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))