Objective: To assess the neurodevelopmental outcome at 2 years of age of children who had been small‐for‐gestational‐age (SGA) term babies with cerebral blood flow redistribution.Methods: Perinatal outcome was assessed in a cohort of 97 term singleton appropriate‐for‐gestational‐age and 125 term singleton SGA fetuses with normal umbilical artery Doppler, stratified according to the presence of cerebral blood flow redistribution. Neurodevelopmental outcome was assessed prospectively at 2 years of age by means of the 24‐month Age & Stage Questionnaire (ASQ).Results: Of the 125 SGA fetuses, 25 had redistribution of the cerebral blood flow, and 100 did not. There were no significant differences in perinatal outcome between these two SGA groups. At 2 years of age, children who had been SGA fetuses with middle cerebral artery (MCA) pulsatility index (PI) < 5^th centile had a higher incidence of suboptimal neurodevelopmental outcome compared with those with normal MCA‐PI (52% vs. 31%; P = 0.049) and a lower mean centile in communication (53.1 vs. 67.4; P = 0.006) and problem‐solving (39.7 vs. 47.4; P = 0.04) areas.Conclusion: SGA fetuses with cerebral blood flow redistribution have a higher risk of subtle neurodevelopmental deficits at 2 years of age. This challenges the concept that fetal cerebral redistribution is an entirely protective mechanism and suggests MCA‐PI as a risk stratifying factor for adverse neurodevelopmental outcome. Copyright © 2008 ISUOG. Published by John Wiley & Sons, Ltd.

Objective: To evaluate the risk of adverse perinatal outcome according to estimated fetal weight (EFW) in a cohort of term small‐for‐gestational‐age (SGA) pregnancies with normal umbilical, fetal middle cerebral and maternal uterine artery Doppler indices.Methods: A cohort of 132 term SGA fetuses with normal umbilical artery pulsatility index (PI), mean uterine artery PI and cerebroplacental ratio was compared to a control group of 132 appropriate‐for‐gestational‐age babies, matched by gestational age at delivery. The capacity of the EFW percentile to predict Cesarean delivery, Cesarean delivery for non‐reassuring fetal status (NRFS), neonatal acidosis and days of neonatal hospitalization was analyzed.Results: As a whole, SGA fetuses with normal Doppler findings did not show a statistically significant difference for intrapartum Cesarean delivery (22.0 vs. 15.9%; P = 0.21) and neonatal acidosis (3.3 vs. 1.5%; P = 0.30), but had significantly higher risk for Cesarean delivery for NRFS (15.9 vs. 5.3%; P < 0.01) and longer neonatal hospitalization (1.39 vs. 0.87 days; P < 0.05) than did controls. SGA fetuses with EFW < 3^rd centile had a significantly higher incidence of intrapartum Cesarean delivery (30.0 vs. 15.3%; P = 0.04), Cesarean delivery for NRFS (25.0 vs. 8.3%; P < 0.01) and longer neonatal hospitalization (2.0 vs. 0.9 days; P < 0.01) than those with EFW ≥ 3^rd centile. SGA cases with EFW ≥ 3^rd centile had perinatal outcomes similar to those of controls with normal EFW.Conclusion: Among SGA fetuses with normal placental and cerebral Doppler ultrasound findings, EFW < 3^rd centile discriminates between those with a higher risk for adverse perinatal outcome and those with outcomes similar to those of normally grown fetuses. Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.

Intrauterine growth restriction (IUGR) affects 5–10% of all newborns and is associated with a high risk of abnormal neurodevelopment. The timing and patterns of brain reorganization underlying IUGR are poorly documented. We developed a rabbit model of IUGR allowing neonatal neurobehavioral assessment and high resolution brain diffusion magnetic resonance imaging (MRI). The aim of the study was to describe the pattern and functional correlates of fetal brain reorganization induced by IUGR. IUGR was induced in 10 New Zealand fetal rabbits by ligation of 40–50% of uteroplacental vessels in one horn at 25 days of gestation. Ten contralateral horn fetuses were used as controls. Cesarean section was performed at 30 days (term 31 days). At postnatal day +1, neonates were assessed by validated neurobehavioral tests including evaluation of tone, spontaneous locomotion, reflex motor activity, motor responses to olfactory stimuli, and coordination of suck and swallow. Subsequently, brains were collected and fixed and MRI was performed using a high resolution acquisition scheme. Global and regional (manual delineation and voxel based analysis) diffusion tensor imaging parameters were analyzed. IUGR was associated with significantly poorer neurobehavioral performance in most domains. Voxel based analysis revealed fractional anisotropy (FA) differences in multiple brain regions of gray and white matter, including frontal, insular, occipital and temporal cortex, hippocampus, putamen, thalamus, claustrum, medial septal nucleus, anterior commissure, internal capsule, fimbria of hippocampus, medial lemniscus and olfactory tract. Regional FA changes were correlated with poorer outcome in neurobehavioral tests. IUGR is associated with a complex pattern of brain reorganization already at birth, which may open opportunities for early intervention. Diffusion MRI can offer suitable imaging biomarkers to characterize and monitor brain reorganization due to fetal diseases.

Background Intrauterine Growth Restriction (IUGR) due to placental insufficiency occurs in 5–10% of pregnancies and is a major risk factor for abnormal neurodevelopment. The perinatal diagnosis of IUGR related abnormal neurodevelopment represents a major challenge in fetal medicine. The development of clinical biomarkers is considered a promising approach, but requires the identification of biochemical/molecular alterations by IUGR in the fetal brain. This targeted metabolomics study in a rabbit IUGR model aimed to obtain mechanistic insight into the effects of IUGR on the fetal brain and identify metabolite candidates for biomarker development. Methodology/Principal Findings At gestation day 25, IUGR was induced in two New Zealand rabbits by 40–50% uteroplacental vessel ligation in one horn and the contralateral horn was used as control. At day 30, fetuses were delivered by Cesarian section, weighed and brains collected for metabolomics analysis. Results showed that IUGR fetuses had a significantly lower birth and brain weight compared to controls. Metabolomics analysis using liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) and database matching identified 78 metabolites. Comparison of metabolite intensities using a t-test demonstrated that 18 metabolites were significantly different between control and IUGR brain tissue, including neurotransmitters/peptides, amino acids, fatty acids, energy metabolism intermediates and oxidative stress metabolites. Principle component and hierarchical cluster analysis showed cluster formations that clearly separated control from IUGR brain tissue samples, revealing the potential to develop predictive biomarkers. Moreover birth weight and metabolite intensity correlations indicated that the extent of alterations was dependent on the severity of IUGR. Conclusions IUGR leads to metabolic alterations in the fetal rabbit brain, involving neuronal viability, energy metabolism, amino acid levels, fatty acid profiles and oxidative stress mechanisms. Overall findings identified aspargine, ornithine, N-acetylaspartylglutamic acid, N-acetylaspartate and palmitoleic acid as potential metabolite candidates to develop clinical biomarkers for the perinatal diagnosis of IUGR related abnormal neurodevelopment.