Placental growth factor testing for suspected pre-eclampsia
Authors: Emmanuel Bujold, Nils Chaillet, John Kingdom
Journal: The Lancet (2019)

Pre-eclampsia affects between 2% and 8% of pregnancies, and this condition remains a leading cause of maternal and perinatal mortality and morbidity worldwide.1Steegers EA von Dadelszen P Duvekot JJ Pijnenborg R Pre-eclampsia.Lancet. 2010; 376: 631-644Google Scholar This syndrome is characterised by new-onset hypertension during pregnancy and it arises from distinct clusters of risk factors.2McLaughlin K Zhang J Lye SJ Parker JD Kingdom JC Phenotypes of pregnant women who subsequently develop hypertension in pregnancy.J Am Heart Assoc. 2018; 7: e009595Google Scholar Common to each cluster is a specific degree of systemic vascular injury that varies between clusters, which leads to specific end-organ disease. Organ-specific injury via ischaemia and inflammation is the pathway that most commonly leads to fetal growth restriction (FGR) and stillbirth (through placental dysfunction), eclampsia, HELLP syndrome, and renal injury.3Mol BWJ Roberts CT Thangaratinam S Magee LA de Groot CJM Hofmeyr GJ Pre-eclampsia.Lancet. 2016; 387: 999-1011Google Scholar Severe multi-organ disease can lead to long-term maternal physical and mental morbidity and, especially in low-resource settings, this effect can be an important cause of maternal death. The more severe and early-onset forms of pre-eclampsia are associated with several placental diseases, the most common of which is maternal vascular malperfusion, which is characterised by reduced placental size, multifocal infarction, haemorrhage, and diseased spiral arteries.4Wright E Audette MC Ye XY et al.Maternal vascular malperfusion and adverse perinatal outcomes in low-risk nulliparous women.Obstet Gynecol. 2017; 130: 1112-1120Google Scholar Explanted placental villi from women with pre-eclampsia, especially those with early or severe disease, show impaired secretion of the pro-angiogenic placental growth factor (PlGF) protein and exaggerated secretion of the splice variant sFLT-1 protein, the splice-variant soluble antagonist of the potent endothelial vasodilator peptide, vascular endothelial growth factor; this soluble fraction, produced by placental villi, is responsible for impaired endothelial cell function.5O'Brien M Baczyk D Kingdom JC Endothelial dysfunction in severe preeclampsia is mediated by soluble factors, rather than extracellular vesicles.Sci Rep. 2017; 7: 5887Google Scholar Women with low circulating PlGF concentrations are at high risk of developing pre-eclampsia, FGR, or both, whereas PlGF concentrations within reference ranges have a high negative predictive value of the woman developing pre-eclampsia.6Rana S Powe CE Salahuddin S et al.Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia.Circulation. 2012; 125: 911-919Google Scholar The ability to accurately and efficiently distinguish between benign blood pressure increases in pregnancy and pre-eclampsia is a highly desired capability for maternity care providers. In tandem, the ability to effectively detect the small fetus at risk of preventable morbidity or death from FGR is equally important. Since both issues have a common placental origin, it is unsurprising that the measurement of these so-called angiogenic growth factors in clinical practice is both highly valuable to confidently exclude pre-eclampsia and to detect true placental FGR.7Gaccioli F Sovio U Cook E Hund M Charnock-Jones DS Smith GCS Screening for fetal growth restriction using ultrasound and the sFLT1/PlGF ratio in nulliparous women: a prospective cohort study.Lancet Child Adolesc Health. 2018; 2: 569-581Google Scholar In The Lancet, Kate Duhig and colleagues8Duhig KE Myers J Seed PT et al.Placental growth factor testing to assess women with suspected pre-eclampsia: a multicentre, pragmatic, stepped-wedge cluster-randomised controlled trial.Lancet. 2019; (published online April 1.)http://dx.doi.org/10.1016/S0140-6736(18)33212-4Google Scholar from the PARROT trial group report their findings of a stepped-wedge cluster-randomised controlled trial of PlGF testing. Over a 16-month period, they tested 1035 women with suspected pre-eclampsia for their circulating PIGF concentrations, and they either revealed the results (alongside the use of a clinical management algorithm) or concealed them from doctors and patients. The study was conducted in the high-resource setting of 11 large maternity units in the UK, which were each responsible for 3000–9000 deliveries per year. The investigators chose the time from presentation with suspected pre-eclampsia to documented pre-eclampsia as their primary outcome, which was shorter by a median of 2·2 days among women in whom PlGF data were revealed versus those in whom these data were concealed. In this high-resource setting, it is perhaps unsurprising that the incidence of predefined severe adverse events was low, that this incidence was slightly reduced in the group in which PlGF data were disclosed (from 5% to 4%; adjusted odds ratio 0·32, 95% CI 0·11–0·96; p=0·043), and that no maternal deaths occurred. The authors were rightly concerned that PlGF testing could result in more iatrogenic preterm births and, hence, they incorporated training in use of a clinical management algorithm with testing, such that this issue was no longer of concern. No significant change was observed in neonatal outcomes. In the context of this high-resource setting, several findings of the secondary outcome measures deserve attention. First, four women had either eclampsia or a stroke in the concealed testing group (all with low PlGF), whereas none did in the revealed group. However, the significant difference observed in maternal severe adverse events (5% in concealed testing vs 4% in revealed testing) is possibly the consequence of the lower prevalence of blood product transfusion (3·1% vs 1·6%), which is not necessarily related to severe peripartum bleeding or long-term complications. Severe umbilical artery Doppler abnormalities were found before delivery in 5–10% of enrolled women, indicating established placental vascular disease, yet one in four women had no ultrasound assessment before delivery. Therefore, future research should focus on the potential role of ultrasound to optimise delivery timing and thereby reduce this risk of perinatal death or severe morbidity. Duhig and colleagues are to be strongly commended for their efforts to advance the care of women at risk of maternal and perinatal harm from diseases largely arising within the placenta, which can be robustly identified using the PlGF blood test. Future large-scale studies need to confirm the effects of its use on severe maternal adverse events and to determine the usefulness of the addition of sFLT-1 testing, especially for the prompt identification of women at risk of organ-specific injury beyond their placenta.9Walker MG Bujold E Kingdom JC Is Canada ready to adopt maternal placental growth factor testing to improve clinical outcomes for women with suspected preeclampsia?.J Obstet Gynaecol Can. 2017; 39: 580-583Google Scholar We declare no competing interests. Placental growth factor testing to assess women with suspected pre-eclampsia: a multicentre, pragmatic, stepped-wedge cluster-randomised controlled trialWe found that the availability of PlGF test results substantially reduced the time to clinical confirmation of pre-eclampsia. Where PlGF was implemented, we found a lower incidence of maternal adverse outcomes, consistent with adoption of targeted, enhanced surveillance, as recommended in the clinical management algorithm for clinicians. Adoption of PlGF testing in women with suspected pre-eclampsia is supported by the results of this study. Full-Text PDF Open Access