ABSTRACT Background Fetal growth restriction is a major determinant of perinatal morbidity and mortality. The condition has no gold standard definition but a widely used proxy is delivery of a small for gestational age (SGA) infant (<10th percentile) combined with an adverse pregnancy outcome. Effective screening for FGR is an area of unmet clinical need. We sought to determine the diagnostic effectiveness of the combination of ultrasonic fetal biometry and measurement of the ratio of soluble fms-like tyrosine kinase receptor 1 (sFLT1) to placenta growth factor (sFLT1:PlGF) in predicting adverse pregnancy outcome associated with delivery of an SGA infant. Methods We recruited 4,512 nulliparous women to a prospective cohort study which involved serial antenatal blood sampling and blinded ultrasound scans. We determined the association between the combination of an elevated sFLT1:PlGF ratio (>85th percentile) and ultrasonically suspected SGA (<10th percentile) at both 28 and 36 weeks of gestational age (wkGA). The outcome following the 28wkGA measurement was preterm delivery of an SGA infant. The outcome following the 36wkGA measurement was subsequent delivery of an SGA infant associated with maternal preeclampsia or perinatal morbidity or mortality. All definitions of exposure and outcome were predefined prior to conducting the analysis. Findings At 28wkGA, 47/3981 (1·2%) women had the combination of ultrasonic SGA and an elevated sFLT1:PlGF ratio: the positive likelihood ratio for preterm delivery of an SGA infant associated with this combination was 41·1 (95% CI 23·0-73·6), the sensitivity was 38·5% and the specificity was 99·1%. At 36wkGA, 102/3747 (2·7%) women had the combination of ultrasonic SGA and an elevated sFLT1:PlGF ratio: the positive likelihood ratio for delivery of an SGA infant associated with maternal preeclampsia or perinatal morbidity or mortality was 17·5 (95% CI 11·8-25·9), the sensitivity was 37·9% and the specificity was 97·8%. The positive likelihood ratios at both gestational ages were much higher than previously described definitions of suspected fetal growth restriction employing purely ultrasonic assessment. Interpretation The combination of ultrasonically suspected SGA plus an elevated sFLT1:PlGF ratio in unselected nulliparous women identifies a relatively small proportion of women who have high absolute risks of clinically important adverse outcomes. Screening and intervention based on this approach is likely to result in net benefit and this would be an appropriate subject for a randomised controlled trial.

Funding NIHR Cambridge Comprehensive Biomedical Research Centre, Medical Research Council, and Stillbirth and neonatal death society (Sands).