Preeclampsia Prediction And Prevention: Are We Entering A New Era? GlobalRPH

Preeclampsia Prediction and Prevention Are We Entering a New Era

Abstract

Preeclampsia remains a major contributor to maternal and perinatal morbidity and mortality worldwide, affecting an estimated 2 to 8 percent of pregnancies. Despite advances in obstetric care, the condition continues to pose significant challenges due to its heterogeneous presentation, unpredictable onset, and limited therapeutic options once established. Early identification of women at increased risk remains central to improving outcomes, as timely preventive interventions have the potential to reduce disease severity and associated complications.

This review examines recent advances in the prediction and prevention of preeclampsia, with a particular focus on whether developments in biomarker discovery, multivariable risk assessment algorithms, and preventive strategies represent a meaningful shift in clinical practice. Drawing on recent observational studies, randomized controlled trials, and international guidelines, the paper evaluates the performance of first trimester screening approaches that integrate maternal risk factors with biophysical and biochemical markers. These include uterine artery Doppler indices, mean arterial pressure, and placental biomarkers such as placental growth factor and pregnancy associated plasma protein A.

Emerging evidence suggests that combined screening models offer substantially improved predictive accuracy compared with traditional risk factor based assessment alone. Several validated algorithms demonstrate higher sensitivity and specificity for early onset preeclampsia, enabling targeted preventive strategies in high risk populations. Among these interventions, low dose aspirin prophylaxis initiated in early pregnancy has shown consistent benefit, with studies indicating a potential reduction in preeclampsia incidence of approximately 10 to 15 percent when appropriately prescribed and timed.

In parallel, advances in data driven risk stratification and digital health technologies are expanding the possibilities for individualized prediction. Machine learning based models and point of care biomarker testing are being explored as tools to enhance early detection, particularly in settings where access to specialist care is limited. However, despite these promising developments, significant barriers to widespread implementation persist. Variability in screening protocols, differences in healthcare infrastructure, and limited availability of cost effectiveness and long term outcome data continue to constrain adoption across diverse clinical environments.

In conclusion, the field of preeclampsia prediction and prevention is undergoing meaningful progress, marked by improved screening performance and evidence based preventive interventions. While these advances signal a shift toward more proactive and personalized care, the transition to a new era in preeclampsia management will depend on further validation, standardized clinical pathways, and equitable access to screening technologies. Continued research is essential to refine prediction models, evaluate long term maternal and offspring outcomes, and ensure that emerging strategies translate into measurable improvements in global maternal health.

Introduction

Preeclampsia remains one of the most complex and clinically significant disorders in modern obstetrics. It is classically defined by the development of new onset hypertension accompanied by proteinuria or evidence of maternal organ dysfunction after 20 weeks of gestation. Affecting millions of pregnancies worldwide, preeclampsia is a leading cause of maternal and perinatal morbidity and mortality, accounting for an estimated 76,000 maternal deaths and more than 500,000 fetal and neonatal deaths annually. Beyond its immediate obstetric implications, preeclampsia is increasingly recognized as a condition with long term health consequences for both mother and offspring, including elevated risks of cardiovascular and metabolic disease later in life.

The clinical challenge of preeclampsia lies in its complex and heterogeneous pathophysiology. The disorder arises from a multifactorial interplay between abnormal placentation, impaired spiral artery remodeling, endothelial dysfunction, immune maladaptation, and dysregulation of angiogenic and antiangiogenic factors. These pathological processes begin early in pregnancy, often well before clinical signs become apparent. However, the timing, severity, and clinical manifestations vary widely among affected individuals, making reliable prediction particularly difficult.

Historically, approaches to preeclampsia management have focused on identifying women at risk using maternal clinical characteristics such as advanced maternal age, obesity, nulliparity, preexisting hypertension, diabetes, and prior history of preeclampsia. While these factors offer some prognostic insight, they lack sufficient sensitivity and specificity to support early, individualized intervention. As a result, clinical care has largely depended on intensified surveillance and monitoring in the second half of pregnancy, with intervention often occurring only after disease onset. By this stage, the underlying pathophysiological mechanisms are already well established, and therapeutic options are limited primarily to symptom management and timely delivery.

Recognition of the limitations of this reactive approach has driven a paradigm shift toward earlier and more precise strategies for prediction and prevention. Over the past decade, substantial advances in the understanding of preeclampsia pathogenesis have facilitated the identification of novel biochemical and biophysical markers reflective of placental dysfunction and vascular maladaptation. These include angiogenic biomarkers, uterine artery Doppler indices, and maternal hemodynamic parameters that can be assessed as early as the first trimester. In parallel, the development of multivariable risk assessment algorithms that integrate clinical data with biomarker and imaging findings has improved the accuracy of early risk stratification.

In addition to advances in screening, growing evidence supports the use of targeted preventive interventions in women identified as high risk. Early initiation of low dose aspirin has been shown to reduce the incidence and severity of preeclampsia in selected populations, reinforcing the clinical value of early detection. Together, these developments signal a transition from reactive disease management toward a more proactive and prevention focused model of care.

The convergence of improved biological insight, advanced risk prediction tools, and evidence based preventive strategies raises an important question for clinicians and researchers. Do these innovations represent incremental refinements to existing practice, or do they collectively mark the beginning of a new era in preeclampsia management defined by early identification, individualized risk assessment, and timely prevention.

Current Understanding of Preeclampsia Pathophysiology

The pathophysiology of preeclampsia begins early in pregnancy with abnormal placentation. During normal pregnancy, extravillous trophoblasts invade the maternal spiral arteries, transforming them from high-resistance, low-flow vessels to high-flow, low-resistance conduits. In preeclampsia, this transformation is incomplete or fails entirely, resulting in reduced placental perfusion.

This placental hypoperfusion triggers the release of anti-angiogenic factors, including soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), while simultaneously reducing pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). The resulting imbalance leads to widespread maternal endothelial dysfunction, manifesting as hypertension, proteinuria, and the various systemic complications associated with preeclampsia.

Understanding this pathophysiology has been crucial in developing new prediction and prevention strategies. The recognition that preeclampsia begins early in pregnancy, despite its clinical manifestation in the second half, has shifted focus toward first-trimester screening and early intervention.

Evolution of Prediction Strategies

Traditional Risk Factors

Historically, preeclampsia prediction relied on maternal clinical and demographic characteristics. These include nulliparity, advanced maternal age, obesity, chronic hypertension, diabetes mellitus, kidney disease, autoimmune conditions, and previous history of preeclampsia. While these factors remain relevant, their positive predictive value for preeclampsia is limited when used alone.

Family history of preeclampsia has long been recognized as a risk factor, suggesting genetic predisposition. Studies indicate that women with a family history of preeclampsia have a 2-5 fold increased risk of developing the condition. However, the complex polygenic nature of preeclampsia inheritance makes genetic screening challenging in routine clinical practice.

Biomarker Development

The past decade has seen substantial progress in identifying biomarkers for preeclampsia prediction. The most extensively studied and clinically implemented biomarkers include:

Placental Growth Factor (PlGF): Decreased PlGF levels in the first trimester have been consistently associated with increased preeclampsia risk. PlGF is produced by placental trophoblasts and plays a crucial role in angiogenesis and vascular development. Studies demonstrate that low PlGF levels at 11-13 weeks of gestation can predict early-onset preeclampsia with reasonable accuracy.

Pregnancy-Associated Plasma Protein-A (PAPP-A): Low first-trimester PAPP-A levels have been associated with increased risk of preeclampsia, particularly early-onset disease. PAPP-A is routinely measured as part of aneuploidy screening, making it readily available for preeclampsia risk assessment without additional testing.

Soluble fms-like tyrosine kinase-1 (sFlt-1): Elevated sFlt-1 levels, particularly when expressed as the sFlt-1/PlGF ratio, have shown promise in both prediction and diagnosis of preeclampsia. The ratio becomes increasingly abnormal as preeclampsia develops and correlates with disease severity.

Mean Arterial Pressure (MAP): First-trimester MAP measurement has emerged as a valuable predictor of preeclampsia. Studies show that women who develop preeclampsia have higher MAP values in early pregnancy compared to those who remain normotensive.

Uterine Artery Pulsatility Index: Doppler assessment of uterine artery blood flow provides information about placental vascularization. Elevated pulsatility index in the first or second trimester indicates impaired trophoblast invasion and increased preeclampsia risk.

Integrated Risk Assessment Algorithms

The most promising development in preeclampsia prediction has been the creation of integrated risk assessment algorithms that combine multiple variables. The most notable example is the Fetal Medicine Foundation (FMF) algorithm, which incorporates maternal characteristics, MAP, uterine artery Doppler, and biomarkers (PAPP-A and PlGF) to calculate individual risk.

These algorithms have demonstrated superior predictive performance compared to traditional risk factor-based approaches. The FMF algorithm can identify approximately 75% of early-onset preeclampsia cases and 45% of term preeclampsia cases at a 10% false-positive rate when applied at 11-13 weeks of gestation.

Recent studies have explored machine learning approaches to improve prediction accuracy further. These methods can identify complex patterns in large datasets and may discover novel predictive relationships not apparent through traditional statistical methods.

Prevention Strategies

Aspirin Prophylaxis

Low-dose aspirin has emerged as the primary pharmacological intervention for preeclampsia prevention. The mechanism of action involves inhibition of thromboxane A2 synthesis, leading to improved placental perfusion and reduced inflammatory response.

Multiple randomized controlled trials and meta-analyses have demonstrated that low-dose aspirin (typically 81-150 mg daily) reduces preeclampsia risk by approximately 15-20% when initiated before 16 weeks of gestation in high-risk women. The effect appears more pronounced for early-onset preeclampsia, with risk reductions of up to 60% reported in some studies.

The optimal aspirin dose remains debated. Recent studies suggest that 150 mg daily may be more effective than 81 mg, particularly for prevention of early-onset disease. However, the increased dose may be associated with slightly higher bleeding risk, requiring careful consideration of the risk-benefit ratio.

Timing of aspirin initiation is crucial for effectiveness. Studies consistently show that aspirin must be started before 16 weeks of gestation to achieve maximum benefit. Ideally, prophylaxis should begin as soon as possible after the first trimester, when organogenesis is complete.

Calcium Supplementation

Calcium supplementation has shown benefit in preventing preeclampsia, particularly in populations with low dietary calcium intake. The World Health Organization recommends calcium supplementation (1.5-2.0 g daily) for pregnant women in areas where calcium intake is low.

The mechanism of calcium’s protective effect likely involves regulation of vascular smooth muscle contractility and reduction of parathyroid hormone levels. However, in populations with adequate calcium intake, supplementation provides minimal additional benefit.

Other Interventions

Various other interventions have been studied for preeclampsia prevention with mixed results. These include:

Antioxidants: Vitamins C and E supplementation showed initial promise but subsequent large trials failed to demonstrate benefit and suggested potential harm.

L-arginine: This nitric oxide precursor has shown some benefit in small studies, but evidence remains limited.

Heparin: Low molecular weight heparin has been studied in women with thrombophilia or previous placental complications, with some studies showing benefit.

Lifestyle Interventions: Diet modification, exercise, and weight management during pregnancy have been studied, but evidence for preeclampsia prevention is limited.

Implementation in Clinical Practice

First-Trimester Screening Programs

Several countries have implemented or are piloting first-trimester preeclampsia screening programs. The United Kingdom’s National Health Service has been evaluating the feasibility of routine screening using the FMF algorithm. Initial results suggest that implementation is feasible but requires substantial resource investment and staff training.

The screening process typically involves:

Collection of maternal demographic and clinical history
Blood pressure measurement and calculation of MAP
Uterine artery Doppler assessment
Biomarker analysis (PAPP-A, PlGF)
Risk calculation using validated algorithms
Counseling and management recommendations

Risk Stratification and Management

Based on calculated risk, women are typically stratified into high, intermediate, and low-risk categories. Management protocols vary but generally include:

High-risk women (typically >1:100 risk): Aspirin prophylaxis, enhanced monitoring, and potential referral to maternal-fetal medicine specialists.

Intermediate-risk women: Individual assessment considering additional risk factors and patient preferences regarding aspirin prophylaxis.

Low-risk women: Routine antenatal care with standard monitoring.

Challenges in Implementation

Despite promising research results, several challenges exist in implementing preeclampsia screening programs:

Cost: First-trimester screening requires additional testing and specialist training, increasing healthcare costs. Cost-effectiveness analyses have shown favorable results in some healthcare systems but may vary based on local factors.

Training Requirements: Healthcare providers require training in risk assessment algorithms, biomarker interpretation, and counseling about prevention strategies.

Laboratory Standardization: Biomarker assays require standardization across laboratories to ensure consistent results and risk calculations.

Patient Acceptance: Some women may be reluctant to take medication during pregnancy, even when benefits clearly outweigh risks.

Comparison with Traditional Approaches

The shift toward prediction-based prevention represents a fundamental change from traditional preeclampsia management. Historical approaches focused on symptom recognition and treatment after disease onset, while new strategies emphasize prevention through early risk identification.

Traditional management relied heavily on clinical judgment and experience, while contemporary approaches incorporate objective risk assessment tools and evidence-based interventions. This shift parallels developments in other areas of medicine where prevention has proven more effective than treatment.

However, traditional clinical skills remain important. Risk assessment algorithms supplement but do not replace clinical judgment. Experienced clinicians must interpret risk scores in the context of individual patient circumstances and preferences.

Evidence from Recent Clinical Trials

Several major clinical trials have provided evidence supporting new approaches to preeclampsia prediction and prevention:

ASPRE Trial: This large randomized controlled trial demonstrated that first-trimester screening followed by aspirin prophylaxis in high-risk women reduced early-onset preeclampsia by 62%. The trial included over 26,000 women across multiple countries and provided strong evidence supporting screening and prevention strategies.

PREDICT Study: This prospective cohort study validated the FMF algorithm in routine clinical practice, confirming its predictive performance across diverse populations.

SPREE Trial: Currently ongoing, this trial is evaluating the implementation of first-trimester screening in routine clinical practice and assessing its impact on pregnancy outcomes.

These trials have provided robust evidence supporting the effectiveness of new prediction and prevention strategies, leading to changes in clinical guidelines and practice recommendations.

Emerging Technologies and Future Directions

Artificial Intelligence and Machine Learning

Artificial intelligence and machine learning technologies offer potential for further improving preeclampsia prediction. These approaches can analyze large datasets to identify complex patterns and interactions between variables that may not be apparent through traditional statistical methods.

Several research groups have developed machine learning models for preeclampsia prediction, with some showing superior performance to existing algorithms. However, these models require validation in diverse populations and clinical settings before widespread implementation.

Novel Biomarkers

Research continues into novel biomarkers for preeclampsia prediction. Areas of active investigation include:

MicroRNAs: Small regulatory RNA molecules that may reflect placental function and predict preeclampsia risk.

Metabolomics: Analysis of metabolic profiles may identify biomarkers reflecting the underlying pathophysiology of preeclampsia.

Proteomics: Large-scale protein analysis may reveal new predictive markers.

Cell-free DNA: Placental DNA in maternal circulation may provide information about placental function and preeclampsia risk.

Personalized Medicine Approaches

Future developments may enable more personalized approaches to preeclampsia prediction and prevention. Genetic testing, detailed phenotyping, and individual biomarker profiles may allow for tailored risk assessment and intervention strategies.

Pharmacogenomics research may identify genetic factors affecting aspirin response, enabling optimization of prevention strategies for individual patients.

Global Perspectives and Health Equity

Preeclampsia disproportionately affects women in low- and middle-income countries, where access to advanced screening technologies and prevention strategies may be limited. The challenge lies in adapting new approaches to resource-constrained settings while maintaining effectiveness.

Simplified screening algorithms using readily available parameters may be more appropriate for some settings. Point-of-care testing for biomarkers could make screening more accessible in areas with limited laboratory infrastructure.

Addressing health equity requires consideration of socioeconomic factors, healthcare access, and cultural preferences in implementing preeclampsia screening and prevention programs.

Limitations and Challenges

Despite progress in preeclampsia prediction and prevention, several limitations remain:

Prediction Accuracy: While improved, current prediction models still have limitations. Many women identified as high-risk will not develop preeclampsia, while some low-risk women will still be affected.

Prevention Effectiveness: Even with aspirin prophylaxis, preeclampsia cannot be completely prevented. The intervention reduces risk but does not eliminate it entirely.

Late-Onset Disease: Current prediction models are less effective for late-onset preeclampsia, which represents the majority of cases.

Population Differences: Risk assessment algorithms developed in one population may not perform as well in different ethnic or geographic groups.

Long-term Outcomes: Limited data exist on long-term outcomes following prevention strategies, including potential effects on child development.

Applications and Use Cases

High-Risk Obstetric Centers

Tertiary care centers specializing in high-risk pregnancies have been early adopters of new prediction and prevention strategies. These centers typically have the resources and expertise necessary for implementation and can demonstrate the benefits of these approaches.

Community Healthcare Settings

Implementation in community settings requires adaptation of protocols to local resources and capabilities. Simplified screening approaches may be necessary while maintaining clinical effectiveness.

Developing Healthcare Systems

In resource-limited settings, focus may need to be on identifying the highest-risk women using simplified, cost-effective screening methods while ensuring access to basic prevention strategies like aspirin.

Research Applications

New prediction and prevention strategies have opened avenues for research into preeclampsia pathophysiology, treatment strategies, and long-term outcomes. These tools enable more precise patient selection for clinical trials and research studies.

Economic Considerations

Cost-effectiveness analyses of preeclampsia screening and prevention programs have generally shown favorable results. The costs of screening and prevention are typically offset by reduced healthcare utilization for preeclampsia complications.

However, economic analyses vary depending on healthcare system structure, local costs, and preeclampsia incidence rates. Each healthcare system must conduct its own economic evaluation to determine the optimal implementation strategy.

The economic burden of preeclampsia extends beyond immediate healthcare costs to include long-term maternal and child health consequences. Prevention strategies may provide even greater value when these long-term costs are considered.

Conclusion

Key Takeaways

The field of preeclampsia prediction and prevention has experienced substantial advancement in recent years. Key developments include:

Improved Risk Assessment: Integrated algorithms combining multiple parameters provide superior prediction compared to traditional risk factors alone.
Effective Prevention: Low-dose aspirin prophylaxis in high-risk women represents an evidence-based intervention that reduces preeclampsia incidence.
Early Intervention: The emphasis has shifted from late pregnancy detection to first-trimester screening and early intervention.
Personalized Approaches: Risk assessment enables individualized management strategies based on each woman’s specific risk profile.
Implementation Challenges: Despite proven effectiveness, implementation requires substantial healthcare system changes and resource investment.

These advances represent meaningful progress toward reducing the global burden of preeclampsia, though challenges remain in ensuring equitable access and optimal implementation across diverse healthcare settings.

Future Research Priorities

Several areas require continued research to further advance preeclampsia prediction and prevention:

Long-term Outcomes: Studies examining long-term maternal and child health outcomes following prevention strategies are needed.

Population Validation: Risk assessment algorithms require validation across diverse ethnic and geographic populations.

Novel Interventions: Research into new prevention strategies beyond aspirin may provide additional options for high-risk women.

Implementation Science: Studies examining optimal methods for implementing screening and prevention programs in various healthcare settings are essential.

Cost-Effectiveness: Continued economic evaluation across different healthcare systems will inform policy decisions.

Personalized Medicine: Research into genetic and other individual factors that influence preeclampsia risk and treatment response may enable more personalized approaches.

Frequently Asked Questions:

FAQ Section

Q: How accurate are current preeclampsia prediction models?

A: Current prediction models can identify approximately 75% of early-onset preeclampsia cases and 45% of term preeclampsia cases at a 10% false-positive rate when applied in the first trimester. While this represents substantial improvement over traditional methods, perfect prediction is not yet possible.

Q: Is aspirin safe during pregnancy?

A: Low-dose aspirin (81-150 mg daily) is considered safe during pregnancy when used for preeclampsia prevention. The benefits clearly outweigh the risks in high-risk women. However, women should always consult with their healthcare provider before starting any medication during pregnancy.

Q: When should aspirin prophylaxis be started?

A: Aspirin should ideally be started before 16 weeks of gestation, as soon as possible after the first trimester. Starting aspirin later in pregnancy provides diminished benefit for preeclampsia prevention.

Q: Can preeclampsia be completely prevented?

A: Currently available interventions can reduce preeclampsia risk but cannot completely prevent it. Low-dose aspirin reduces risk by approximately 15-20% in high-risk women, which represents substantial benefit but not complete prevention.

Q: What is the cost of first-trimester preeclampsia screening?

A: Costs vary by healthcare system and specific screening protocol. While screening requires additional testing and resources, economic analyses generally show favorable cost-effectiveness ratios due to reduced complications and associated healthcare costs.

Q: Are these new approaches available in all healthcare settings?

A: Implementation varies widely across healthcare systems. While some centers have fully implemented screening and prevention programs, others are still in pilot phases or have not yet adopted these approaches due to resource or infrastructure limitations.

Q: How do I know if I’m at high risk for preeclampsia?

A: Risk assessment should be performed by qualified healthcare providers using validated algorithms that consider multiple factors including medical history, blood pressure, ultrasound findings, and biomarker levels. Individual risk calculation requires professional medical assessment.

Q: What happens if I’m identified as high-risk?

A: High-risk women are typically recommended to start low-dose aspirin prophylaxis and receive enhanced monitoring during pregnancy. This may include more frequent appointments, additional testing, and potential referral to maternal-fetal medicine specialists.

Q: Do these approaches work for all types of preeclampsia?

A: Current prediction and prevention strategies are most effective for early-onset preeclampsia (before 34 weeks). Late-onset preeclampsia is more difficult to predict and prevent with current methods, though research continues in this area.

Q: Are there any side effects from aspirin prophylaxis?

A: Low-dose aspirin is generally well-tolerated during pregnancy. The main concern is slightly increased bleeding risk, but serious bleeding complications are rare. Women should discuss potential risks and benefits with their healthcare provider.

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