Results
Between 27 April 2016 and 24 December 2018, we recruited 501 women to
the PEACOCK study, across 36 maternity units in England and Wales
(Figure S1). There were no statistically or clinically relevant
differences across the participants who received expectant management as
usual care outside the trial (n=182) and within the PHOENIX trial
allocation arm (n=159) (Table 1, Table S1). Women in the two PHOENIX
trial allocation arms (presented here as women in planned delivery group
included for secondary analysis) were, as expected, balanced for
baseline characteristics (Table S2).
There were similar outcomes in women randomised to expectant management
group and those participating in the non-randomised expectant management
group (Table 2), whilst outcomes in the planned delivery and randomised
expectant management groups (Table S3) reflect those in the larger
PHOENIX trial, with earlier gestation at delivery, as expected.(2) In
women managed expectantly, 211 of 341 (61.9%) women delivered within
seven days; in these women, 81 (50.9%) of those randomised and 95
(52.2%) of those non-randomised (i.e. outside the trial) had indicated
delivery due to clinical concerns for maternal or fetal wellbeing. There
were no perinatal deaths in the study.
For the PlGF test by the Quidel assay, the test performance for PlGF in
determining need for delivery within seven days at low (<100
pg/mL) and very low (PlGF <12 pg/mL) is shown in Table S4. The
test performance for PlGF <100 pg/ml in determining need for
delivery within seven days had sensitivity of 97.9% (94.8-99.4%) for
delivery within seven days; the negative predictive value was 71.4%
(41.9-91.6%) and the specificity was 8.4% (4.1-14.9%). Similar test
performance statistics for determining need for delivery within 14 days
are shown in Table S5 and within two days in Table S6.
For the sFlt-1:PlGF ratio by the Roche assay, the test performance for
sFlt-1/PlGF ≥83 in determining need for delivery within seven days had
sensitivity of 91.4 % (86.3-95.1%) for delivery within seven days; the
negative predictive value was 60.5% (43.4-76.0%) and the specificity
was 20.9% (13.7-29.7%). Similar test performance statistics for
determining need for delivery within 14 days are shown in Table S5 and
within two days in Table S6.
For evaluation of the PREP-S prognostic model in this cohort, baseline
predictor variables were assessed in the PEACOCK study cohort and
compared with the original PREP-S cohort (Table S7). There were
important differences between the two cohorts, particularly relating to
gestation at enrolment (as different inclusion criteria were used),
definitions used for (and therefore incidence of) adverse maternal
outcomes.
The Receiver Operator Curve (ROC) areas for PlGF (Quidel), sFlt-1:PlGF
ratio (Roche) and PREP-S are shown in Table 3 (and Figure 1), with
consideration of the PREP-S model for a dichotomised endpoint (delivery
within seven days). PREP-S was also assessed in combination with PlGF
(Quidel), and with the sFlt-1:PlGF ratio (Roche), treating PREP-S as a
single predictor.(4) The corresponding ROC areas for the clinical
prediction model (PREP-S), PlGF (Quidel) and sFlt-1:PlGF (Roche) in this
cohort in determining need for delivery within seven days was 0.64
(standard error (SE) 0.03), 0.60 (SE 0.03), and 0.63 (SE 0.03)
respectively. The ROC area for PREP-S in combination with PlGF (Quidel)
in determining need for delivery within seven days was 0.65 (SE 0.03),
and PREP-S in combination with sFlt-1:PlGF (Roche) was 0.64 (SE 0.03).
PREP-S (when used to determine a binary outcome), and PlGF have limited
clinical applicability in this cohort in determining need for delivery
within seven days.
Performance of the PREP-S model, PlGF (Quidel), and sFlt-1:PlGF ratio
(Roche) was similar in determining delivery in 14 days and in 2 days in
this cohort (Table S8 and Figures S2 and S3), with these predictors
having limited clinical applicability in this setting.
The Kaplan-Meier time to delivery estimates for women in the expectant
management groups, stratified by four PREP-S risk categories (as
observed) are shown in Figure S4 and the recalibrated estimates in
Figure S5.
Calibration of the PREP-S model is shown in Table S9, with calibration
in the large and of the slope assessed for predicting delivery for
preeclampsia within seven days. Calibration of the PREP-S model in this
cohort was less good than that achieved in the original PREP-S cohorts.
Overall, approximately the same number of women had the outcome as
predicted by the model (expected value 0; calculated value -0.13; not
significantly different). However, calibration of the slope was 0.375
(expected value 1.0), suggesting that the difference between adverse
outcome event rates between low and high risk groups was not as great as
the PREP-S model suggested, with PREP-S consistently over-predicting the
adverse event rate in the higher risk groups. Recalibration of the model
slightly improved the calibration of the PREP-S probabilities (Tables
S10-S12), so that the notional probabilities were slightly closer to the
actual event rate in the various subgroups.
Calibrations plots are shown for PREP-S for delivery within seven days
(Figure S6, Table S10), two days (Figure S7 Table S11) and 14 days
(Figure S8, Table S12), used as a prognostic model to determine time to
delivery within a certain number of days as a binary outcome, not as a
time-to-survival model. Evaluation of other thresholds for PlGF did not
substantially improve test performance (Table S13) over and above the
pre-specified thresholds.