Pre-eclampsia is a serious condition that can develop in pregnancy, often characterised by persistent high blood pressure often accompanied by other symptoms such as protein in urine, headache, migraine, visual disturbances, and epigastric pain. It is leading cause of maternal and foetal morbidity and mortality worldwide. It can be difficult to diagnose as the symptoms are common and non-specific, may develop quickly or slowly, and can be overlapping with other conditions or by superimposed comorbidities. While pre-eclampsia can lead to eclampsia, stroke, seizures, and death for the pregnant patient, it is also a leading cause preterm birth and results in significant health care costs1. Today, pre-eclampsia affects up to 5% of pregnancies in the UK2. The NHS report that 65,000 pregnant women are admitted to hospital every year for up to three days to be monitored for the condition3. There has been a need for better diagnostic tests which are specific for the disease. 

It was 21 years ago that the seminal paper was published in the New England Journal of Medicine by Levine and colleagues at NICHD showing that increased levels of sFLT-1 (soluble fms-like tyrosine kinase-1) and reduced levels of PLGF (placental growth factor) predicted subsequent development of preeclampsia4. Proteins secreted by the placenta, angiogenic biomarkers, regulate the growth of new blood vessels, or angiogenesis, during pregnancy. They are important for the development of the placenta and other aspects of placentation. In pre-eclampsia these biomarkers are imbalanced, sFLT is produced at higher levels, binding to and preventing PLGF interaction with endothelial receptors. By effectively ‘mopping up’ PLGF, levels of PLGF are significantly lower than found in a normal healthy pregnancy. Low circulating PLGF precedes the manifestation of the clinical disease in pre-eclamptic pregnancies and intrauterine growth restriction. Low PLGF therefore is a marker of abnormal placentation. 

PLGF was discovered in 1991 by an Italian scientist, Maria Graziella Persico, and it has taken many years and many clinical trials (e.g. PELICAN, PARROT, PROGNOSIS, PEACHES and others) to validate the diagnostic tests we now have available5. Key contributors to this have been Kings College London and Oxford University whose work has helped to establish the useful cut-offs for diagnosis and prognosis, and pathway implementation. Today, NICE recommends use of PLGF alone, and also the sFLT/PLGF ratio for the rule in and rule out of pre-eclampsia. 

PLGF is used when women present with signs and/or symptoms of preterm pre-eclampsia, usually between 20 and 37 weeks. Used alongside signs and symptoms, PLGF can increase the diagnosis and prognostic precision by including a biomarker that is a direct measure of placental dysfunction. The predictive value of PLGF significantly benefits high-risk groups, including those disproportionately impacted by risk factors such as race, history of pre-eclampsia and chronic disease before pregnancy. The predictive ability of PLGF provides scope to enhance faster decision-making and reduced admission rates. Most of the tests currently available are laboratory tests requiring a serum or plasma sample. Point of care testing is also available. Originally only through using a plasma sample, newer methods are available utilising whole venous blood samples. Development of easier to access fingerstick tests are also now in development, that have the potential to transform access, making the test available to women who are not close to a major hospital, without the requirement for a venous blood draw and with results in minutes. 

Recently, Scotland has launched a programme for PLGF and sFLT/PLGF testing across the nation for cases of suspected pre-eclampsia.  Evaluating PLGF tests, in the lab or at the point of care is not straightforward. Tests have different cut off levels, sensitivity, specificity and NPV values, some require processing to serum or plasma. You need to carefully review the pack insert to understand the clinical performance of the tests and how to use them. For example, use as an aid in diagnosis of pre-eclampsia, versus prognosis for delivery at 2, 7, 14 or 28 days. Extensive testing has been undertaken and published, and the NICE recommendation from an expert panel supports the clinical and cost effectiveness of these tests. It’s important to remember these tests are an aid in the diagnosis and prognosis of preeclampsia and to be used alongside clinical signs and symptoms, and clinical management. However, unlike relying on hypertension and / or proteinuria, they detect development of placental dysfunction, earlier, meaning clinicians can spot patients who are at highest risk for pre-eclampsia or may require early delivery, as well as those with lower risk. 

Preeclampsia used to be a difficult to diagnose condition, developing rapidly and leading to tragic loss of mothers and babies. The discovery of PLGF, and our understanding of angiogenic biomarkers, is starting to unravel the complexity of placental dysfunction, and transform care of suspected preeclampsia helping to improve diagnosis, prevent maternal complications, reduce still births and prevent pre-term deliveries. Understanding the physiology of these biomarkers, and mechanisms regulating them, is opening new therapeutic as well as diagnostic approaches. 

1 Fishel Bartal, M & Sabai, B. 2022. AJOG Expert Revs https://www.ajog.org/article/S0002-9378(20)31128-5/fulltext

2 RCOG https://www.rcog.org.uk/for-the-public/browse-our-patient-information/pre-eclampsia/ 

3 NHS England. https://www.england.nhs.uk/2021/08/life-saving-world-first-nhs-test-for-pregnant-women/#:~:text=The%20test%20means%20the%20condition,be%20monitored%20for%20the%20condition.  

4 Levine, R, et al 2004, New England Journal Medicine. https://pubmed.ncbi.nlm.nih.gov/14764923/

5  NICE Diagnostics Guidance DG49 https://www.nice.org.uk/guidance/dg49

Dr Jayne Ellis is Managing Partner and Co-Founder of JEMMDx (www.jemmdx.com ).