Rationale
Preeclampsia remains a leading cause of maternal and neonatal complications despite established preventive strategies. Evidence from randomised trials and implementation studies indicates that early identification of women at increased risk, followed by prophylactic low-dose acetylsalicylic acid, can substantially reduce the occurrence of preterm disease. However, risk assessment based solely on maternal characteristics has shown limited performance in routine care settings, resulting in missed opportunities for prevention.
Multivariable first-trimester risk assessment models that combine maternal characteristics with physiological and biochemical markers have demonstrated improved predictive accuracy across diverse populations. The Fetal Medicine Foundation (FMF) model integrates maternal history, mean arterial pressure, uterine artery Doppler indices, placental growth factor, and pregnancy-associated plasma protein-A into an individualized risk estimate. Danish evaluation studies have confirmed the model's predictive performance and feasibility within existing prenatal screening infrastructure, supporting progression from validation to national implementation.
The present study evaluates the real-world introduction of structured first-trimester preeclampsia risk assessment within a healthcare system characterized by universal antenatal care coverage, established first-trimester screening pathways, and comprehensive national registries. The study is designed to generate implementation evidence addressing effectiveness, feasibility, safety, workflow integration, and population reach.
Implementation strategy
The study uses a phased national implementation approach in which maternity hospitals transition from existing practice to structured first-trimester risk assessment according to a predefined sequence. The staggered rollout allows continuous evaluation while maintaining clinical service delivery and minimizing disruption to established prenatal pathways.
Hospitals are organized into clusters based on associated clinical biochemistry departments. Each cluster initiates screening at a different time point, enabling comparison of outcomes across baseline and implementation periods while accounting for temporal trends. This design supports causal inference in the absence of a concurrent randomized control group and reflects pragmatic conditions typical of large-scale health service changes.
The screening pathway is embedded within the existing first-trimester assessment workflow. Measurements required for risk calculation are obtained during routine visits, and laboratory analyses are performed within current biochemistry infrastructure. Risk calculation is conducted using software platforms already deployed in fetal medicine units nationwide, facilitating standardization and reducing additional training requirements.
Clinical pathway integration
Risk assessment occurs alongside established prenatal screening procedures. Information on maternal characteristics and medical history is collected using standardized forms. Physiological measurements and ultrasound parameters are obtained during routine scanning, and biochemical markers are analysed from blood samples collected within the first trimester window.
Women identified as having increased risk are managed according to clinical guidance for prophylactic therapy and counselling. Integration with routine care ensures that screening results inform clinical decision-making without creating parallel care pathways.
The implementation also evaluates alignment with aneuploidy screening workflows, including timing of blood sampling and data entry processes. Adjustments to sampling windows and analytical procedures are monitored to ensure that introduction of additional biomarkers does not negatively affect existing screening performance.
Data sources and data flow
The study leverages multiple complementary data sources:
Local fetal medicine databases containing screening measurements and calculated risk estimates
Laboratory information systems providing biochemical marker values and quality control metrics
National prescription registries enabling assessment of prophylactic treatment uptake
National health registers capturing pregnancy outcomes, maternal diagnoses, neonatal outcomes, and healthcare utilization
Data linkage is enabled through unique personal identifiers, allowing longitudinal follow-up across pregnancy, delivery, and postnatal periods. Data extraction procedures are standardized across sites, and harmonization protocols are applied before analysis.
Quality assurance includes periodic audits of key variables, validation of risk calculations, and cross-checking between local databases and registry data. This framework supports consistent data capture across geographically distributed sites.
Analytical framework
The evaluation focuses on population-level changes associated with implementation rather than individual treatment assignment. Analytical models account for time, site, and clustering effects to distinguish intervention-related changes from secular trends.
Interrupted time series methods with multiple baselines provide repeated internal comparisons across sites and time points. Bayesian modelling approaches allow incorporation of uncertainty and flexible modelling of temporal effects. Sensitivity analyses address missing data, model assumptions, and potential external influences on outcomes.
Subgroup analyses explore heterogeneity across maternal characteristics, regional implementation patterns, and adherence to prophylactic therapy. Process indicators are analysed alongside clinical outcomes to understand mechanisms underlying observed effects.
Safety monitoring
Although prophylactic therapy is widely used and considered low risk, systematic surveillance is incorporated to detect rare adverse outcomes. Safety monitoring relies on aggregated registry data, with predefined indicators related to maternal bleeding complications and neonatal outcomes. Monitoring occurs throughout the implementation period to identify potential signals requiring review.
Feasibility and acceptability evaluation
Implementation success depends on operational feasibility and stakeholder engagement. The study therefore evaluates:
Uptake of screening across sites
Timing and completeness of measurements
Integration with routine workflows
Adherence to recommended prophylactic therapy
Feedback from healthcare professionals regarding training, workload, and communication
Acceptability among pregnant women through structured feedback mechanisms
These indicators provide insight into scalability and sustainability of national screening.
Training and standardization
Before site initiation, personnel receive training covering measurement protocols, data entry procedures, counselling approaches, and software use. Certification requirements for ultrasound measurements follow established fetal medicine standards. Ongoing support includes refresher sessions and technical guidance to maintain consistency.
Decision framework
Interim evaluation informs decisions regarding continuation, modification, or expansion of screening. Criteria include trends in clinical outcomes, implementation indicators, and safety signals. Findings will support recommendations to national health authorities regarding long-term integration into routine care.
Generalizability
The study is conducted within a publicly funded healthcare system with standardized prenatal care and comprehensive registries. These characteristics enhance internal validity while also providing a model for other settings with organized screening programs. Replication in external cohorts will support assessment of broader applicability.
Dissemination
Results will be reported through peer-reviewed publications, conference presentations, and stakeholder engagement activities. Findings will inform clinical guidance, health policy, and future research on prevention of hypertensive disorders of pregnancy.
