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

Brook, A, Hoaksey, A, Gurung, R, Yoong, EEC, Sneyd, R, Baynes, CG, Bischof, H, Jones, S, Higgins, LE, Jones, C, Greenwood, SL, Jones, RL, Gram, M, Lang, I, Desoye, G, Myers, J, Schneider, H, Hansson, SR, Crocker, IP and Brownbill, P (2018) Cell free hemoglobin in the fetoplacental circulation: a novel cause of fetal growth restriction? The FASEB Journal, 32 (10). pp. 5436-5446. ISSN 0892-6638

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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. FGR fetal 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 sequestered NO in acute and chronic exposure models (P < 0.001), and fHbF-primed placental endothelial cells developed a proinflammatory phenotype, demonstrated by activation of NF-κB pathway, 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. This unrecognized mechanism for fetal compromise offers a novel insight into FGR as well as a potential explanation for associated poor fetal outcomes such as fetal demise and stillbirth.