Miriam Illa

Neurodevelopmental outcome in 2‐year‐old infants who were small‐for‐gestational age term fetuses with cerebral blood flow redistribution

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.

Altered small-world topology of structural brain networks in infants with intrauterine growth restriction and its association with later neurodevelopmental outcome.

Intrauterine growth restriction (IUGR) due to placental insufficiency affects 5-10% of all pregnancies and it is associated with a wide range of short- and long-term neurodevelopmental disorders. Prediction of neurodevelopmental outcomes in IUGR is among the clinical challenges of modern fetal medicine and pediatrics. In recent years several studies have used magnetic resonance imaging (MRI) to demonstrate differences in brain structure in IUGR subjects, but the ability to use MRI for individual predictive purposes in IUGR is limited. Recent research suggests that MRI in vivo access to brain connectivity might have the potential to help understanding cognitive and neurodevelopment processes. Specifically, MRI based connectomics is an emerging approach to extract information from MRI data that exhaustively maps inter-regional connectivity within the brain to build a graph model of its neural circuitry known as brain network. In the present study we used diffusion MRI based connectomics to obtain structural brain networks of a prospective cohort of one year old infants (32 controls and 24 IUGR) and analyze the existence of quantifiable brain reorganization of white matter circuitry in IUGR group by means of global and regional graph theory features of brain networks. Based on global and regional analyses of the brain network topology we demonstrated brain reorganization in IUGR infants at one year of age. Specifically, IUGR infants presented decreased global and local weighted efficiency, and a pattern of altered regional graph theory features. By means of binomial logistic regression, we also demonstrated that connectivity measures were associated with abnormal performance in later neurodevelopmental outcome as measured by Bayley Scale for Infant and Toddler Development, Third edition (BSID-III) at two years of age. These findings show the potential of diffusion MRI based connectomics and graph theory based network characteristics for estimating differences in the architecture of neural circuitry and developing imaging biomarkers of poor neurodevelopment outcome in infants with prenatal diseases.

Estimated weight centile as a predictor of perinatal outcome in small‐for‐gestational‐age pregnancies with normal fetal and maternal Doppler indices

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.

Neurobehavioral outcomes in preterm, growth‐restricted infants with and without prenatal advanced signs of brain‐sparing

To evaluate the neurobehavioral outcomes of preterm infants with intrauterine growth restriction (IUGR), with and without prenatal advanced brain‐sparing.

Neonatal Neurobehavior and Diffusion MRI Changes in Brain Reorganization Due to Intrauterine Growth Restriction in a Rabbit Model

Background 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. Methodology/Principal Findings 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. Conclusions 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.

Metabolomics Reveals Metabolic Alterations by Intrauterine Growth Restriction in the Fetal Rabbit Brain

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.

Growth deficit in term small-for-gestational fetuses with normal umbilical artery Doppler is associated with adverse outcome

Abstract Aim: The association between the growth deficit and the occurrence of adverse outcome was analyzed in a cohort of small-for-gestational age fetuses delivered at term. Methods: A cohort of consecutive singleton fetuses suspected of being SGA during the late third trimester and delivered beyond 37 weeks was selected. Growth deficit area was calculated as that between the individual 10th centile curve of the customized optimal fetal weight and the individual fetal growth curve. Results: A total of 55 women were included. Of these, 16 had 28 adverse events: eight cases of umbilical artery pH<7.15, 9 cases of caesarean section for fetal distress and 11 cases of admission to neonatal intensive care unit. Whereas the mean area of growth deficit was 8.8 kg×week units (SD 7.6) for cases with normal outcomes, it was 13.9 (SD 8.04) for cases with adverse outcomes (P=0.03). A growth area deficit >10 units, predicted the occurrence of adverse outcome with a sensitivity and specificity of 62% and 68%, respectively. Conclusion: In term growth restricted fetuses the degree of growth deficit from the optimal customized growth may be used to identify a subgroup of fetuses at high-risk for adverse outcomes.

Prediction of adverse perinatal outcome at term in small-for-gestational age fetuses: comparison of growth velocity vs. customized assessment.

Abstract Objective: To explore the ability of growth velocity and customized standards of fetal weight to predict adverse outcomes in small fetuses delivered at term. Methods: We evaluated a cohort of 86 consecutive singletons suspected to be small for gestational age during the third trimester (estimated fetal weight <10th centile), who had normal umbilical artery Doppler and ultimately delivered at term. Conditional growth velocity and customized fetal growth were compared for the prediction of adverse outcome. Results: Overall, customized growth assessment showed better sensitivity than growth velocity assessment (57.1% vs. 42.9% for a 10th centile cut-off) for the prediction of adverse outcome, but with comparable specificity. The odds of having an adverse outcome for women with a positive test compared with women with a negative test were 1.54 and 3.22 for the 10th centile growth velocity and customized definitions, respectively. The area under the curve for the prediction of adverse outcome was larger for customized than for growth velocity standards (0.65 vs. 0.59), albeit without statistical significance. Conclusions: Our study suggests that customized growth assessment may have better accuracy in predicting adverse perinatal outcome than growth velocity in small fetuses with normal umbilical Doppler delivered at term.

Long-Term Functional Outcomes and Correlation with Regional Brain Connectivity by MRI Diffusion Tractography Metrics in a Near-Term Rabbit Model of Intrauterine Growth Restriction

Background Intrauterine growth restriction (IUGR) affects 5–10% of all newborns and is associated with increased risk of memory, attention and anxiety problems in late childhood and adolescence. The neurostructural correlates of long-term abnormal neurodevelopment associated with IUGR are unknown. Thus, the aim of this study was to provide a comprehensive description of the long-term functional and neurostructural correlates of abnormal neurodevelopment associated with IUGR in a near-term rabbit model (delivered at 30 days of gestation) and evaluate the development of quantitative imaging biomarkers of abnormal neurodevelopment based on diffusion magnetic resonance imaging (MRI) parameters and connectivity. Methodology At +70 postnatal days, 10 cases and 11 controls were functionally evaluated with the Open Field Behavioral Test which evaluates anxiety and attention and the Object Recognition Task that evaluates short-term memory and attention. Subsequently, brains were collected, fixed and a high resolution MRI was performed. Differences in diffusion parameters were analyzed by means of voxel-based and connectivity analysis measuring the number of fibers reconstructed within anxiety, attention and short-term memory networks over the total fibers. Principal Findings The results of the neurobehavioral and cognitive assessment showed a significant higher degree of anxiety, attention and memory problems in cases compared to controls in most of the variables explored. Voxel-based analysis (VBA) revealed significant differences between groups in multiple brain regions mainly in grey matter structures, whereas connectivity analysis demonstrated lower ratios of fibers within the networks in cases, reaching the statistical significance only in the left hemisphere for both networks. Finally, VBA and connectivity results were also correlated with functional outcome. Conclusions The rabbit model used reproduced long-term functional impairments and their neurostructural correlates of abnormal neurodevelopment associated with IUGR. The description of the pattern of microstructural changes underlying functional defects may help to develop biomarkers based in diffusion MRI and connectivity analysis.

A magnetic resonance image based atlas of the rabbit brain for automatic parcellation.

Rabbit brain has been used in several works for the analysis of neurodevelopment. However, there are not specific digital rabbit brain atlases that allow an automatic identification of brain regions, which is a crucial step for various neuroimage analyses, and, instead, manual delineation of areas of interest must be performed in order to evaluate a specific structure. For this reason, we propose an atlas of the rabbit brain based on magnetic resonance imaging, including both structural and diffusion weighted, that can be used for the automatic parcellation of the rabbit brain. Ten individual atlases, as well as an average template and probabilistic maps of the anatomical regions were built. In addition, an example of automatic segmentation based on this atlas is described.