Cell free hemoglobin in the fetoplacental circulation: A novel cause of fetal growth restriction?

Abstract

Cell free hemoglobin impairs vascular function and blood flow in adult cardiovascular disease. In this study, we investigated the hypothesis that free fetal hemoglobin (fHbF) compromises vascular integrity and function in the fetoplacental circulation, contributing to the increased vascular resistance associated with fetal growth restriction (FGR). Women with normal and FGR pregnancies were recruited and their placentas collected freshly postpartum. FGRfetal capillaries showed evidence of erythrocyte vascular packing and extravasation. Fetal cord blood fHbF levels were higher in FGR than in normal pregnancies (P < 0.05) and the elevation of fHbF in relation to heme oxygenase-1 suggests a failure of expected catabolic compensation,which occurs in adults.During ex vivo placental perfusion, pathophysiological fHbF concentrations significantly increased fetal-side microcirculatory resistance (P<0.05). fHbF sequesteredNOinacute andchronic exposuremodels (P<0.001), andfHbF-primed placental endothelial cellsdevelopedaproinflammatoryphenotype,demonstratedby activationofNF-κBpathway, generation of IL-1α and TNF-α (both P < 0.05), uncontrolled angiogenesis, and disruption of endothelial cell flow alignment. Elevated fHbF contributes to increased fetoplacental vascular resistance and impaired endothelial protection.Thisunrecognizedmechanismfor fetal compromise offers a novel insight into FGRaswell as a potential explanation for associated poor fetal outcomes such as fetal demise and stillbirth.