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

Objective To perform a comprehensive assessment of the placental aging process in small term fetuses classified as being small-for-gestational age (SGA) or having fetal growth restriction (FGR) through analysis of senescence and apoptosis markers. 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(-Delta Delta Ct) 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 RNAexpression (mean +/- SD 2(-Delta Delta Ct), 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(-Delta Delta Ct), 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(-Delta Delta Ct), 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(-Delta Delta Ct), 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 (c) 2018 ISUOG. Published by John Wiley & Sons Ltd.