Angiogenic factors alone or in combination with ultrasound Doppler criteria for risk classification among late-onset small fetuses with or without pre-eclampsia

Objective: To investigate the prognostic value of maternal angiogenic factors in late-onset small fetuses, alone or in combination with the ultrasound and Doppler parameters currently used for the classification of low-risk small-for-gestational-age (SGA) fetuses or high-risk fetal growth restriction (FGR), overall and according to the presence or absence of pre-eclampsia. Methods: This was a prospective cohort study of women with a singleton pregnancy with a diagnosis of late-onset fetal smallness (defined as birth weight < 10^th centile) and a gestational age of ≥ 34 weeks at delivery. Ultrasound assessment of estimated fetal weight (EFW) and Doppler assessment of uterine artery pulsatility index (UtA-PI) and cerebroplacental ratio (CPR) were performed every 1–2 weeks. Biochemical analysis of the angiogenic factors placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) in maternal peripheral venous blood samples was performed using enzyme-linked immunosorbent assay within 1–2 weeks after diagnosis of SGA or FGR. The primary outcome was adverse perinatal outcome, defined as a composite of emergency Cesarean section for non-reassuring fetal status, metabolic acidosis (umbilical artery pH < 7.0), neonatal unit admission and/or perinatal death. The predictive value of EFW < 3^rd centile, Doppler parameters (UtA-PI > 95^th centile and CPR < 5^th centile) and sFlt-1/PlGF ratio > 95^th centile, alone or in combination, was assessed using logistic regression analysis in the overall population and stratified by presence or absence of pre-eclampsia developing at any time before delivery. Results: Among the 602 included cases, 91 (15.1%) developed pre-eclampsia and 511 (84.9%) did not. In the overall study population, all parameters were associated independently with adverse perinatal outcome: EFW < 3^rd centile (adjusted odds ratio (aOR), 2.58 (95% CI, 1.67–4.00)), UtA-PI > 95^th centile (aOR, 1.92 (95% CI, 1.25–2.94)), CPR < 5^th centile (aOR, 2.35 (95% CI, 1.46–3.78)) and sFlt-1/PlGF ratio > 95^th centile (aOR, 1.71 (95% CI, 1.09–2.69)). Only sFlt-1/PlGF ratio > 95^th centile was associated independently with adverse perinatal outcome in cases with pre-eclampsia, whereas in those without pre-eclampsia, only EFW < 3^rd centile and CPR < 5^th centile were associated independently with adverse perinatal outcome. In the overall population, the detection rate (DR) and false-positive rate for adverse perinatal outcome were, respectively: 39.8% (95% CI, 31.7–47.9%) and 16.9% (95% CI, 10.7–23.1%) for sFlt-1/PlGF ratio > 95^th centile alone; 86.8% (95% CI, 83.4–90.2%) and 61.9% (95% CI, 57.1–66.7%) for a combined model of EFW < 3^rd centile, UtA-PI > 95^th centile and CPR < 5^th centile; 81.3% (95% CI, 77.3–85.3%) and 52.3% (95% CI, 47.1–57.5%) for a combined model of EFW < 3^rd centile and sFlt-1/PlGF ratio > 95^th centile; and 88.5% (95% CI, 85.4–91.6%) and 64.5% (95% CI, 59.8–69.2%) for a combined model including all the abovementioned observed parameters. Conclusions: sFlt-1/PlGF ratio alone had a low predictive value for adverse perinatal outcome, but when combined with EFW, its predictive performance was similar to that of EFW combined with Doppler parameters. Combining sFlt-1/PlGF ratio with EFW and Doppler criteria achieved the highest DR for adverse perinatal outcome, and additionally, might help to identify imminent pre-eclampsia in pregnancies complicated by fetal smallness. These findings support the use of angiogenic factors as an additional criterion to those currently used for identifying high-risk FGR among late-onset small fetuses, but do not support their use as a standalone biomarker.