Background
Pre-eclampsia is associated with increased adverse maternal and perinatal outcomes, as well as substantial costs for healthcare providers.1 The schedule of antenatal care in the United Kingdom, similar to many other high-income settings, is designed for early detection of pre-eclampsia to minimise adverse outcomes. Maternal mortality has dramatically decreased in the United Kingdom over the last 70 years, likely due to the provision of free antenatal care and implementation of evidence-based guidelines, alongside adoption of recommendations from the landmark Confidential Enquiries into Maternal Deaths.2 However, risks to the woman persist, child morbidity and mortality remain, and pre-eclampsia is the most common cause of iatrogenic preterm delivery.3 The diagnosis of pre-eclampsia is evolving, particularly on a background of chronic medical co-morbidities. Proteinuria is not a pre-requisite for diagnosis, which can be made on the premise of new-onset or worsening of hypertension in association with neurological, biochemical or haematological abnormalities or fetal growth restriction.4, 5 Hypertension alone may predict only 20% of adverse outcomes in pre-eclampsia, and therefore there is a need for better risk stratification and targeted surveillance.6 Around 10% of women may present with suspected pre-eclampsia, often asymptomatic, even in the presence of severe disease.7 At present, women are unnecessarily admitted to hospital with suspected pre-eclampsia, whilst more severe cases may go undiagnosed. The uncertain management of this group presents a considerable workload within maternity care.
Placental growth factor (PlGF) is an angiogenic protein, which is secreted by the syncytiotrophoblast and promotes placental angiogenesis. In a healthy pregnancy, PlGF concentrations increase as gestation advances, reaching a peak at 26 to 30 weeks’ gestation, before decreasing towards term.8, 9 Low concentrations of PlGF precede the clinical onset of pre-eclampsia and abnormalities in angiogenic factors may predate the clinical syndrome by 10 weeks.10 Soluble fms-like tyrosine kinase (sFlt-1) is a circulating anti-angiogenic protein which adheres to the receptor-binding domains of PlGF and vascular endothelial growth factor (VEGF), preventing their interaction with endothelial receptors and inducing endothelial dysfunction. sFlt-1 concentrations increase towards term in healthy pregnancies, but are prematurely elevated in women with pre-eclampsia.8 Low PlGF concentrations in pre-eclampsia may reflect down-regulated expression as well as high levels of sFlt-1 reducing the bioavailability of PlGF.11 Therefore, low PlGF and high sFlt-1 are secondary markers of placental dysfunction in pre-eclampsia, in contrast to hypertension and blood pressure, which are tertiary, downstream features.12 This has focused research on whether angiogenic biomarkers may aid diagnosis of pre-eclampsia and reduce adverse outcomes.
The last decade has seen the development of fully automated, commercially available assays, replacing manual enzyme-linked immunosorbent assays. This has led to standardised, inexpensive measurements, with a high turnover and minimal sample handling. Some PlGF-based tests measure PlGF alone, whereas others quantify sFlt-1 and PlGF, presenting the results as a ratio. There are currently four commercially available PlGF-based assays. The thresholds associated with diagnosis are not interchangeable, as the assays have varying affinity to PlGF isomers and this has implications for clinical practice and implementation of PlGF-based testing. The National Institute for Health and Care Excellence has released specific diagnostics guidance relating to PlGF-based testing13 and has recommended two tests for routine adoption into the NHS, to be used as rule-out tests for women with suspected preterm pre-eclampsia. These are the Triage PlGF test (Quidel) and the Elecsys sFlt-1/PlGF ratio (Roche Diagnostics).5, 13