Role of sFlt-1 and PlGF in the screening of small-for-gestational age neonates during pregnancy: A systematic review

Abstract

Background Fetal growth restriction, i.e. the restriction of genetically predetermined growth potential due to placental dysfunction, is a major cause of neonatal morbidity and mortality. The consequences of inadequate fetal growth can be life-long, but the risks can be reduced substantially if the condition is identified prenatally. Currently, screening strategies are based on ultrasound detection of a small-for-gestational age fetus and do not take into account the underlying vascular pathology in the placenta. Measurement of maternal circulating angiogenic biomarkers placental growth factor, sFlt-1 (soluble FMS-like tyrosine kinase-1) are increasingly used in studies on fetal growth restriction as they reflect the pathophysiological process in the placenta. However, interpretation of the role of angiogenic biomarkers in prediction of fetal growth restriction is hampered by the varying design, population, timing, assay technique and cut-off values used in these studies. Methods We conducted a systematic-review in PubMed (MEDLINE), EMBASE (Ovid) and Cochrane to explore the predictive performance of maternal concentrations of placental growth factor, sFlt-1 and their ratio for fetal growth restriction and small-for-gestational age, at different gestational ages, and describe the longitudinal changes in biomarker concentrations and optimal discriminatory cut-off values. Results We included 26 studies with 2514 cases with small-for-gestational age, 27 cases of fetal growth restriction, 582 cases mixed small-for-gestational age/fetal growth restriction and 29,374 reference. The largest mean differences for the two biomarkers and their ratio were found after 26 weeks of gestational age and not in the first trimester. The ROC-AUC varied between 0.60 and 0.89 with sensitivity and specificity matching the different cut-off values or a preset false-positive rate of 10%. Conclusions Most of the studies did not make a distinction between small-for-gestational age and fetal growth restriction, and therefore the small-for-gestational age group consists of fetuses with growth restriction and fetuses that are constitutionally normal. The biomarkers can be a valuable screening tool for small-for-gestational age pregnancies, but unfortunately, there is not yet a clear cut-off value to use for screening. More research is needed to see if these biomarkers are sufficiently able to differentiate growth restriction on their own and how these biomarkers in combination with other relevant clinical and ultrasound parameters can be used in clinical routine diagnostics.

The potential association between a new angiogenic marker fractalkine and a placental vascularization in preeclampsia

“…In this case, when we observe an increased expression of CX3CL1/CX3CR1 in placenta and corresponding restrained development of placental vessels, we suggest that the increase in CX3CL1 synthesis is rather the consequence of low angiogenesis in a kind of negative feedback after TNF-α stimulation. The interesting question is the correlation between Doppler parameters and CX3CL1 levels as there is a potential role of CX3CL1 to be another biomarker for clinical decisions, when used together with other biomarkers and clinical data [ 38 ].…”

The role of sFlt1/PlGF ratio in the assessment of preeclampsia and pregnancy-related hypertensive disorders

“…Data from the PROGNOSIS study showed that patients with an elevated sFlt1/PlGF ratio, but who did not develop preeclampsia, were at greater risk of giving birth to a growth-restricted baby [7]. These data, found in several smaller studies, were recently summarised in a systematic review [23]. Its findings, given the irreducible variety in design and methodology of the studies it reviews, do not allow the ratio to be recommended in current clinical practice as a reliable predictor of IUGR.…”

Editorial: Research Model Innovations in Advancing Neonatal Care

“…Of note, despite being different animal models, the hyperoxia and intrauterine infection exposure resulted similarly in growth restriction. Indeed, growth restriction is a potent risk factor for BPD as the associated increase in sFlt-1 (soluble FMS-like tyrosine kinase-1) ( 6 ) has a negative impact on growth factors such as VEGF, a mediator that regulates vascular growth closely linked to the alveolarization process ( 7 ). As shown by Ruan et al , the effects of oxygen toxicity resulted in increased pulmonary vascular permeability, likely from endothelial damage, and reduced Twist1 that may potentially modify VEGF as well.…”