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