Research ReportDifferential vulnerability of gray matter and white matter to intrauterine growth restriction in preterm infants at 12 months corrected age
Introduction
Intrauterine growth restriction (IUGR) is one of the common reasons indicated for preterm delivery. This condition, due to placental insufficiency, affects 5–10% of all pregnancies and is associated with chronic hypoxia and under-nutrition during fetal life. The combination of preterm birth and IUGR results in a higher rate of perinatal complications and consequently worse long-term outcomes (Geva et al., 2006, Guellec et al., 2011, Leitner et al., 2007).
The structural alterations underlying the effects of IUGR on the preterm brain are only partially documented. In this respect, studies have been hampered by the widespread practice of using the terms small for gestational age (SGA) and IUGR synonymously. Defining SGA as a birth weight (BW) below a given threshold compared to appropriate for gestational age (AGA) groups, SGA children had smaller brain volumes (De Bie et al., 2011, Martinussen et al., 2009, Xydis et al., 2013) and altered white matter (WM) microstructure (Eikenes et al., 2012, Lepomaki et al., 2013). In contrast, comparisons between preterm neonates with and without intrauterine growth restriction, defined as BW below the 10th percentile and abnormal Doppler values within the umbilical artery, showed that IUGR is associated with reduced volumes of the cortical gray matter (GM; Tolsa et al., 2004), decreased volumes of the hippocampus (Lodygensky et al., 2008) and a discordant pattern of gyrification (Dubois et al., 2008) related to behavioral alterations. At 12 months, comparisons between preterm infants with and without growth restriction and term-born controls suggested that the most pronounced differences in the IUGR preterm group were related to a different distribution of the GM and WM (Padilla et al., 2011) as well as a different cortical brain complexity (Esteban et al., 2010), both associated to neurodevelopmental difficulties. However, the GM alterations induced by IUGR, and the existence of microstructural WM differences, in preterm infants at 12 months, excluding the influence of prematurity itself, have not been investigated.
The aims of this study were (1) to detect specific regional GM volume changes as a consequence of IUGR in preterm infants at 12 months corrected age (CA); (2) to explore whether IUGR induces specific WM microstructure alterations in the same population; and (3) to correlate these changes with birth weight and gestational age at birth. For this, we included a control group of preterm infants appropriate for gestational age (AGA) to exclude the effect of prematurity per se.
Section snippets
Results
A total of 57 infants with IUGR, 70 preterm AGA infants and 72 term-born infants were initially included. The final sample included 20 infants with IUGR, 20 preterm AGA infants and 20 term-born infants (Fig. 1). Perinatal, demographic, and anthropometric characteristics of the infants are detailed in Table 1. There were no significant differences in perinatal data between the subjects scanned and those who were not scanned. As expected, full-term children differed significantly in neonatal data
Intrauterine growth restricted group
Infants with IUGR had significantly reduced absolute global GM volumes compared to preterm AGA and term-born infants. However, relative volumes were not significantly different between groups (Table 1). Compared with term-born infants, those with IUGR had GM reductions involving predominantly the temporal lobe bilaterally, the hippocampus, the amygdala and the right perirolandic area. Additional areas of GM volume reduction were found in the right frontal lobe, left parietal lobe, perirolandic
Intrauterine growth restricted group
Compared with the preterm AGA group, infants with IUGR had clusters of decreased FA predominantly localized in the splenium of the corpus callosum, and increased FA in the anterior corona radiata (Fig. 3a, b). Additionally, IUGR infants showed clusters of increased AD comprising the forceps minor and anterior corona radiata (Fig. 3c). No significant differences were identified in any other diffusivity parameter. The analyses were repeated at different thresholds; however, no between-group
Discussion
The results of the current study suggest that in preterm infants with IUGR at 12 months CA without apparent brain lesions, the GM and WM are differentially affected. In terms of GM, the current results expand on our previous studies that have reported GM brain alterations in infants with IUGR at 12 months (Padilla et al., 2011; Esteban et al., 2010) and further demonstrate that IUGR is associated with a specific set of structural GM decrements comprising the amygdala, basal ganglia, thalami,
Correlation analysis
The correlations between FA and perinatal data suggest that increasing prematurity at birth and lower birth weight have negative effects on WM microstructure that are evident at 12 months in preterm infants with IUGR. A similar finding has been suggested in studies assessing the repercussions of prematurity in older subjects (Allin et al., 2011, Eikenes et al., 2011). In regional GM volumes, correlations were found with birth weight but not with gestational age at birth. This finding highlights
Conclusion
The current study reveals a differential effect of IUGR on the developing GM and WM with the GM exclusively being affected at 12 months CA. The GM decrements affected a specific set of structures and correlated with birth weight only. The WM in IUGR infants showed an unusual developmental pattern with increased FA and AD and correlated with birth weight and gestational age at birth. Findings in GM are consistent with and provide further support to previous results in this prenatal disorder.
Subjects
Between 2007 and 2009 a cohort of consecutive singleton infants was selected with the following inclusion criteria: (i) gestational age at birth less than 34 weeks; (ii) fetal weight below the 10th percentile for gestational age confirmed at birth, and (iii) umbilical artery Doppler pulsatility index >95th percentile in at least 2 consecutive examinations 24 h apart. The preterm and term control groups were singleton AGA infants, with a BW between the 10th and 90th customized centiles according
Acknowledgments
Funding support was provided by grants from the Cerebra Foundation for the brain-injured child (Carmarthen-Wales, UK), The Thrasher Research Fund (Salt-Lake-City, USA). NP was supported by a Sara Borrell post-doctoral fellowship (CD09/00263), Instituto de Salud Carlos III, Spain. The authors would like to thank all the participating infants and the parents, Marta Garcia and Alba Camacho for contacting and booking the infants, and Cesar Garrido for imaging acquisition.
References (35)
A fast diffeomorphic image registration algorithm
Neuroimage
(2007)- et al.
Atypical development of white matter microstructure in adolescents with autism spectrum disorders
Neuroimage
(2010) - et al.
Young adults born preterm with very low birth weight demonstrate widespread white matter alterations on brain DTI
Neuroimage
(2011) - et al.
Fractal-dimension analysis detects cerebral changes in preterm infants with and without intrauterine growth restriction
Neuroimage
(2010) - et al.
Customized birthweight standards for a Spanish population
Eur. J. Obstet. Gynecol. Reprod. Biol.
(2008) - et al.
Differential effects of intrauterine growth restriction on brain structure and development in preterm infants: a magnetic resonance imaging study
Brain Res.
(2011) - et al.
Advances in functional and structural MR image analysis and implementation as FSL
Neuroimage
(2004) - et al.
Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data
Neuroimage
(2006) - et al.
Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water
Neuroimage
(2002) - et al.
Intrauterine growth restriction affects the maturation of myelin
Exp. Neurol.
(2011)