The goal of this clinical study is to learn if a new first-trimester screening program can better find pregnant women who are at high risk of developing preeclampsia and help prevent the condition with early treatment.

Preeclampsia is a pregnancy condition that causes high blood pressure and can affect the mother's organs and the baby's growth. Early detection allows doctors to offer preventive treatment, such as low-dose aspirin, which may lower the risk of serious illness.

The study includes pregnant women with a single pregnancy who attend their routine first-trimester scan at maternity hospitals in Denmark.

The main questions it aims to answer are:

Does the new screening program lower the number of women who develop preterm preeclampsia (preeclampsia before thirty-seven weeks of pregnancy)?

Can the screening program be carried out safely and be acceptable for pregnant women and healthcare professionals?

Researchers will gradually introduce the new screening program across hospitals and compare outcomes before and after the program starts. Women who are found to have a high risk of preeclampsia will be offered preventive treatment with low-dose aspirin.

Participants will:

Receive information about preeclampsia and the screening during their first-trimester visit

Have their blood pressure measured and an ultrasound assessment of blood flow to the uterus during the routine scan

Have routine blood samples analysed to estimate their personal risk of preeclampsia

Be offered daily low-dose aspirin until late pregnancy if they are identified as high risk

Continue standard pregnancy care while researchers follow pregnancy outcomes using national health records

The study will help researchers understand whether this screening approach works in everyday care and whether it should become part of routine pregnancy care in Denmark.

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.

Inclusion Criteria:

• Pregnant women with a viable singleton pregnancy
• Attendance at a routine first-trimester ultrasound scan at 11+0 to 13+6 weeks of gestation at a Danish maternity hospital during the study period
• Valid Danish personal identification number (CPR number) enabling linkage with national health registries

Exclusion Criteria:

• Multiple pregnancy (e.g., twins or higher-order gestations)
• Major fetal anomaly diagnosed before completion of first-trimester screening
• Miscarriage or pregnancy loss diagnosed before completion of first-trimester screening

The study population consists of pregnant women in Denmark who participate in the routine first-trimester screening program for chromosomal abnormalities performed at public maternity hospitals. The cohort is therefore drawn from the general pregnant population receiving antenatal care within the Danish public healthcare system.