It is under debate how preferential perfusion of the brain (brain-sparing) in fetal growth restriction (FGR) relates to long-term neurodevelopmental outcome. Epigenetic modification of neurotrophic genes by altered fetal oxygenation may be involved. To explore this theory, we performed a follow-up study of 21 FGR children, in whom we prospectively measured the prenatal cerebroplacental ratio (CPR) with Doppler sonography. At 4 years of age, we tested their neurodevelopmental outcome using the Wechsler Preschool and Primary Scale of Intelligence, the Child Behavior Checklist, and the Behavior Rating Inventory of Executive Function. In addition, we collected their buccal DNA to determine the methylation status at predefined genetic regions within the genes hypoxia-inducible factor-1 alpha (HIF1A), vascular endothelial growth factor A (VEGFA), erythropoietin (EPO), EPO-receptor (EPOR), brain-derived neurotrophic factor (BDNF), and neurotrophic tyrosine kinase, receptor, type 2 (NTRK2) by pyrosequencing. We found that FGR children with fetal brain-sparing (CPR <1, n = 8) demonstrated a trend (0.05 < p < 0.1) toward hypermethylation of HIF1A and VEGFA at their hypoxia-response element (HRE) compared with FGR children without fetal brain-sparing. Moreover, in cases with fetal brain-sparing, we observed statistically significant hypermethylation at a binding site for cyclic adenosine monophophate response element binding protein (CREB) of BDNF promoter exon 4 and hypomethylation at an HRE located within the NTRK2 promoter (both p <0.05). Hypermethylation of VEGFA was associated with a poorer Performance Intelligence Quotient, while hypermethylation of BDNF was associated with better inhibitory self-control (both p <0.05). These results led us to formulate the hypothesis that early oxygen-dependent epigenetic alterations due to hemodynamic alterations in FGR may be associated with altered neurodevelopmental outcome in later life. We recommend further studies to test this hypothesis.

Sow litter sizes have increased, subjecting more small piglets to intra-uterine growth restriction (IUGR). Research on the development and growth of IUGR pigs is limited. The objective of this study was to compare the body composition and organ development of IUGR pigs at weaning, and to estimate their growth performance from birth to 30 kg. A total of 142 IUGR and 142 normal piglets were classified at birth based on their head morphology. At weaning, 20 IUGR and 20 normal piglets were collected, a whole-body dual-energy x-ray absorption scan was performed, and the piglets were euthanized for organ measurements. Body weight (BW) was measured weekly from birth to 30 kg, rectal temperature and whole-blood glucose levels were measured weekly from birth to weaning, and blood samples were collected at days 7, 14 and 21 for IGF-1 analysis. Results showed that IUGR pigs have a similar percentage of adipose tissue (P > 0.05) compared to normal pigs at 24 days of age. Organs were smaller (P < 0.001) in IUGR pigs than in normal pigs, whereas brain, liver, lungs and adrenal glands were relatively larger (P < 0.05) in relation to the BW of IUGR pigs. Average birth weight (BiW) of normal pigs was greater (P < 0.001) compared with IUGR pigs (1.38 v. 0.75 kg), and the average daily gain (ADG) of IUGR pigs was reduced from day 0 to 14, day 0 to 28 (weaning) and from weaning to 30 kg compared to normal pigs. From birth to weaning at day 28, IUGR piglets had a 72.9 g/day greater fractional ADG (FADG) in relation to their BiW (P < 0.05), but FADG did not differ (P > 0.05) from weaning to 30 kg. Rectal temperature of IUGR piglets was greater (P < 0.05) on day 7 compared with normal piglets, and, even though blood glucose levels were decreased (P < 0.001) in IUGR piglets at day 0, neither glucose nor IGF-1 concentrations differed (P > 0.05) between IUGR and normal piglets. In conclusion, IUGR piglets exhibited some relatively larger organs at weaning compared to normal pigs, but body composition was similar between IUGR and normal pigs. In addition, IUGR pigs had a reduced ADG from birth to 30 kg, and, although they exhibited a greater FADG during nursing, IUGR pigs still require six additional days to reach a BW of 30 kg in comparison to normal pigs.