Prevention of Preeclampsia in Denmark: A National Implementation Study (PREPRED)

Prevention of Preeclampsia in Denmark (PREPRED): A National Implementation Study

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.

Study Overview

• Status: Recruiting
• Conditions: Preeclampsia (PE)
• Intervention / Treatment: Other: First trimester screening for preeclampsia

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 80000

Contacts and Locations

• Study Contact: Name: Charlotte Kvist Ekelund, Consultant, ass. prof. PhD; Phone Number: +45 28265042; Email: charlotte.kvist.ekelund@regionh.dk
• Study Contact Backup: Name: Iben Riishede, MD, PhD; Phone Number: +45 21701481; Email: ichr0089@regionh.dk

Study Locations

• Denmark
  • Aarhus, Denmark, 8200
    • Recruiting
    • Aarhus University
    • Contact: Iben Riishede, MD, PhD; Phone Number: +45 21701481; Email: ichr0089@regionh.dk
    • Contact: Charlotte Kvist Ekelund, Consultant, Ass. prof., PhD; Phone Number: +45 28265042; Email: charlotte.kvist.ekelund@regionh.dk
    • Principal Investigator: Puk Sandager, Consultant, MD
  • Copenhagen, Denmark, 2100
    • Recruiting
    • University of Copenhagen
    • Contact: Iben Riishede, MD, PhD; Phone Number: +45 21701481; Email: ichr0089@regionh.dk
    • Contact: Charlotte Kvist Ekelund, Consultant, Ass. prof., PhD; Phone Number: +45 28265042; Email: charlotte.kvist.ekelund@regionh.dk
    • Sub-Investigator: Marie Helmbæk, MD
    • Principal Investigator: Charlotte Kvist Ekelund, Consultant, ass. prof., PhD
  • Hillerød, Denmark, 3400
    • Recruiting
    • University of Copenhagen
    • Contact: Iben Riishede, MD, PhD; Phone Number: +45 21701481; Email: ichr0089@regionh.dk
    • Contact: Charlotte Kvist Ekelund, Consultant, Ass. prof., PhD; Phone Number: +45 28265042; Email: charlotte.kvist.ekelund@regionh.dk
    • Principal Investigator: Anne Cathrine Roslev, Consultant

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

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.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
First trimester screening for preeclampsia	Other: First trimester screening for preeclampsia; Screening for preeclampsia using maternal factors, Mean arterial pressure, flow in the uterine arteries and Placental Growth Factor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Preterm Preeclampsia (<37 Weeks' Gestation)	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.	From first-trimester assessment (11-14 weeks' gestation) until delivery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Early Preeclampsia (<34 Weeks' Gestation)	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.	From first-trimester assessment until delivery.
Incidence of Preterm Delivery (<32, <34, and <37 Weeks' Gestation)	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.	Pregnancy through delivery
Fetal growth restriction and stillbirth	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.	Pregnancy through delivery.
Neonatal Intensive Care Unit (NICU) Admission	Any admission to a neonatal intensive care unit recorded in national registry data, including duration of admission where available.	At delivery/birth
Screening Uptake	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.	Through study completion, an average of 2 years
Screen-Positive Rate (High-Risk Classification)	Proportion of screened women classified as high risk for preterm preeclampsia according to the predefined FMF risk cut-off (target approximately 10%).	At time of first-trimester screening (11-14 weeks' gestation).
Aspirin Prophylaxis Uptake and Adherence	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.	From screening result until 36+0 weeks' gestation or delivery, whichever occurs first.
Number of participants with severe postpartum hemorrhage identified using diagnosis and procedure codes in the Danish National Patient Register	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	From delivery to discharge from the delivery hospitalization
Number of participants with placental abruption identified using diagnosis codes in the Danish National Patient Register	Placental abruption events identified through registry-based diagnosis codes recorded in the Danish National Patient Register. Unit of Measure: Number of participants	From 11+0 weeks of gestation to delivery
Number of maternal or neonatal intracranial hemorrhage events identified using diagnosis codes in the Danish National Patient Register	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	From 11+0 weeks of gestation to discharge from the birth hospitalization

Collaborators and Investigators

• Sponsor: Copenhagen University Hospital at Herlev
• Collaborators: Odense University Hospital; Zealand University Hospital; Aarhus University Hospital Skejby; Aalborg University Hospital; Holbaek Sygehus; Gødstrup Hospital; Nykøbing Falster County Hospital; Copenhagen University Hospital, Hvidovre; Horsens Hospital; Slagelse Hospital; Viborg Regional Hospital; Copenhagen University Hospital Nordsjælland; Bornholm Hospital, Denmark; Lillebaelt Hospital, Kolding and Vejle, Denmark; Hospital of Southern Jutland, Aabenraa, Denmark; Esbjerg Hospital - University Hospital of Southern Denmark
• Investigators: Principal Investigator: Charlotte Kvist Ekelund, Consultant, ass. prof., MD, Rigshospitalet, Denmark

Publications and helpful links

General Publications

• Rolnik DL, Wright D, Poon LC, O'Gorman N, Syngelaki A, de Paco Matallana C, Akolekar R, Cicero S, Janga D, Singh M, Molina FS, Persico N, Jani JC, Plasencia W, Papaioannou G, Tenenbaum-Gavish K, Meiri H, Gizurarson S, Maclagan K, Nicolaides KH. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. N Engl J Med. 2017 Aug 17;377(7):613-622. doi: 10.1056/NEJMoa1704559. Epub 2017 Jun 28.
• O'Gorman N, Wright D, Poon LC, Rolnik DL, Syngelaki A, de Alvarado M, Carbone IF, Dutemeyer V, Fiolna M, Frick A, Karagiotis N, Mastrodima S, de Paco Matallana C, Papaioannou G, Pazos A, Plasencia W, Nicolaides KH. Multicenter screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks' gestation: comparison with NICE guidelines and ACOG recommendations. Ultrasound Obstet Gynecol. 2017 Jun;49(6):756-760. doi: 10.1002/uog.17455.
• Wright D, Rolnik DL, Syngelaki A, de Paco Matallana C, Machuca M, de Alvarado M, Mastrodima S, Tan MY, Shearing S, Persico N, Jani JC, Plasencia W, Papaioannou G, Molina FS, Poon LC, Nicolaides KH. Aspirin for Evidence-Based Preeclampsia Prevention trial: effect of aspirin on length of stay in the neonatal intensive care unit. Am J Obstet Gynecol. 2018 Jun;218(6):612.e1-612.e6. doi: 10.1016/j.ajog.2018.02.014. Epub 2018 Mar 2.
• Riishede I, Rode L, Sperling L, Overgaard M, Ravn JD, Sandager P, Skov H, Wagner SR, Norgaard P, Clausen TD, Jensen CAJ, Pihl K, Jorgensen FS, Munk JK, Zingenberg HJ, Pedersen NG, Andersen MR, Wright A, Wright D, Tabor A, Ekelund CK. Pre-eclampsia screening in Denmark (PRESIDE): national validation study. Ultrasound Obstet Gynecol. 2023 Jun;61(6):682-690. doi: 10.1002/uog.26183. Epub 2023 May 5.
• O'Gorman N, Wright D, Poon LC, Rolnik DL, Syngelaki A, Wright A, Akolekar R, Cicero S, Janga D, Jani J, Molina FS, de Paco Matallana C, Papantoniou N, Persico N, Plasencia W, Singh M, Nicolaides KH. Accuracy of competing-risks model in screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks' gestation. Ultrasound Obstet Gynecol. 2017 Jun;49(6):751-755. doi: 10.1002/uog.17399. Epub 2017 May 14.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 2025
• Primary Completion (Estimated): November 1, 2027
• Study Completion (Estimated): November 1, 2027

Study Registration Dates

• First Submitted: March 3, 2026
• First Submitted That Met QC Criteria: March 16, 2026
• First Posted (Actual): March 20, 2026

Study Record Updates

• Last Update Posted (Actual): March 20, 2026
• Last Update Submitted That Met QC Criteria: March 16, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Screening; Prevention; Preeclampsia
• Additional Relevant MeSH Terms: Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Pregnancy Complications; Hypertension, Pregnancy-Induced; Pre-Eclampsia
• Other Study ID Numbers: F-24005144

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No