This study demonstrates that measuring the diameters of the cerebral structures and the cerebral cavity on raw MRI images at term may represent a simple and reliable approach for the evaluation of brain size and hence brain growth in the at-risk infant. Our results show striking differences between preterm and full term infants. The bifrontal cerebral, biparietal cerebral and transverse cerebellar diameters were clearly reduced in preterm infants, without an increase in the fronto-occipital diameter. The ventricular size was larger in preterm infants, the difference being significant only for the left side. In preterm infants as in full term infants, the gestational age at MRI was correlated with the cerebral diameters which continued to increase over the last weeks of gestation. The ventricular size and the extra axial space dimensions were not affected by the gestational age at MRI. Gender influenced some parameters with males having larger bifrontal and biparietal diameters. Brain metrics, as one-dimensional measures on qualitative MR images, were well correlated to the 3-dimensional volumetric data previously calculated in this cohort and were also correlated at a lesser degree with the head circumference.
The measures obtained in our full term infants appear in accordance with those previously published with the same methodology on fetal MRIs9
. The transverse cerebellar diameter observed in the term infants scanned at 40 weeks PMA was slightly larger than the fetal brain results obtained at 37–38 weeks GA. That is likely to be explained by the rapid growth rate of the cerebellum during the last trimester11
. Few data exist about such MRI measures utilized postnatally. In one study comparing ultrasound and MRI measures in 26 preterm and 8 term infants scanned after 37 weeks, similar measures for the length of the corpus callosum and transverse cerebellum to those in our study were documented12
also observed a similar length for the corpus callosum, splenium of the corpus callosum, the bitemporal diameter and the fronto-occipital diameter in 20 term infants. This study then compared these measures with 24 low risk preterm infants at term after reconstruction of the sagittal and axial slices and alignment on the Talairach atlas. The authors found similar results to ours for the length of the corpus callosum (no difference) and the bitemporal diameter (decreased in preterm infants). But they observed a significant increase in the fronto-occipital diameter, which they hypothesized reflected the non-synostotic dolichocephaly commonly observed in preterm infants14
due to their sideway head position required by the respiratory support. In contrast in our study, we did not find any difference in the fronto-occipital diameter in our preterm infants. This may have differed as many of the infants in our cohort had water pillows, a method known to prevent head deformation15,16
and were nursed supine from the first days of life as early endotracheal extubation to nasal CPAP was the common practice in the NICU.
Smaller brain volumes in children and adolescents born preterm have been described in several studies, along with ventricular enlargement and an increased volume of CSF. Brain metrics, similar to those used in this study have been applied in evaluating adolescents born preterm with reductions noted in coronal and sagittal diameters and length of corpus callosum17
. Using manual measurement in 66 preterm and 48 full term individuals scanned at 15 years, Nosarti7
also demonstrated a decreased whole brain volume (−6%), reduced cortical grey matter (−11.8%) and enlarged ventricles (+42 %) which persisted after controlling for brain volume. Semi-automated volumetric techniques have explored both regional and tissue specific alterations in brain structure in preterm adolescents. A recent large study demonstrated decreased grey matter volume in temporal, frontal and occipital cortices as well as in cerebellum, putamen and thalamus18
. In this study, loss in white matter volume was observed in the brain stem, the internal capsule and the temporal and frontal lobes. Interestingly some cerebral regions demonstrated increased grey matter and white matter volume. These increases were most marked in adolescents who had suffered from major neonatal neuropathologies and suggest that a compensatory abnormal cytoarchitectural organization may have developed secondary to cerebral injury Consistent with the hypothesis of abnormal organization, alterations in orbito frontal sulcal formation has been shown in ex-preterm adolescents19
Importantly, reduced volume and/or altered cerebral structure have been linked to suboptimal functional outcomes. For example, lower IQ has been shown to be associated with smaller corpus callosum in very preterm infants 20,21
, bilateral reduction of the parieto-occipital volumes22
, and reduced cerebellar volumes23
Computational morphometric volumetric techniques have notable variation in the findings in preterm infants at term equivalent. There is a consensus across the studies documenting increased CSF and reduced deep gray matter volumes24,25
. However, variation exists in the delineation of reductions in cerebellar volumes which are found universally in one study11
, or only in the presence of injury in others 27,28
. Variation also exists in relation to total brain tissue volumes. Previous data in this same cohort identified a reduction in total brain tissue volume6
in both low and high risk preterm infants compared with term infants in a similar fashion to another previous smaller cohort study28
. However, other studies with a smaller number of subjects have not demonstrated this reduction in brain volume in preterm infants 29
. In one larger study (89 preterm compared to 20 full term) Boardman30
described increased ventricular CSF volume with similar total brain volumes. In contrast to our study, the Boardman cohort consisted of more mature low risk preterm infants (mean GA at birth 29.9 weeks, mean birthweight 1290 g) whose head circumference did not differ from the control population. Such discrepancies had raised the question of the timing of the alterations in brain structure - either during the neonatal period or later in childhood. Our results using simple measurements confirm that impairment in brain growth or brain atrophy may be present at term-equivalent age. This emphasizes the need for a better understanding of the factors influencing brain growth during the stay within the NICU. The apparent discordant results within this field may be related to differences in population characteristics as large variations in prenatal and postnatal standard of cares between countries have been demonstrated31
There are limitations to our approach. The imaging protocol and sequence acquisition varied throughout the study period due to considerations regarding volumetric analyses. The small size of the control cohort further weakened the statistical analysis. In particular, the small number of control infants with sagittal slices lowered the statistical power for the group comparisons for the fronto-occiptal diameter and the length of corpus callosum. The positions of the landmarks were not precisely defined as the images were not realigned in AC-PC space. As the principal aim was to develop a simple and widely applicable method for standard clinical practice, we choose to use the raw MR images, displayed with a Dicom Browser without reconstructions. This choice led us to eliminate some MRIs from the study because of an inaccurate orientation of the slices. However, the landmarks chosen allowed good reproducibility, with the exception of ventricular size.
It should also be noted that there was a high rate of multiple pregnancies (42%) in our preterm cohort. Twin pregnancies are associated with lower birthweight32
and higher risk of neurological impairment33
. Even though the proportion of IUGR (11%) in our population was the range of the rates previously published in similar cohorts34,35
these factors - associated with an enhanced role of genetic factors on brain size - may affect our results.
We did not adjust the brain metrics for head circumference because we considered that the skull growth in our population may reflect directly the cerebral tissue growth or CSF expansion, and not external factors. We chose to study the whole cohort including the infants with cerebral injury, including intraventricular hemorrhage. The number of infants with severe cerebral injury (cystic PVL and IVH grade 4) was low representing less than 10 % of the population. Moreover, it appears that such neuropathologies may represent only the visible component of a much more diffuse lesion that could be detected by brain metrics.