Discussion
Main Findings
In this group of women with late preterm pre-eclampsia, PlGF and
sFlt-1:PlGF measurement, and the PREP-S clinical prognostic model are
not likely to add to the current clinical assessment to help plan care
for these women around timing of delivery. Although PlGF testing had
high sensitivity (97.9%) for delivery within seven days, the negative
predictive value was only 71.4% and the specificity was low (8.4%).
The areas under the curve for the clinical prediction model (PREP-S),
PlGF and sFlt-1:PlGF in this cohort in determining need for delivery
within seven days were all lower than 0.7, below the threshold deemed
clinically useful.(10)
Strengths and Limitations
The PEACOCK study was nested within a larger trial (PHOENIX) which
evaluated timing of delivery in women with late preterm pre-eclampsia.
We were necessarily constrained by the design of the PHOENIX trial such
that we studied women of a different gestational age window (34 up to 37
weeks) compared to the original PREP study (up to 34 weeks’ gestation),
and we chose a different, binary outcome (clinically indicated need for
delivery by seven days) and initial statistical analysis (presenting ROC
areas). We originally chose measurement of PlGF concentrations as a
potential predictor, based on our other work describing strong test
performance of PlGF concentrations in women with suspected
pre-eclampsia. However, from our study reported here, the distribution
of PlGF concentrations in women with confirmed pre-eclampsia was clearly
very different to those presenting with suspected disease, with a high
proportion of women (over 90%) having low or very low PlGF values.
Although sensitivity of the test remained high, specificity, predictive
values and likelihood ratios were all sub-optimal, and the area under
the curves for both PlGF and sFlt-1:PlGF in determining need for
delivery in seven days was too low to be clinically useful.
PlGF and sFlt-1:PlGF biomarkers are considered reasonably ‘upstream’ in
the pathophysiological process of the development of pre-eclampsia. The
low overall prognostic performance in this group may be because the need
for delivery from pre-eclampsia within seven days is associated with a
variety of multi-organ, end-stage clinical parameters, and therefore an
‘upstream’ biomarkers such as PlGF or sFlt-1:PlGF are unable to
discriminate which individuals are at higher risk. In addition,
clinicians act upon early signs of impending clinical deterioration
(such as abnormal liver transaminases) in order to avoid severe hepatic
dysfunction (as used within the original PREP-S study, in women with
pre-eclampsia prior to 34 weeks’ gestation). Treatment paradox (e.g.
decision for delivery based on early derangement of liver transaminases)
could impact on the performance of prognostic markers or models, as
women will have the primary outcome (clinically indicated need for
delivery within seven days) without necessarily going on to develop
severe maternal adverse outcomes. Although our chosen primary outcome
(need for delivery for pre-eclampsia within seven days) acts as a
surrogate to represent clinician concern of substantial fetal or
maternal compromise, the suboptimal performance of PlGF and sFlt-1:PlGF
for predicting delivery in this group may also reflect the complex,
multi-pathological nature of this endpoint, and that a single biomarker
is unable to determine both fetal and maternal compromise which has
considerably different pathology (albeit the same clinical end point of
early delivery). Whilst PlGF measurements have shown considerable
potential as a diagnostic adjunct in women with suspected disease, (11)
and the distribution of low and very low PlGF concentrations in the
PEACOCK cohort confirms that we had participating women with placental
dysfunction, this test does not appear to have strong prognostic value
(for need for delivery) in this setting.
The PREP-S model was developed in early onset pre-eclampsia population
(prior to 34 weeks), while the PEACOCK population was those with late
preterm pre-eclampsia (34 to 37 weeks). The underlying contributions
from maternal and placental pathophysiology may vary across these two
groups, and hence the model cannot automatically be transported for use
in the different population. Importantly, clinicians are likely to have
lower threshold for delivery in women with late preterm pre-eclampsia
than early onset pre-eclampsia since the risk of prematurity related
complications is lower for births after than before 34 weeks’ gestation.
While the PREP-S model has consistently shown accurate performance both
in the development dataset, and in two separate validation datasets of
early onset pre-eclampsia,(4) we found that the model cannot be
transported to a late preterm pre-eclampsia population to predict a
different outcome.
At the time of conception of this study, there were a number of studies
suggesting strong test performance for angiogenic factors measured in
pregnancy, but the majority of the studies focused on women with
suspected pre-eclampsia and the role of measurement in confirmed
pre-eclampsia was under-explored. One early study by Verlohren and
colleagues (12) assessed sFlt-1:PlGF in 95 women with pre-eclampsia
after 34 weeks’ gestation and compared duration of remaining pregnancy
between women in the upper and lowest quartiles of sFlt-1:PlGF (but did
not report other test performance statistics for this outcome). They
reported that women with pre-eclampsia with a sFlt-1:PlGF in the upper
quartile had a significantly reduced duration of pregnancy. However, a
more recent study by Lou and colleagues (13) found that in women with
pre-eclampsia after 34 weeks’ gestation, there was no significant
difference in sFlt-1:PlGF between those who delivered within seven days
compared to those who delivered later. Meler and colleagues (14)
similarly concluded that the predictive role of a low PlGF concentration
in predicting maternal complications in early onset pre-eclampsia was
limited because of both its low specificity and low positive predictive
value.
Interpretation
PlGF and sFlt-1:PlGF testing, and the PREP-S prediction model cannot be
recommended to help plan care for late preterm pre-eclampsia regarding
timing of delivery. A high proportion of women in this cohort already
had low PlGF concentrations at the time of confirmed diagnosis, reducing
the ability of PlGF measurement to further predict adverse outcomes.
This is important and timely information given the current NHS-wide
adoption of PlGF based testing as a diagnostic adjunct in the assessment
of women with suspected pre-eclampsia, a different population to that
studied here. Despite the confirmed diagnostic utility of PlGF in women
with suspected pre-eclampsia, PlGF and sFlt-1:PlGF do not appear to have
a role in assisting clinicians in determining timing of delivery in
women with established preterm pre-eclampsia. The PREP-S model both
alone, and in combination with PlGF, and in combination with sFlt-1:PlGF
appears to have only limited clinical applicability for determining
which women would require delivery in seven days from pre-eclampsia in
women with late preterm pre-eclampsia.
Conclusions
In women with late preterm
pre-eclampsia, PlGF and sFlt-1:PlGF measurements are not likely to add
to the current clinical assessment to help plan care regarding timing of
delivery. Existing models developed in women with early onset
pre-eclampsia to predict complications cannot be used to predict
clinically indicated need for delivery in women with late preterm
pre-eclampsia.
Disclosure of Interests
The authors have no interests to disclose
Contribution to Authorship
LCC and AS were involved in the study conception and in securing funding
for the study. Clinical study data analysis was undertaken by KD, LCC
and PS. The manuscript was written by KD and LCC, with assistance from
PS, AP, JS, CG, AB, EH, AS, ST and AS. All authors approved the final
version of the manuscript.
Ethical Approval
The study was approved by South Central – Hampshire B Research Ethics
Committee (13/SC/0645), March 2016.
Funding Source
The study was funded by the HTA Monitoring Add on Studies Programme (ID
15/59/06), National Institute for Health Research Professorship
(Chappell RP-2014-05-019), and by the National Institute for Health
Research Biomedical Research Centre based at Guy’s and St Thomas’ NHS
Foundation Trust and King’s College London. PTS is partly funded by
Tommy’s and by CLAHRC South London (NIHR). The funders had no
involvement in the study design, collection and analysis of data, data
interpretation report writing or the decision to submit the article for
publication.