risk by FMF; these pregnancies generally exhibited less abnormal conventional first-trimester profiles, including fewer maternal risk factors, lower mean arterial pressure and lower uterine artery pulsatility index, yet 8 of 12 (66.7%) subsequently developed severe EOPE. Exploratory implementation analyses showed that universal MaiRa screening achieved the highest EOPE detection, whereas a contingent strategy using FMF for triage and reflex MaiRa testing reduced molecular testing to 35.7% of pregnancies while maintaining 77.8% sensitivity and 97.0% specificity.  ConclusionMaiRa provided greater first-trimester discrimination for EOPE than conventional combined screening and detected additional pregnancies that later developed severe disease despite less abnormal conventional screening profiles. The findings suggest that maternal plasma cfRNA profiling captures biological alterations not fully reflected by combined first-trimester screening and support further prospective evaluation in an independent, unselected obstetric population.  CONDENSATIONO_ST_ABSTweetable StatementC_ST_ABSMaiRa outperformed combined screening for early-onset preeclampsia and identified severe cases with less abnormal conventional risk profiles, supporting the added clinical value of molecular screening.  AJOG at a GlanceA. Why was this study conducted? O_LICombined first-trimester screening identifies women eligible for aspirin prophylaxis but leaves a proportion of early-onset preeclampsia at clinically acceptable specificity. C_LIO_LIIn the same individuals, we evaluated whether MaiRa, a test derived from maternal cell-free RNA, could improve first-trimester prediction and assessed strategies for its clinical implementation. C_LI B. What are the key findings? O_LIAt a fixed 10% false-positive rate, MaiRa detected 92.6% of early-onset preeclampsia cases compared with 70.4% for combined screening. C_LIO_LIIt also identified additional severe cases with less abnormal conventional risk profiles, supporting cfRNA profiling to capture the biological complexity of early-onset preeclampsia. C_LIO_LIUniversal MaiRa screening achieved the highest detection, whereas a contingent strategy reduced molecular testing while maintaining high performance. C_LI C. What does this study add to what is known? O_LIMolecular cfRNA-based risk assessment can identify early-onset preeclampsia cases missed by combined screening and informs translation into clinical pathways. C_LI
ER  -