Premature placental aging in term small-for-gestational-age and fetal-growth-restricted fetuses

: 足月小于胎龄儿和生长受限胎儿胎盘过早老化 目的: 通过衰老和细胞凋亡标志物分析，对足月小于胎龄儿(SGA)或生长受限(FGR)胎儿的胎盘老化过程进行综合评估。 方法: 这是一项对足月分娩的单胎妊娠进行的前瞻性巢式病例对照研究，研究纳入21例胎儿正常发育的对照组妊娠和36例小胎儿:SGA(出生体重介于3%和9%之间，胎儿胎盘多普勒正常；n=18)或FGR(出生体重<3%和/或脑胎盘比值异常和/或子宫动脉多普勒异常；n=18)。出生时采集胎盘标本，分别检测端粒酶活性、端粒长度(通过将端粒序列(T)的扩增产物数量与基因36B4(S)的单一拷贝扩增产物数量进行比较来量化)及衰老的RNA表达(Sirtuins 1、3、6)和细胞凋亡(p53、p21、BAX、Caspases 3、9)标志物(利用2-∆∆Ct 法分析)，并在三组中进行比较。 结果: 与正常发育的胎儿相比，SGA和FGR妊娠均表现出胎盘老化加速的迹象，包括降低的端粒酶活性(均数 ± 标准差，对照组12.8 ± 6.6% vs SGA组7.98 ± 4.2% vs FGR组7.79 ± 4.6%；P=0.008)、缩短的端粒(均数 ± 标准差 T/S 比值，对照组1.20 ± 0.6 vs SGA组1.08 ± 0.9 vs FGR组0.66 ± 0.5； P=0.047)及Sirtuin-1 RNA表达减弱(均数 ± 标准差2-∆∆Ct ；对照组1.55 ± 0.8 vs SGA组0.91 ± 0.8 vs FGR组0.63 ± 0.5；P=0.001)和P53 RNA表达增强(中位数(四分位数间距)2-∆∆Ct ，对照组1.07(0.3-3.3) vs SGA组5.39(0.6-15)vs FGR组3.75(0.9-7.8)； P=0.040)。与对照相相比，FGR病例出现细胞凋亡迹象，并伴随caspase-3 RNA水平升高(中位数(四分位数间距)2-∆∆Ct ,，对照组0.94(0.7-1.7)vs FGR组3.98(0.9-31)；P=0.031)及caspase-9 RNA水平升高(中位数(四分位数间距)2-∆∆Ct，对照组1.21(0.6-4.0)vs FGR组3.87(1.5-9.0)；P=0.037)。此外，随着病情的加重，Sirtuin-1 RNA的表达、端粒酶活性、端粒长度和Caspase-3活性在各组间呈明显的线性趋势。 结论: 两种临床形式的迟发性胎小症(SGA和FGR)均出现胎盘加速老化的现象，支持共同的病理生理机制，并对SGA胎儿天生小的概念提出质疑。. METHODS: This was a prospective nested case-control study of singleton pregnancies delivered at term, including 21 control pregnancies with normally grown fetuses and 36 with a small fetus classified as SGA (birth weight between the 3rd and 9th percentiles and normal fetoplacental Doppler; n = 18) or FGR (birth weight < 3rd percentile and/or abnormal cerebroplacental ratio and/or uterine artery Doppler; n = 18). Telomerase activity, telomere length (quantified by comparing the amount of amplification product for the telomere sequence (T) to that of a single copy of the gene 36B4 (S)) and RNA expression of senescence (Sirtuins 1, 3 and 6) and apoptosis (p53, p21, BAX and Caspases 3 and 9) markers (analyzed using the 2-ΔΔCt method) were determined in placental samples collected at birth and compared between the three groups. RESULTS: Compared to pregnancies with a normally grown fetus, both SGA and FGR pregnancies presented signs of accelerated placental aging, including lower telomerase activity (mean ± SD, 12.8 ± 6.6% in controls vs 7.98 ± 4.2% in SGA vs 7.79 ± 4.6% in FGR; P = 0.008), shorter telomeres (mean ± SD T/S ratio, 1.20 ± 0.6 in controls vs 1.08 ± 0.9 in SGA vs 0.66 ± 0.5 in FGR; P = 0.047) and reduced Sirtuin-1 RNA expression (mean ± SD 2-ΔΔCt , 1.55 ± 0.8 in controls vs 0.91 ± 0.8 in SGA vs 0.63 ± 0.5 in FGR; P = 0.001) together with increased p53 RNA expression (median (interquartile range) 2-ΔΔCt , 1.07 (0.3-3.3) in controls vs 5.39 (0.6-15) in SGA vs 3.75 (0.9-7.8) in FGR; P = 0.040). FGR cases presented signs of apoptosis, with increased Caspase-3 RNA levels (median (interquartile range) 2-ΔΔCt , 0.94 (0.7-1.7) in controls vs 3.98 (0.9-31) in FGR; P = 0.031) and Caspase-9 RNA levels (median (interquartile range) 2-ΔΔCt , 1.21 (0.6-4.0) in controls vs 3.87 (1.5-9.0) in FGR; P = 0.037) compared with controls. In addition, Sirtuin-1 RNA expression, telomerase activity, telomere length and Caspase-3 activity showed significant linear trends across groups as severity of the condition increased. CONCLUSIONS: Accelerated placental aging was observed in both clinical forms of late-onset fetal smallness (SGA and FGR), supporting a common pathophysiology and challenging the concept of SGA fetuses being constitutionally small. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.