Brain metabolite alterations in infants born preterm with intrauterine growth restriction: association with structural changes and neurodevelopmental outcome.
BACKGROUND
Intrauterine growth restriction and premature birth represent 2 independent problems that may occur simultaneously and contribute to impaired neurodevelopment.


OBJECTIVE
The objective of the study was to assess changes in the frontal lobe metabolic profiles of 1 year old intrauterine growth restriction infants born prematurely and adequate-for-gestational-age controls, both premature and term adequate for gestational age and their association with brain structural and biophysical parameters and neurodevelopmental outcome at 2 years.


METHODS
A total of 26 prematurely born intrauterine growth restriction infants (birthweight <10th centile for gestational age), 22 prematurely born but adequate for gestational age controls, and 26 term adequate-for-gestational-age infants underwent brain magnetic resonance imaging and magnetic resonance spectroscopy at 1 year of age during natural sleep, on a 3 Tesla scanner. All brain T1-weighted and diffusion-weighted images were acquired along with short echo time single-voxel proton spectra from the frontal lobe. Magnetic resonance imaging/magnetic resonance spectroscopy data were processed to derive structural, biophysical, and metabolic information, respectively. Neurodevelopment was evaluated at 2 years of age using the Bayley Scales 3rd edition, assessing cognitive, language, motor, socioemotional, and adaptive behavior.


RESULTS
Prematurely born intrauterine growth restriction infants had slightly smaller brain volumes and increased frontal lobe white matter mean diffusivity compared with both prematurely born but adequate for gestational age and term adequate for gestational age controls. Frontal lobe N-acetylaspartate levels were significantly lower in prematurely born intrauterine growth restriction than in prematurely born but adequate for gestational age infants but increased in prematurely born but adequate for gestational age compared with term adequate-for-gestational-age infants. The prematurely born intrauterine growth restriction group also showed slightly lower choline compounds, borderline decrements of estimated glutathione levels, and increased myoinositol to choline ratios, compared with prematurely born but adequate for gestational age controls. These specific metabolite changes were locally correlated to lower gray matter content and increased mean diffusivity and reduced white matter fraction and fractional anisotropy. Prematurely born intrauterine growth restriction infants also showed a tendency for poorer neurodevelopmental outcome at 2 years, associated with lower levels of frontal lobe N-acetylaspartate at 1 year within the preterm subset.


CONCLUSIONS
Preterm intrauterine growth restriction infants showed altered brain metabolite profiles during a critical stage of brain maturation, which correlate with brain structural and biophysical parameters and neurodevelopmental outcome. Our results suggest altered neurodevelopmental trajectories in preterm intrauterine growth restriction and adequate-for-gestational-age infants, compared with term adequate-for-gestational-age infants, which require further characterization.
BCNatal-Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu), Fetal i+D Fetal Medicine Research Center, IDIBAPS, University of Barcelona, Barcelona, Spain; Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain; Fundació Hospital Sant Joan de Déu, Barcelona, Spain. Electronic address: portasferre@clinic.ub.es.
Rui V
RV
Simões
BCNatal-Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu), Fetal i+D Fetal Medicine Research Center, IDIBAPS, University of Barcelona, Barcelona, Spain; Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain.
Emma
E
Muñoz-Moreno
Fetal Medicine and Surgery Research Unit, Fetal Medicine Mexico, Unidad de Investigación en Neurodesarrollo, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Campus Juriquilla, Querétaro, Mexico.
Mónica
M
Cruz-Lemini
BCNatal-Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu), Fetal i+D Fetal Medicine Research Center, IDIBAPS, University of Barcelona, Barcelona, Spain; Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain.
Elisenda
E
Eixarch
Department of Radiology and Centre de Diagnostic per la Imatge, Hospital Clínic, Barcelona, Spain; Magnetic Resonance Image Core Facility, Institut d'Investigacions Biomediques August Pi i Sunyer, IDIBAPS Barcelona, Spain.
Núria
N
Bargalló
BCNatal-Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu), Fetal i+D Fetal Medicine Research Center, IDIBAPS, University of Barcelona, Barcelona, Spain; Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain.
Magdalena
M
Sanz-Cortés
BCNatal-Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu), Fetal i+D Fetal Medicine Research Center, IDIBAPS, University of Barcelona, Barcelona, Spain; Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain.
Eduard
E
Gratacós
D000223:Adaptation, Psychological; D016880:Anisotropy; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D002675:Child, Preschool; D002794:Choline / Q000378:metabolism; D003071:Cognition; D015331:Cohort Studies; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D005317:Fetal Growth Retardation / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000523:psychology; D005625:Frontal Lobe / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D066128:Gray Matter / Q000000981:diagnostic imaging / Q000473:pathology; D006801:Humans; D007223:Infant; D007234:Infant, Premature; D007294:Inositol / Q000378:metabolism; D007804:Language Development; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009929:Organ Size; D047928:Premature Birth; D011446:Prospective Studies; D066127:White Matter / Q000000981:diagnostic imaging / Q000473:pathology
D001224:Aspartic Acid; D007294:Inositol; C000179:N-acetylaspartate; D005978:Glutathione; D002794:Choline
brain metabolism; brain structure; intrauterine growth restriction; magnetic resonance spectroscopy; neurodevelopment; preterm birth