Uncomplicated Intraventricular Hemorrhage Is Followed by Reduced Cortical Volume at Near-Term Age - Pediatrics
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Uncomplicated Intraventricular Hemorrhage Is Followed by Reduced
Cortical Volume at Near-Term Age
George T. Vasileiadis, MD*‡; Neil Gelman, PhD‡; Victor K.M. Han, MD*; Lori-Anne Williams, BESc‡;
Rupinder Mann, BESc‡; Yves Bureau, PhD‡; and R. Terry Thompson, PhD‡
ABSTRACT. Background. Intraventricular hemor- The impairment was demonstrated by a 16% reduction in
rhage (IVH) is the most common brain injury among cerebral CGM volume at near-term age. The finding sup-
premature infants. Neonates with IVH are at greater risk ports concerns regarding possible glial precursor cell loss
of impaired neurodevelopmental outcomes, compared after germinal matrix IVH, but its clinical significance is
with those without IVH. IVH causes destruction of the still unclear. The alteration in brain development dem-
germinal matrix and glial precursor cells, with possible onstrated in this report supports closer neurodevelop-
effects on cortical development. mental follow-up monitoring of preterm infants with
Objective. To investigate cortical development after uncomplicated IVH. Pediatrics 2004;114:e367–e372. URL:
uncomplicated IVH (with no parenchymal involvement http://www.pediatrics.org/cgi/content/full/114/3/e367; in-
and no posthemorrhagic hydrocephalus). We hypothe- traventricular hemorrhage, brain development, brain vol-
sized that uncomplicated IVH would be followed by umes, premature infants, magnetic resonance imaging.
reduced cortical volume among premature infants at
near-term age.
Methods. A prospective cohort study was conducted, ABBREVIATIONS. IVH, intraventricular hemorrhage; CSF, cere-
with preset selection criteria. Infants with small-for-ges- brospinal fluid; CGM, cortical gray matter; SGM, subcortical gray
matter; WM, white matter; MRI, magnetic resonance imaging; CI,
tational age birth weight, congenital abnormalities or
confidence interval.
brain malformations, metabolic disorders, recurrent sep-
sis, or necrotizing enterocolitis were excluded. Also, in-
I
fants with posthemorrhagic hydrocephalus, parenchymal ntraventricular hemorrhage (IVH) is the most
involvement of hemorrhage, cystic periventricular leu- common brain injury among premature infants
komalacia, or persistent ventriculomegaly were ex-
and is the most common type of neonatal intra-
cluded, on the basis of routine serial ultrasonographic
assessments. Three-dimensional images were acquired cranial hemorrhage.1,2 The incidence is directly cor-
for 23 infants at near-term age, with 3-T magnetic reso- related with the degree of prematurity. As the sur-
nance imaging and a magnetization-prepared rapid gra- vival rates for premature infants continue to
dient echo sequence. Image analysis and segmentation of increase, IVH will continue to be a major problem in
the cerebrum in different tissue types were based on modern neonatal intensive care units.1,2 It is known
signal contrast and anatomic localization. The cortical that IVH with associated ventriculomegaly or paren-
gray matter (CGM), subcortical gray matter, white matter, chymal involvement is associated with neurodevel-
and intraventricular cerebrospinal fluid volumes of 12 opmental handicaps and disabilities.3–5 Furthermore,
infants with uncomplicated IVH were compared with studies have indicated that even children with IVH
those of 11 infants without IVH, using multivariate anal-
ysis of variance.
but no ventriculomegaly or parenchymal involve-
Results. The multivariate analysis of variance for the ment are at relatively higher risk for cognitive or
regional brain volumes in the 2 groups indicated signif- motor disabilities, compared with those without
icance (Wilks’ ⴝ 0.546). The CGM volume was signif- IVH.6,7
icantly reduced in the IVH group (no-IVH group: 122 ⴞ The basic lesion in IVH is bleeding into the highly
12.9 mL; IVH group: 102 ⴞ 14.6 mL; F ⴝ 13.218). This cellular, richly vascularized, primitive tissue of the
finding remained significant after testing for possible subependymal germinal matrix. Bleeding into the
confounding factors and adjustment for size differences germinal matrix causes destruction and possible loss
between the infants (F ⴝ 9.415). There was no difference of glial precursor cells, which are still in the process
in the volumes of subcortical gray matter, white matter,
and cerebrospinal fluid.
of migrating to the cortical layers.8,9 This may im-
Conclusions. This is the first study to document im- pede neural development, which may be manifested
paired cortical development after uncomplicated IVH. as reduced cortical volume. We therefore hypothe-
sized that uncomplicated IVH (defined as IVH with
no parenchymal involvement and no posthemor-
From the Departments of *Pediatrics and ‡Medical Biophysics, Lawson rhagic hydrocephalus) would be followed by re-
Health Research Institute, University of Western Ontario, London, Ontario,
Canada. duced cortical gray matter (CGM) volume.
Accepted for publication Apr 12, 2004. To assess the effects of IVH on cortical volume, a
DOI: 10.1542/peds.2004-0500 cohort study was conducted. Serial ultrasonographic
Reprint requests to (G.T.V.) St Joseph’s Hospital, Neonatal Medicine, Room assessments were used for the diagnosis of brain
E407, 268 Grosvenor St, London, Ontario N6A 4V2, Canada. E-mail:
gvasilei@uwo.ca
pathologic conditions, and our specialized, neonatal,
PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad- 3-T magnetic resonance imaging (MRI) system was
emy of Pediatrics. used as the investigational tool for volumetric anal-
http://www.pediatrics.org/cgi/content/full/114/3/e367 PEDIATRICS Vol. 114 No. 3 September 2004
Downloaded from www.aappublications.org/news by guest on November 6, 2021
e367yses. Three-dimensional images of the cerebrum
were segmented into CGM, subcortical gray matter
(SGM), and white matter (WM), allowing quantita-
tive volumetric analyses of these tissues.
METHODS
Subjects
Subjects were recruited from the neonatal intensive care unit of
St. Joseph’s Hospital (London, Canada). Infants with birth weights
of ⬍1500 g, appropriate for gestational age, were eligible to enter
the study.10 Exclusion criteria included congenital infections or
malformations, metabolic diseases or hypoglycemia, central ner-
vous system infections, brain malformations, seizures, hypoxic-
ischemic injury, necrotizing enterocolitis, bowel perforation, and
recurrent sepsis (defined as ⬎2 episodes of positive blood cul-
tures). Also, infants with cystic periventricular leukomalacia, per-
sistent ventriculomegaly (ventriculomegaly present at near-term
age), or any brain hemorrhage with parenchymal involvement
and posthemorrhagic hydrocephalus were excluded, on the basis
of clinical criteria and routine ultrasonographic findings. The in-
fants entered the study when they completed their 34th week
(postmenstrual age) and written informed consent was obtained
from the parents (with ethics approval from the University of
Western Ontario Health Sciences Research Ethics Board).
Routine Ultrasonography
Infants underwent serial routine cranial ultrasonographic as-
sessments. All infants enrolled in the study underwent an ultra-
sonographic evaluation at the postnatal age of 7 days, all under-
went assessments at least monthly, and all underwent ⱖ2
assessments before the corrected gestational age of 34 weeks. In all
cases, there was no evidence of IVH at the postmenstrual age of 34
weeks. Evaluations were performed by qualified radiology tech- Fig 1. Segmentation of the CGM at the level of the body of the
nicians, with a HDI 3500 scanner (Advanced Technology Labora- lateral ventricles.
tories, Bothell, WA) with a broadband transducer of 5 to 8 MHz.
Each scan received a formal clinical reading by a radiologist, who Foundation, Rochester MN). The analyst was trained in neonatal
provided a diagnosis and grading of IVH, on the basis of the brain anatomy and was blinded with respect to the subjects ana-
criteria described by Papile et al.11 For all neonates, the diagnosis lyzed. The volumetric analysis included the cerebral hemispheres,
and grading of IVH were consistent with assessments by a neo-
natologist.
MRI
The infants in our cohort underwent MRI at near-term post-
menstrual age. The infants in our cohort underwent MRI at near-
term postmenstrual age, when the contrast between gray matter
and WM is still relatively low. The use of higher-than-conven-
tional field strength (3 T) provides a greater signal-to-noise ratio.12
MRI studies were performed at 34.3 to 37.3 weeks postmenstrual
age, with a dedicated, neonatal, 3-T MRI system (IMRIS, Win-
nipeg, Canada). To avoid the need for repeated sequences (be-
cause of motion) and to minimize the time that the infants spent in
the MRI scanner, a single dose of chloral hydrate (50 mg/kg) was
administered orally, for sedation, before scanning. A neonatal
nurse and a neonatologist were present with the infant for the
duration of the scanning. Infants were continuously monitored
with pulse oximetry (8600 FO; Nonin Medical, Plymouth, MN).
The heads of the infants were lightly cushioned with towels. To
reduce acoustic noise, the head coil was lined with a layer of
barium sulfate-loaded, vinyl-foam composite (type B-14C sound-
proofing material; Wilrep Ltd, Mississauga, Ontario, Canada). In
addition, the image sequences were optimized for low acoustic
noise exposure (⬍85 dB), and ear shields (Ear Classic; Aearo Co,
Indianapolis, IN) were used to reduce noise.
Three-dimensional images of the cerebrum were acquired in 6.5
minutes with a center-out acquisition, magnetization-prepared
rapid gradient echo sequence, with timing parameters optimized
for neonatal brain imaging.13–15 Imaging parameters were as fol-
lows: intersegment repeat time: 5200 milliseconds; inversion time:
2250 milliseconds; repeat time: 10 milliseconds; echo time: 5 mil-
liseconds; image bandwidth: 33.3 kHz; flip angle: 10 degrees;
matrix size: 120 ⫻ 120 ⫻ 75; field of view: 160 ⫻ 160 ⫻ 100 mm
(giving an isotropic resolution of 1.3 mm).
Image Analysis
Three-dimensional images were analyzed by the same analyst, Fig 2. CGM at the level of the body of lateral ventricles after
with Analyze 4.0 software (Biomedical Imaging Resources, Mayo extraction.
e368 IVH IS FOLLOWED BY REDUCED CORTICAL VOLUME
Downloaded from www.aappublications.org/news by guest on November 6, 2021TABLE 1. Demographic Data (Prenatal and Birth)
Parameter No IVH (n ⫽ 11) IVH (n ⫽ 12) Significance
Maternal age, y* 28.3 ⫾ 5.8 (19–39) 26.8 ⫾ 5.5 (19–35) t ⫽ 0.61, P ⫽ .55
Pregnancy-induced hypertension (inf.) 1 1 2 ⫽ 0.01, P ⫽ .95
Prenatal corticosteroids (inf.) 9 8 2 ⫽ 0.68, P ⫽ .41
Chorioamnionitis (inf.) 0 0
Cesarean section (inf.) 4 3 2 ⫽ 0.35, P ⫽ .55
Male (inf.) 8 3 2 ⫽ 5.24, P ⬍ .05
Twins (inf.) 6 5 2 ⫽ 0.38, P ⫽ .54
Cord arterial pH* 7.27 ⫾ 0.05 (7.20–7.33) 7.28 ⫾ 0.07 (7.16–7.36) t ⫽ ⫺0.43, P ⫽ .67
Cord arterial base deficit* 5.4 ⫾ 2.1 (1.4–7.9) 4.6 ⫾ 2.5 (1.5–8.1) t ⫽ 0.79, P ⫽ .44
Apgar score at 5 min† 8 (7–9) 8 (8–9) Z ⫽ ⫺1.4, P ⫽ .16‡
Gestational age at birth, wk* 27.9 ⫾ 2.5 (24.6–31.7) 27.9 ⫾ 2.2 (24.6–32) t ⫽ 0.02, P ⫽ .99
Birth weight, g* 1106 ⫾ 277 (645–1455) 1047 ⫾ 257 (570–1470) t ⫽ 0.53, P ⫽ .60
Birth head circumference, cm* 25.9 ⫾ 2.3 (22–29) 25.5 ⫾ 2.2 (21–28.5) t ⫽ 0.37, P ⫽ .72
inf. indicates infant. All P values are 2-tailed.
* Mean ⫾ SD (range).
† Median (range).
‡ Wilcoxon test.
the lateral and third ventricles, the thalamus, and the basal gan- komalacia, diagnosed ultrasonographically, and 3 in-
glia. The brainstem was extracted below the level of the antero- fants had persistent ventriculomegaly, defined qual-
posterior commissure.
Segmentation was based on the signal contrast between tissues
itatively).
and the anatomic localization, allowing grouping of voxels into Thirty-four infants were eligible to enter the study.
regions and definition of the boundaries of different structures. After written informed consent was obtained, 25 pre-
Segmentation of regions within the cerebrum was performed on mature infants of very low birth weight were en-
axial slices, by using signal intensity thresholds and tracing (com- rolled. All infants were of white ethnicity. No preg-
bination of automated and manual functions; Figs 1 and 2). Images
were segmented into CGM, WM, intraventricular cerebrospinal nancy was a result of fertility treatment (including in
fluid (CSF), and SGM (basal ganglia and thalamus could not be vitro fertilization). No infant received repeated
differentiated from each another at the very young age of these courses of prenatal corticosteroids, and in no case
subjects). was chorioamnionitis clinically diagnosed. MRI
For each slice, the volumes of CGM, SGM, WM, and intraven-
tricular CSF were calculated as the products of the total number of
scans obtained for 2 infants were marred by motion
voxels in the segmented brain image, the dimensions of the voxels, artifacts and were excluded from subsequent analy-
and the thickness of the segmented brain slice. The total volumes ses. For 11 infants, no brain pathologic lesions were
of the different tissue types were calculated by adding the vol- identified in routine ultrasonographic assessments;
umes of all slices. The total cerebral volume represented the sum the infants were assigned to the no-IVH group. For
of the volumes of the different tissue types. The SD of the intraob-
server variability was ⬍2.1%. The difference between 2 analysts 12 infants, IVH was demonstrated in routine cranial
was ⬍2.5%. ultrasonographic assessments; these infants were as-
signed to the IVH group (7 infants had grade I IVH,
Statistical Analyses 4 infants had grade II IVH, and 1 infant had grade III
A power analysis was conducted first, to ensure an adequate IVH, with no persistent ventriculomegaly; the IVH
sample size for hypothesis testing. We wished to have power of was bilateral for 8 infants). Thirteen infants had sep-
⬎0.8 with ␣ of ⱕ.05, to detect a 15% reduction in CGM volume.
The size of our sample met these criteria.16,17 sis resulting from Gram-positive streptococci, as con-
Statistical analyses were performed with SPSS 11.5 for Win- firmed with positive blood cultures. Five infants re-
dows (SPSS Inc, Chicago, IL), to test for differences in the regional ceived 1 course of dexamethasone therapy for
brain volumes between the 2 groups. Multivariate analysis of bronchopulmonary dysplasia (0.1 mg/kg per day for
variance was conducted for the regional brain volumes (CGM,
SGM, WM, and CSF), to minimize the family-wise type 1 error
3 days and 0.05 mg/kg per day for 2 days).
from multiple univariate analyses (multiple tests of between-sub- Demographic data (before and at birth) are shown
jects effects). Potential confounding factors were tested for signif- in Table 1. The variations of neonatal clinical data are
icance by using a multiple regression analysis and removing the shown in Table 2.
overlapping variability with other covariates.18
Confounding Factors
RESULTS
Gestational age at birth, gender, sepsis, corrected
Subjects gestational age, and weight at the time of MRI were
During the patient recruitment period, 77 prema- tested as possible confounding factors for the cere-
ture infants of very low birth weight were admitted bral volumes between the 2 groups. Tested sepa-
to the neonatal intensive care unit. Forty-three in- rately, gestational age at birth, gender, and sepsis
fants were excluded from the study, on the basis of were not significant confounding factors (all P ⬎ .2),
the preset selection criteria (18 infants were small for whereas the corrected gestational age and weight at
gestational age, 7 infants had IVH with parenchymal MRI were significant (P ⬍ .01). Similarly, in the
involvement or posthemorrhagic hydrocephalus, 6 multiple regression analysis (step-down model), ges-
infants had congenital abnormalities or brain malfor- tational age, gender, and sepsis were not significant
mations, 6 infants had ⬎2 episodes of sepsis with covariates and were sequentially discarded. Also,
positive blood cultures, 1 infant had necrotizing there was overlapping variability between the re-
enterocolitis, 2 infants had cystic periventricular leu- maining variables of corrected gestational age and
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e369TABLE 2. Neonatal Clinical Data
Parameter No IVH (n ⫽ 11) IVH (n ⫽ 12) Significance
Respiratory distress syndrome (inf.) 10 9 ⫽ 1.01, P ⫽ .32
2
Inotropes (inf.) 6 6 2 ⫽ 0.05, P ⫽ .83
Postnatal indomethacin (inf.) 6 3 2 ⫽ 2.10, P ⫽ .15
Postnatal corticosteroids (inf.) 2 3 2 ⫽ 0.16, P ⫽ .69
Sepsis (inf.) 5 8 2 ⫽ 1.05, P ⫽ .31
Blood transfusion (inf./transfusions per inf.)* 8/2 (0–8) 9/3 (0–10) 2 ⫽ 0.02, P ⫽ .90
Caffeine (inf.) 5 4 2 ⫽ 0.35, P ⫽ .55
Bronchopulmonary dysplasia at 36 wk (inf.) 8 8 2 ⫽ 0.10, P ⫽ .75
Ventilation, d* 37 (0–70) 33 (0–61) Z ⫽ ⫺0.7, P ⫽ .50†
Breast milk (inf.) 9 11 2 ⫽ 0.49, P ⫽ .48
Full feeds, d* 33 (12–50) 30 (8–51) Z ⫽ ⫺0.7, P ⫽ .64†
Postmenstrual age at scan, wk‡ 35.9 ⫾ 0.8 (34.6–36.9) 35.7 ⫾ 0.9 (34.3–37.3) t ⫽ 0.47, P ⫽ .65
Weight at scan, g‡ 2365 ⫾ 291 (1960–2890) 2138 ⫾ 294 (1760–2836) t ⫽ 1.85, P ⫽ .08
inf. indicates infant. All P values are 2-tailed.
* Median (range).
† Wilcoxon test.
‡ Mean ⫾ SD (range).
weight at MRI. The significant confounding factor
was weight (Wilks’ ⫽ 0.440, P ⬍ .01, for weight;
Wilks’ ⫽ 0.645, P ⫽ not statistically significant, for
the corrected gestational age), and the data on brain
volumes were adjusted for the infants’ weight at the
time of MRI.
Cerebral Volumes
The multivariate analysis of variance for the re-
gional brain volumes (CGM, SGM, WM, and CSF) in
the 2 groups indicated significance with raw data
(Wilks’ ⫽ 0.546, P ⬍ .05) or adjusted data (Wilks’
⫽ 0.586, P ⬍ .05). The tests of between-subjects ef-
fects showed that the volume of the CGM (hypoth-
esis) was significantly reduced in the IVH group
(Table 3; Figs 3 and 4). There was no difference in the
SGM, WM, and CSF volumes (Table 3).
The total cerebral volume, as the sum of CGM,
SGM (basal ganglia and thalami), WM, and intraven-
tricular CSF volumes, was 274 mL (SD: 16.2 mL; 95%
confidence interval [CI]: 263-285 mL) for the infants Fig 3. CGM volumes for the infants without and with IVH. Error
with no IVH and 252 mL (SD: 28.7 mL; 95% CI: bars show mean ⫾ 1 SEM.
235-271 mL) for the infants with IVH (F ⫽ 4.851, P ⫽
.039). The difference reflected the reduction in the
CGM volume. The relative CGM volume (as a per- neuronal precursors.20,21 After 24 weeks of gestation,
centage of the total cerebral volume) was 44.7% (SD: the neuronal migration has been completed but the
4.5%; 95% CI: 41.7-47.7%) for the infants with no IVH germinal matrix still provides glial precursors, which
and 40.1% (SD: 2.6%; 95% CI: 38.4-41.7%) for the become cerebral oligodendroglia and astrocytes. At
infants with IVH (F ⫽ 9.281, P ⫽ .006). this late gliogenesis stage, astrocytes migrate to the
upper cortical layers and are crucial for neuronal
DISCUSSION survival and normal development of the cerebral
The germinal matrix represents the remains of the cortex.8 IVH and germinal matrix destruction may
germinative zone; it becomes less prominent during cause loss of astrocytic precursor cells and have ef-
the final 12 to 16 weeks of gestation and is essentially fects on cortical development.9,22
exhausted by term.19 Between 10 and 24 weeks of To our knowledge, this is the first study to docu-
gestation, this cellular region is the source of cerebral ment impaired cortical development after uncompli-
TABLE 3. Regional Cerebral Volumes
No IVH (n ⫽ 11) IVH (n ⫽ 12) F P F* P*
CGM (mL) 122 ⫾ 12.9 (114–131) 102 ⫾ 14.6 (92–111) 13.218 .002 9.415 .006
SGM (mL) 14 ⫾ 1 (13.4–14.7) 12.9 ⫾ 1.6 (10.7–16.5) 4.123 NS 1.023 NS
WM (mL) 128 ⫾ 19 (115–141) 128 ⫾ 14 (120–137) 0.001 NS 0.235 NS
CSF (mL) 9.5 ⫾ 5 (6.1–12.9) 9.5 ⫾ 4.4 (6.7–12.3) 0.000 NS 0.231 NS
Data are displayed as mean ⫾ SD (95% CI of mean). NS indicates not significant.
* Values corrected for infant’s weight at the time of MRI.
e370 IVH IS FOLLOWED BY REDUCED CORTICAL VOLUME
Downloaded from www.aappublications.org/news by guest on November 6, 2021among infants, alone or in combination with other
parameters, cannot be excluded.
It is important to note that, even with the statisti-
cally significant reduction in CGM volume among
infants with IVH, it is unclear whether the reduction
is clinically significant. At this early age, the brain is
still undergoing a process of dramatic growth and
maturation.17 It is possible that compensatory mech-
anisms may support additional development at later
times.
Our finding of reduced CGM volume in the IVH
group is consistent with concerns raised in the liter-
ature regarding the possible effects of astrocytic loss
on cortical development.8,9 Moreover, in view of de-
velopmental follow-up studies that reported that
premature infants with low-grade IVH were at rela-
tively greater risk of impaired outcomes, compared
with those without IVH,6,7 our finding of reduced
cortical volume may be of clinical significance and
may be associated with impaired developmental out-
comes.
Fig 4. CGM volumes adjusted for infants’ weight at the time of
MRI (CGM*). Error bars show mean ⫾ 1 SEM.
This volumetric brain analysis, performed with
advanced MRI techniques, provides insight into the
pathologic features of uncomplicated IVH, which is
cated IVH. The impairment was demonstrated by a the most common brain injury among premature
reduction in cerebral CGM volume in the IVH group, infants. The alterations in brain development dem-
and this finding remained statistically significant onstrated in this report may be taken into consider-
even after correction for the significant confounding ation when parents are consulted, and closer devel-
factor of weight at the time of MRI and removal of opmental follow-up monitoring for infants with
scaling effects and overall size differences between uncomplicated IVH may be considered. A follow-up
the infants in the 2 groups. Similarly, there was a study at older ages, incorporating volumetric MRI
statistically significant reduction in the relative CGM and neurodevelopmental outcome assessments, is re-
volume (as a percentage of total cerebral volume) in quired for full evaluation of the effects of uncompli-
the IVH group. cated IVH on brain development.
The prospective design of our study, with strict
preset selection criteria, was important because we ACKNOWLEDGMENT
excluded brain pathologic conditions and complica- We thank Dr Kevin Coughlin for assistance with patient re-
tions that are known to have or could potentially cruitment.
have effects on cortical development.23–25 However,
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e372 IVH IS FOLLOWED BY REDUCED CORTICAL VOLUME
Downloaded from www.aappublications.org/news by guest on November 6, 2021Uncomplicated Intraventricular Hemorrhage Is Followed by Reduced Cortical
Volume at Near-Term Age
George T. Vasileiadis, Neil Gelman, Victor K.M. Han, Lori-Anne Williams, Rupinder
Mann, Yves Bureau and R. Terry Thompson
Pediatrics 2004;114;e367
DOI: 10.1542/peds.2004-0500
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Downloaded from www.aappublications.org/news by guest on November 6, 2021Uncomplicated Intraventricular Hemorrhage Is Followed by Reduced Cortical
Volume at Near-Term Age
George T. Vasileiadis, Neil Gelman, Victor K.M. Han, Lori-Anne Williams, Rupinder
Mann, Yves Bureau and R. Terry Thompson
Pediatrics 2004;114;e367
DOI: 10.1542/peds.2004-0500
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/114/3/e367
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