The Future of PlGF
The National Institute for Health and Care Excellence recommends a single Triage PlGF test or Elecsys sFlt-1/PlGF ratio as a rule-out test, concluding that the evidence is currently insufficient to recommend use as a rule in test.13 Furthermore, the guidance is clear that testing should be used to aid diagnosis of pre-eclampsia, and not a wider syndrome of placental disease.
The role of repeat PlGF sampling has not been fully investigated and the impact of repeat testing on maternal and perinatal outcomes is unknown. This is particularly important in women in whom a clear risk trajectory or diagnosis is not reached at initial presentation, but ongoing suspicion of disease remains. One study has recently suggested that repeat PlGF testing retains high diagnostic accuracy, with a high sensitivity and NPV.29 Another study demonstrated increasing sFlt-1/PlGF ratios in women who went on to develop pre-eclampsia or adverse perinatal outcomes.30However, before repeat testing is recommended, clinical and cost-effectiveness need to be established, given as an explicit research recommendation in the diagnostic guideline.13 This is being addressed by the PARROT-2 trial, a multicentre randomised controlled trial of repeat revealed PlGF-based testing compared to usual care with repeat concealed testing (ISRCTN85912420).
The role of PlGF in the assessment of pre-eclampsia in multi-fetal pregnancy is uncertain, as normal ranges and interpretation have not been defined. There are a few small studies to date, with conflicting results.31-33 The largest of these studied 79 women, presenting with suspected pre-eclampsia and found elevated sFlt-1/PlGF ratio was associated with adverse outcomes.31 Although a smaller population of women, use of PlGF-based testing remains an important challenge due to the higher prevalence of pre-eclampsia in multi-fetal pregnancy.
PlGF-based testing in the assessment of early-onset fetal growth restriction warrants further study and there is conflicting evidence. One study of 213 pregnancies showed that low PlGF had a sensitivity of 98.2% with a NPV of 99.2% for placental fetal growth restriction (confirmed on placental histology).34 A large prospective cohort study of 4,512 women found that addition of the sFlt-1/PlGF ratio to ultrasonic assessment improved the positive likelihood ratio for delivering a small-for-gestational-age infant.35 Another study demonstrated that PlGF outperformed both ultrasound and numerous other biomarkers.36 However, a multicentre study including 592 women demonstrated that PlGF performed no better than estimated fetal weight <5th centile in predicting delivery of a small-for-gestational-age infant.37
Other outstanding issues include the ability of PlGF-based tests to risk stratify in established disease, as well as the role of PlGF in low-resource countries. By far the greatest burden of morbidity and mortality due to pre-eclampsia is borne by women and their infants in low and middle-income settings. Initial evidence of the impact of PlGF-based testing in this setting is promising.38, 39
Finally, now that value in diagnosis of pre-eclampsia has been proven, PlGF and sFlt-1 may prove informative to guide treatments that influence the outcome or ameliorate development of the disease.40