We know that we can improve the clinical phenotyping of participating women using plasma placental growth factor (PlGF), which is a marker of placental dysfunction in both HICs and LMICs.
The diagnosis of pre-eclampsia by BP and proteinuria is of limited use as these are tertiary, downstream features of the disease. Similarly, discriminating between placentally-mediated FGR and constitutionally-small fetuses is a challenge in obstetric practice. PlGF is an angiogenic factor, a secondary marker of associated placental dysfunction of pre-eclampsia, with known low plasma concentrations in the disease. In UK women presenting with suspected pre-eclampsia at 20+0-34+6wks gestation25, low maternal plasma PlGF concentration (<5th centile for gestation, Alere Triage® assay) identified women who delivered with confirmed pre-eclampsia within 14d (sensitivity 0.96 [95% CI 0.89–0.99], negative predictive value (NPV) 0.98 [95% CI 0.93–0.995]) [see image lower left]). In addition, in UK, Canadian and NZ women with suspected FGR, low PlGF identified placental FGR with an AUC ROC 0.96 [95% CI 0.93-0.98], sensitivity 0.98 [95% CI 0.91-0.999], specificity 0.75 [95% CI 0.68-0.82] specificity, NPV 0.99 [95% CI 0.95-0.999] and PPV 0.59 [95% CI 0.48-0.69]26. Low PlGF outperformed other variables in predicting placental FGR. Very low PlGF (<12 pg/mL) was associated with shorter sampling-to-delivery intervals than normal PlGF (13 vs. 29.5 days, p < 0.0001 [see image below centre]). In terms of a LMIC, we studied maternal plasma PlGF in women with suspected pre-eclampsia attending two antenatal clinics in Maputo, Mozambique27. The clinic-to-delivery interval was shorter in low PlGF, compared with normal PlGF, women (median 24d [IQR 10-49] vs 44d [24-81], p=0.0042 [see image below right]). Also, low PlGF was associated with a confirmed diagnosis of preeclampsia, higher blood pressure, transfer for higher care, earlier gestational age delivery, delivery within 7d and 14d, preterm birth, Caesarean delivery, lower birth weight, and perinatal loss.
Unpublished pilot data from PRE-EMPT’s Global Pregnancy Collaboration show that in 45 women destined to suffer a stillbirth, the gestational age-corrected median plasma PlGF was 0.012 multiples of the median compared with >1000 normal pregnancies (p=0.004). In PRECISE, we will not only utilise PlGF, but source additional funding to carry out an ‘unsupervised’ biomarker programme to develop new tools for prediction, diagnosis and management with potential for point of care testing. The existence of these cohorts will greatly facilitate the sourcing of leveraged funding from UK and global partners.
Time-of-disease risk assessment with miniPIERS, PIERS on the Move & phone oximetry
The LMIC-based demographics-, symptom- and sign-based miniPIERS (Pre-eclampsia Integrated Estimate of RiSk) prediction model provides a simple, evidence-based tool to identify pregnant women at increased risk of death or major hypertensive-related complications17. The model includes: parity (nulliparous vs parous); gestational age; headache/visual disturbances; chest pain/dyspnoea; vaginal bleeding with abdominal pain; systolic BP; and dipstick proteinuria (AUC ROC 0.77 [95% CI 0.74–0.80]). A predicted probability ≥25% to define a positive test classifies women with 85.5% accuracy. Thus, miniPIERS identifies women at increased risk of adverse maternal outcomes to guide MgSO4 and antihypertensive therapy, or transfer to a higher level of care. Also, we have developed and are externally validating the extended fullPIERS model that includes demographics (gestational age), symptoms (chest pain/dyspnoea), signs (SpO2) and laboratory tests (platelet count, serum creatinine and AST) (AUC ROC 0.88 [95% CI 0•84–0•92])18. External validation in the LMIC-based miniPIERS cohort confirms good fullPIERS performance in these settings (see image, upper right)19.
The PIERS On the Move (POM) app integrates miniPIERS with a decision algorithm to provide mHealth support to community health workers screening women for pregnancy hypertension and initiating life-saving therapy within the community before transfer to referral centres for definitive care20;21. In the photo (right), empowered ASHA CLIP workers proudly hold up their POM devices. Also, we have developed an integrated miniPIERS and fullPIERS app, Kenek PIERS®. SpO2 is a significant independent predictor of risk in women with pregnancy hypertension, and addition of pulse oximetry improves miniPIERS model22. The POM app integrates phone oximetry20; the Kenek Edge pulse oximeter® plugs into the audio port on a smart device to measure, record and export heart rate and SpO2. A miniPIERS data set-based fetal time-of-disease risk model, for use ≥32+0wks includes maternal age; symptoms (0, 1 or ≥2); and dipstick proteinuria (AUC ROC 0.75 [95% CI 0.71–0.80])23. Also, we have developed the WHO Maternal Morbidity Tool to guide care and to track health systems5;6;24.