PRETWINSCREEN: Advancing Personalised Prenatal Care for Twin Pregnancies

Below is a summary of key PRETWINSCREEN studies, each addressing the unique complexities and risks of twin pregnancies — one of the most challenging areas in modern perinatal care.

A Global Collaboration for Better Outcomes

The international consortium built a comprehensive, evidence-based framework for managing twin pregnancies. The project followed 649 women and 1168 fetuses of which 24 were born as singletons since their other twin was either lost spontaneously or reduced due to a major genetic or structural abnormality. Women were enrolled from the first trimester of their pregnancy to birth, integrating data from clinical, biochemical, imaging, and genetic markers throughout. This large-scale, prospective, multi-center, multi-ethnic study strengthened the reliability and global applicability of the findings.

Key findings and innovations developed through PRETWINSCREEN include:

1. Advanced risk prediction models for preeclampsia:
   • First Trimester: PRETWINSCREEN developed a novel first-trimester prediction model for preeclampsia in twin pregnancies by analysing levels of cell-free fetal DNA (cffDNA), placental growth factor (PlGF), and maternal blood pressure (MAP). This model achieved a 90% detection rate at a 10% false positive rate, offering early intervention opportunities and improving pregnancy management. Unlike in singleton pregnancies, traditional markers like uterine artery blood flow (UtA-PI) were less effective in twins, emphasizing the need for tailored models. These findings were published in Prenatal Diagnosis.
   • Making third trimester preeclampsia risk assessment in twin pregnancy accessible: Recognising the need for cost-effective diagnostics in resource-limited settings, the project developed a simplified third-trimester biochemical screening method for preeclampsia using just two biomarkers (sFLT-1 and PlGF). This approach is particularly beneficial for rural clinics and public health systems, ensuring wider access to prenatal risk assessment. This method is published in Fetal Diagnosis and Therapy (2025).
   • A comprehensive three trimester model of preeclampsia prediction in twin pregnancies: Using machine learning, the PRETWINSCREEN consortium developed a comprehensive preeclampsia prediction model that incorporates data from all three trimesters. The study demonstrated that longitudinal testing improves predictive accuracy and revealed that having blood type B may be an additional risk factor in twin pregnancies. It also highlighted the need for tailored algorithms when predicting term versus preterm preeclampsia. Notably, the model enables clinicians to monitor the effectiveness of preventive treatments such as aspirin, supporting more personalised care. The results were presented at the 22^nd Congress of Fetal Medicine in Prague (2025) and have been submitted for publication.
2. Broader contributions to clinical practice and public health:
   • Twin-specific growth charts: The project challenged the longstanding assumption that it is normal for twins to be smaller than singletons. By analysing growth trajectories, PRETWINSCREEN showed that healthy twin growth closely matches that of singletons. These findings, recently published in Obstetrics and Gynecology Research, led to the development of new twin-specific growth charts to help clinicians more accurately identify and manage true growth restrictions in twins.
   • Early detection of fetal structural malformations: PRETWINSCREEN implemented a structured screening protocol based on anatomical ultrasound scans performed during all three trimesters, specifically adapted for twin pregnancies. Results from this large, multi-center study showed that over 80% of fetal malformations could be detected during the first and second trimesters, with more than 40% identified as early as the first trimester. The third trimester added further value by revealing developmental concerns relevant for delivery planning and postnatal newborn development monitoring. This approach allowed for improved prenatal counseling, earlier medical intervention, and better planning for delivery and neonatal care. Importantly, a cost-benefit model demonstrated that implementing this protocol would add only about 2 NIS (~0.5 €) per pregnancy in Israel, underscoring its affordability and potential for integration into standard prenatal care, thus leading to a proposal for changing the protocol for anatomical scans in twin pregnancies in Israel and a publication of the proposal for fetal structural anomalies evaluation across all three trimesters in twin pregnancies in the Archives of Gynecology and Obstetrics.
   • Enhanced Non-Invasive Prenatal Screening (NIPS): PRETWINSCREEN demonstrated that combining first-trimester ultrasound with cell-free fetal DNA (cffDNA) testing significantly improves early fetal gender identification and the detection of X-linked disorders in twin pregnancies. This integrated approach enables more accurate genetic counseling and earlier, better-informed decision-making for families and healthcare providers. The findings were published in BMC Pregnancy and Childbirth (2023), based on a prospective study of twin pregnancies.
   • Public health impact during COVID-19 pandemic: The project was one of the first to demonstrate that pre-pregnancy COVID-19 vaccination provided stronger immunity and better protection against complications in twin pregnancies. These findings, published in Scientific Reports, directly supported updates to public health recommendations and helped shape clinical guidance on optimal maternal vaccination timing.