Research data for a study on haemoglobin and heme defences - "EVERREST" study

Background: Unregulated elevations of free plasma fetal hemoglobin (HbF) are observed in fetal growth restriction (FGR) at term and preeclampsia; both conditions are associated with altered long-term trajectories of cardiovascular and brain development. Objectives: To assess fetal circulating HbF levels and heme defences, correlated to fetal circulatory biometry and fetal sex in severe early-onset fetal growth restriction. Methods: In a prospective study of pregnancies with severe early-onset FGR (the EVERREST study; estimated fetal weight <3rd centile and <600g at 20-26+6 weeks of gestation; N=20) with close clinical management, free HbF and the heme-scavengers hemopexin, haptoglobin and alpha-1 microglobulin, were quantified in cord blood. Results were compared with data from normal non-FGR term births (N=26) and births with late-onset FGR (N=12) for comparison. Results: Free HbF was elevated in early FGR deliveries compared with normal pregnancy (P<0.0001). Pregnancies with male fetuses had higher HbF levels after early FGR compared with normal non-FGR male births at term (P<0.001). Hemopexin-mediated clearance was significantly blunted in both early- and late-onset FGR groups compared with normal births (P<0.0001). In EVERREST, antenatally-derived ratios of mid-cerebral artery and umbilical artery pulsatility indices correlated positively with heme-scavenger levels (hemopexin and a heme-handling composite measure: P<0.01), indicating lower levels are associated with cerebral vascular redistribution, itself linked to earlier delivery and lower birthweight. Conclusion: Free HbF overproduction may be one route to placental vascular compromise in early-onset FGR.