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.

研究背景：足月胎儿生长受限（fetal growth restriction, FGR）及子痫前期（preeclampsia）患者中，均可观察到游离血浆胎儿血红蛋白（HbF）的不受控升高；上述两种疾病均与心血管及脑发育的长期轨迹改变相关。
研究目的：评估重度早发性FGR患者的胎儿循环HbF水平及血红素防御系统状态，并分析其与胎儿循环生物测量指标及胎儿性别的相关性。
研究方法：本研究为一项针对重度早发性FGR妊娠的前瞻性队列研究（EVERREST研究；纳入孕20~26+6周时估计胎儿体重<第3百分位且<600g的受试者，共20例），所有受试者均接受严密临床管理。研究人员对脐带血中的游离HbF及血红素清除剂——血液结合素（hemopexin）、触珠蛋白（haptoglobin）及α1-微球蛋白（alpha-1 microglobulin）进行定量检测，并将结果与正常非FGR足月分娩受试者（26例）及晚发性FGR分娩受试者（12例）的数据进行对比分析。
研究结果：与正常妊娠相比，早发性FGR分娩组的游离HbF水平显著升高（P<0.0001）。与足月正常非FGR男性分娩组相比，早发性FGR妊娠中男性胎儿的HbF水平更高（P<0.001）。与正常分娩组相比，早发性及晚发性FGR组的血液结合素介导的清除功能均显著受损（P<0.0001）。在EVERREST研究队列中，产前检测的大脑中动脉（mid-cerebral artery）与脐动脉（umbilical artery）搏动指数（pulsatility indices）比值与血红素清除剂水平（血液结合素及血红素处理综合指标）呈显著正相关（P<0.01），提示清除剂水平较低与脑血管重分布相关，而脑血管重分布又与更早分娩及更低出生体重相关。
研究结论：早发性FGR患者的游离HbF过度生成，可能是导致胎盘血管损伤的潜在机制之一。