Reduced circulating NrCAM as a biomarker for fetal growth restriction.

Abstract

Placental insufficiency underpins pregnancy complications, fetal growth restriction (FGR) and preeclampsia, yet predictive biomarkers are limited. Neuronal Cell Adhesion Molecule (NrCAM) may be a promising biomarker of placental dysfunction. This study investigated whether NrCAM can predict diseases of placental insufficiency. Circulating NrCAM was measured across independent cohorts. Plasma NrCAM was assessed at 36 weeks' gestation in women who later delivered FGR infants (<3rd centile birthweight), or developed preeclampsia at term. Circulating NrCAM was also measured in international cohorts: a UK high-risk cohort of women presenting with reduced fetal movements and delivered an FGR infant; a high-risk cohort from South Africa diagnosed with preeclampsia or eclampsia. NrCAM was also assessed in pregnancies with preterm FGR or preeclampsia (<34 weeks gestation). The effect of hypoxia on NrCAM expression was measured in trophoblast stem cells, primary trophoblasts, and a murine FGR model. Circulating NrCAM was reduced at 36 weeks' gestation in women who later delivered FGR infants (p = 4.75 x 10^-6, AUC = 0.76, n = 26 FGR, n = 957 controls). In the UK cohort, reduced NrCAM levels were associated with FGR (p = 9.34 × 10^-3, AUC = 0.72, n = 12 FGR, n = 235 control). In the South Africa cohort, circulating NrCAM was reduced with preeclampsia (p = 0.03, AUC = 0.70, n = 27 preeclampsia, n = 15 control). Placental NrCAM expression was lower in FGR (p = 0.0003, n = 23 FGR) and preeclampsia (p = 0.0003, n = 41 preeclampsia, n = 20 controls). Hypoxia reduced NrCAM expression in human trophoblast stem cells (p < 0.01) primary trophoblasts (p < 0.0001) and in a murine FGR model (p < 0.01, n = 9 per group). Reductions in plasma and placental NrCAM are strongly associated with FGR and may be driven by hypoxia. This study was funded by a grant from National Health and Medical Research Council.