Prevention of Preeclampsia in Denmark: A National Implementation Study

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.

• First trimester screening for preeclampsia (Other): Screening for preeclampsia using maternal factors, Mean arterial pressure, flow in the uterine arteries and Placental Growth Factor

Primary outcomes

• Incidence of Preterm Preeclampsia (<37 Weeks' Gestation) [From first-trimester assessment (11-14 weeks' gestation) until delivery]: Proportion of pregnancies complicated by preeclampsia with delivery before 37+0 weeks' gestation. Preeclampsia will be defined according to the 2018 International Society for the Study of Hypertension in Pregnancy (ISSHP) criteria. Cases will be identified using mandatory ICD-10 diagnosis codes recorded in the Danish National Patient Register and linked with gestational age at delivery from the Danish Medical Birth Register. The outcome will be assessed at the population level comparing baseline and implementation periods.

Secondary outcomes

• Incidence of Early Preeclampsia (<34 Weeks' Gestation) [From first-trimester assessment until delivery.]: Proportion of pregnancies complicated by preeclampsia with delivery before 34+0 weeks' gestation, defined according to ISSHP 2018 criteria and identified through national health register data and gestational age at delivery.
• Incidence of Preterm Delivery (<32, <34, and <37 Weeks' Gestation) [Pregnancy through delivery]: Proportion of pregnancies resulting in delivery before 32+0, 34+0, and 37+0 weeks' gestation, regardless of cause. Gestational age at delivery will be obtained from the Danish Medical Birth Register and compared across baseline and implementation periods.
• Fetal growth restriction and stillbirth [Pregnancy through delivery.]: Occurrence of fetal growth restriction as defined by registry-based diagnosis codes and/or birthweight below gestational age-specific reference standards recorded in the Danish Medical Birth Register and National Patient Register. Stillbirth recorded in the Danish Medical Birth Register according to national definitions and registry coding.
• Neonatal Intensive Care Unit (NICU) Admission [At delivery/birth]: Any admission to a neonatal intensive care unit recorded in national registry data, including duration of admission where available.
• Screening Uptake [Through study completion, an average of 2 years]: Proportion of eligible women undergoing FMF-based first-trimester preeclampsia screening among all women attending first-trimester assessment at participating hospitals, reported by cluster and time period.
• Screen-Positive Rate (High-Risk Classification) [At time of first-trimester screening (11-14 weeks' gestation).]: Proportion of screened women classified as high risk for preterm preeclampsia according to the predefined FMF risk cut-off (target approximately 10%).
• Aspirin Prophylaxis Uptake and Adherence [From screening result until 36+0 weeks' gestation or delivery, whichever occurs first.]: Among women identified as high risk, proportion filling prescriptions for low-dose aspirin (150 mg daily until 36+0 weeks' gestation) as recorded in the Danish National Prescription Registry.
• Number of participants with severe postpartum hemorrhage identified using diagnosis and procedure codes in the Danish National Patient Register [From delivery to discharge from the delivery hospitalization]: Severe postpartum hemorrhage events identified through registry-based diagnosis and procedure codes recorded in the Danish National Patient Register. Unit of Measure: Number of participants
• Number of participants with placental abruption identified using diagnosis codes in the Danish National Patient Register [From 11+0 weeks of gestation to delivery]: Placental abruption events identified through registry-based diagnosis codes recorded in the Danish National Patient Register. Unit of Measure: Number of participants
• Number of maternal or neonatal intracranial hemorrhage events identified using diagnosis codes in the Danish National Patient Register [From 11+0 weeks of gestation to discharge from the birth hospitalization]: Maternal and neonatal intracranial hemorrhage events identified through registry-based diagnosis codes recorded in the Danish National Patient Register. Unit of Measure: Number of participants

Sex: Female, accepts healthy volunteers

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

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• Charlotte Kvist Ekelund, Consultant, ass. prof., MD, Principal investigator, Copenhagen University Hospital, Rigshospitalet