Placenta-derived exosomes may represent an additional pathway by which the placenta communicates with the maternal system to induce maternal vascular adaptations to pregnancy and it may be affected during Fetal growth restriction (FGR). The objective of this study was to quantify the concentration of total and placenta-derived exosomes in maternal and fetal circulation in small fetuses classified as FGR or small for gestational age (SGA). Prospective cohort study in singleton term gestations including 10 normally grown fetuses and 20 small fetuses, sub-classified into SGA and FGR accordingly to birth weight (BW) percentile and fetoplacental Doppler. Exosomes were isolated from maternal and fetal plasma and characterized by morphology, enrichment of exosomal proteins, and size distribution by electron microscopy, western blot, and nanoparticle tracking analysis, respectively. Total and specific placenta-derived exosomes were determined using quantum dots coupled with CD63+ve and placental-type alkaline phosphatase (PLAP)+ve antibodies, respectively. Maternal concentrations of CD63+ve and PLAP+ve exosomes were similar between the groups (all p > 0.05). However, there was a significant positive correlation between the ratio of placental-derived to total exosomes (PLAP+ve ratio) and BW percentile, [rho = 0.77 (95% CI: 0.57 to 0.89); p = 0.0001]. The contribution of placental exosomes to the total exosome concentration in maternal and fetal circulation showed a significant decrease among cases, with lower PLAP+ve ratios in FGR compared to controls and SGA cases. Quantification of placental exosomes in maternal plasma reflects fetal growth and it may be a useful indicator of placental function.

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 3^rd and 9^th percentiles and normal fetoplacental Doppler; n = 18) or FGR (birth weight < 3^rd 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.

Fetal growth may be impaired by poor placental function or maternal conditions, each of which can influence the transfer of nutrients and oxygen from the mother to the developing fetus. Large-scale studies of metabolites (metabolomics) are key to understand cellular metabolism and pathophysiology of human conditions. Herein, maternal and cord blood plasma samples were used for NMR-based metabolic fingerprinting and profiling, including analysis of the enrichment of circulating lipid classes and subclasses, as well as the number of sub-fraction particles and their size. Changes in phosphatidylcholines and glycoproteins were prominent in growth-restricted fetuses indicating significant alterations in their abundance and biophysical properties. Lipoprotein profiles showed significantly lower plasma concentrations of cholesterol-intermediate density lipoprotein (IDL), triglycerides-IDL and high-density lipoprotein (HDL) in mothers of growth-restricted fetuses compared to controls (p < 0.05). In contrast, growth-restricted fetuses had significantly higher plasma concentrations of cholesterol and triglycerides transporting lipoproteins [LDL, IDL, and VLDL, (p < 0.005; all)], as well as increased VLDL particle types (large, medium and small). Significant changes in plasma concentrations of formate, histidine, isoleucine and citrate in growth-restricted fetuses were also observed. Comprehensive metabolic profiling reveals that both, mother and fetuses of pregnancies complicated with fetal growth restriction have a substantial disruption in lipid metabolism.