Supplementary Material for: Blood biomarkers in the fetally growth restricted and small for gestational age neonate: associations with brain injury

Fetal growth restriction (FGR) and small for gestational age (SGA) infants have increased risk of mortality and morbidity. Although both FGR and SGA infants have low birthweights for gestational age, a diagnosis of FGR also requires assessments of umbilical artery Doppler, physiological determinants, neonatal features of malnutrition and in utero growth retardation. Both FGR and SGA are associated with adverse neurodevelopmental outcomes ranging from learning and behavioural difficulties to cerebral palsy. Up to 50% of FGR newborns are not diagnosed until around the time of birth, yet this diagnosis lacks further indication of the risk of brain injury or adverse neurodevelopmental outcomes. Blood biomarkers may be a promising tool. Defining blood biomarkers indicating an infant’s risk of brain injury would provide the opportunity for early detection and therefore earlier support. The aim of this review is to summarise the current literature to assist in guiding the future direction for the early detection of adverse brain outcomes in FGR and SGA neonates. The studies investigated potential diagnostic blood biomarkers from cord and neonatal blood or serum from FGR and SGA human neonates. Results were often conflicting with heterogeneity common in the biomarkers examined, timepoints, gestational age, and definitions of FGR and SGA used. Due to these variations, it was difficult to draw strong conclusions from the results. The search for blood biomarkers of brain injury in FGR and SGA neonates should continue as early detection and intervention is critical to improve outcomes for these neonates.胎儿生长受限（FGR）与小于胎龄儿（SGA）的新生儿，其死亡与发病风险均显著升高。尽管两类新生儿均存在胎龄对应出生体重偏低的情况，但胎儿生长受限的诊断还需结合脐动脉多普勒评估、生理判定指标、新生儿营养不良特征以及宫内生长迟缓状况。胎儿生长受限与小于胎龄儿均与不良神经发育结局密切相关，此类结局涵盖学习与行为障碍、脑瘫等多种病症。目前约有50%的胎儿生长受限新生儿直至分娩前后才得以确诊，且此类诊断无法进一步提示脑损伤或不良神经发育结局的风险。血液生物标志物或许是一项颇具前景的辅助工具，若能确立可反映新生儿脑损伤风险的血液生物标志物，将为早期筛查乃至更早的临床干预提供契机。本综述旨在梳理当前相关研究文献，为未来探索胎儿生长受限与小于胎龄儿不良脑结局的早期筛查方向提供参考依据。本综述所纳入的相关研究均针对胎儿生长受限与小于胎龄儿人类新生儿的脐带血、新生儿血或血清中的潜在诊断性血液生物标志物展开了调研。现有研究结果常存在分歧，且在检测的生物标志物类型、采样时间点、胎龄以及胎儿生长受限与小于胎龄儿的定义等方面普遍存在异质性。受上述差异影响，难以从研究结果中得出确凿可靠的结论。鉴于早期筛查与干预对改善此类新生儿结局至关重要，针对胎儿生长受限与小于胎龄儿脑损伤相关血液生物标志物的探索仍需持续推进。