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.