Methods
We undertook a prospective observational cohort study between February
2016 and December 2018, nested in 36 maternity units participating in
the PHOENIX trial (2) in women with late preterm pre-eclampsia. The
PHOENIX trial was a multicentre randomised controlled trial, in which
901 women from 46 units across England and Wales with preterm
pre-eclampsia from 34+0 to 36+6weeks’ gestation were randomly allocated to planned delivery or
expectant management. Results of the PHOENIX study have been reported
separately.(2)
Women were eligible for this nested PEACOCK study if they were between
34+0 and 36+6 weeks’ gestation, with
a diagnosis of pre-eclampsia (as defined by the International Society
for the Study of Hypertension in Pregnancy),(6) with a singleton or
dichorionic diamniotic twin pregnancy and at least one viable fetus.
Women were aged 18 years or over and gave written informed consent for
participation. Exclusion criteria included a decision to deliver within
the next 48 hours. All women eligible for the PHOENIX trial were
eligible for participation in the PEACOCK study, whether they agreed or
declined randomisation to the main PHOENIX trial. The study was approved
by the South Central— Hampshire B Research Ethics Committee (no
13/SC/0645).
Women were approached individually and asked to provide both plasma
(EDTA) and serum blood sample at the time of recruitment, which were
processed within four hours of sampling. Samples were centrifuged at
1400g for 10 minutes, and the separated supernatant aliquoted and stored
at -80°C. Samples were shipped back to the coordinating centre, thawed,
and processed after completion of all participants in the study on an
electronic Triage™ instrument for PlGF (Quidel Cardiovascular Inc: San
Diego, CA), and for sFlt-1 and PlGF on the automated Cobas Elecsys™
assay (Roche Diagnostics, GmbH, Mannheim, Germany) according to the
manufacturer’s instructions. The readings were concealed from the
clinical team involved in the woman’s care and all laboratory staff were
masked to clinical outcomes. Definitions and outcomes were pre-specified
in the study protocol (version 4.0). Outcomes were collected until the
primary hospital discharge of the woman and infant.
Development of the original PREP-S model
PREP-S is a prediction model that was developed and validated in early
onset preeclampsia before 34 weeks’ gestation, from 53 maternity units
across the United Kingdom.(4) The primary outcome for the PREP-S study
was maternal complications of preeclampsia that included maternal death,
neurological, hepatic, cardiorespiratory, renal or haematological
complications, or delivery before 34 weeks’ gestation. All candidate
predictors identified in the development of the PREP-S as predictor
variables were collected in order to determine the performance of PREP-S
within our cohort of women with late preterm preeclampsia.
Clinical predictor variables
PlGF and sFlt-1 concentrations at enrolment were evaluated as predictor
variables. PREP-S predictor variables were measured at study entry.
PREP-S consisted of the following predictor variables, collected at
diagnosis: maternal age (years), gestational age (weeks), exaggerated
tendon reflexes, medical history (two or more of the following
conditions: chronic hypertension, renal disease, previous history of
pre-eclampsia, autoimmune disease and diabetes mellitus), systolic blood
pressure (mmHg, highest over 6 hours), abnormal oxygen saturation
(<95% on air), platelet count (x109/dl),
alanine aminotransferase (IU/L), serum urea (mmol/L), serum creatinine
(µmol/L), urine protein creatinine ratio (mg/mmol), treatment with
oral/parenteral antihypertensives, treatment with magnesium sulphate.
These were combined using the model equation published:(7)
S(t) = S0 (t)§ ^exp ((β1*X1 +⋯+
βn*Xn))
S(t) = S0(t)^exp(– 0.031*maternal
age + 1.514*((Log(GA at diagnosis/10))–2 –
0.8345136) + 5.707*((Log(GA at diagnosis/10))–2*
ln(log(GA at diagnosis/10)) – 0.0652155) + 0.122 (exaggerated tendon
reflexes) – 0.169 (one pre-existing medical condition) – 0.384 (two or
more pre-existing medical conditions) + 0.016*systolic blood pressure +
0.797 (oxygen saturation < 94% on air) – 0.002*platelet
count + 0.126*log(alanine amino transferase) + 0.605*log(serum
urea)2 – 0.144*log(serum urea)3 +
0.265*log(serum creatinine) + 0.080*log(protein creatinine ratio) +
0.176
(baseline treatment with any antihypertensive) + 1.066 (baseline
treatment with magnesium sulfate))