Evaluation of angiogenic factors in prediction of growth‐related neonatal morbidity at term and comparison with competing‐risks model
Authors: Papastefanou I. , Nobile Recalde A. , Silva Souza Y. , Syngelaki A. , Nicolaides K. H. 
Published: November 2023

ABSTRACTObjectivesFirst, to describe the distribution of biomarkers of impaired placentation in small‐for‐gestational‐age (SGA) pregnancies with neonatal morbidity; second, to examine the predictive performance for growth‐related neonatal morbidity of a high soluble fms‐like tyrosine kinase‐1 (sFlt‐1)/placental growth factor (PlGF) ratio or low PlGF; and, third, to compare the performance of a high sFlt‐1/PlGF ratio or low PlGF with that of the competing‐risks model for SGA in predicting growth‐related neonatal morbidity.MethodsThis was a prospective observational study of women attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation in two maternity hospitals in England. The visit included recording of maternal demographic characteristics and medical history, an ultrasound scan and measurement of serum PlGF and sFlt‐1. The primary outcome was delivery within 4 weeks after assessment and at < 42 weeks' gestation of a SGA neonate with birth weight < 10th or < 3rd percentile, combined with neonatal unit (NNU) admission for ≥ 48 h or a composite of major neonatal morbidity. The detection rates in screening by PlGF < 10th percentile, sFlt‐1/PlGF ratio > 90th percentile, sFlt‐1/PlGF ratio > 38 and the competing‐risks model for SGA, using combinations of maternal risk factors and Z‐scores of estimated fetal weight (EFW) with multiples of the median values of uterine artery pulsatility index, PlGF and sFlt‐1, were estimated. The detection rates by the different methods of screening were compared using McNemar's test.ResultsIn the study population of 29 035 women, prediction of growth‐related neonatal morbidity at term provided by the competing‐risks model was superior to that of screening by low PlGF concentration or a high sFlt‐1/PlGF concentration ratio. For example, at a screen‐positive rate (SPR) of 13.1%, as defined by the sFlt‐1/PlGF ratio > 38, the competing‐risks model using maternal risk factors and EFW predicted 77.5% (95% CI, 71.7–83.3%) of SGA < 10th percentile and 89.3% (95% CI, 83.7–94.8%) of SGA < 3rd percentile with NNU admission for ≥ 48 h delivered within 4 weeks after assessment. The respective values for SGA with major neonatal morbidity were 71.4% (95% CI, 56.5–86.4%) and 90.0% (95% CI, 76.9–100%). These were significantly higher than the respective values of 41.0% (95% CI, 34.2–47.8%) (P < 0.0001), 48.8% (95% CI, 39.9–57.7%) (P < 0.0001), 37.1% (95% CI, 21.1–53.2%) (P = 0.003) and 55.0% (95% CI, 33.2–76.8%) (P = 0.035) achieved by the application of the sFlt‐1/PlGF ratio > 38. At a SPR of 10.0%, as defined by PlGF < 10th percentile, the competing‐risks model using maternal factors and EFW predicted 71.5% (95% CI, 65.2–77.8%) of SGA < 10th percentile and 84.3% (95% CI, 77.8–90.8%) of SGA < 3rd percentile with NNU admission for ≥ 48 h delivered within 4 weeks after assessment. The respective values for SGA with major neonatal morbidity were 68.6% (95% CI, 53.1–83.9%) and 85.0% (95% CI, 69.4–100%). These were significantly higher than the respective values of 36.5% (95% CI, 29.8–43.2%) (P < 0.0001), 46.3% (95% CI, 37.4–55.2%) (P < 0.0001), 37.1% (95% CI, 21.1–53.2%) (P = 0.003) and 55.0% (95% CI, 33.2–76.8%) (P = 0.021) achieved by the application of PlGF < 10th percentile.ConclusionAt 36 weeks' gestation, the prediction of growth‐related neonatal morbidity by the competing‐risks model for SGA, using maternal risk factors and EFW, is superior to that of a high sFlt‐1/PlGF ratio or low PlGF. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.