Published online September 1, 2006
PEDIATRICS Vol. 118 No. 3 September 2006, pp. 951-960 (doi:10.1542/peds.2006-0553)
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ARTICLE

Detection of Impaired Growth of the Corpus Callosum in Premature Infants

Nigel G. Anderson, MBChB, FRANZCRa, Isabelle Laurent, MDb, Lianne J. Woodward, MA, PhDc and Terrie E. Inder, MD, PhDd

a Department of Radiology, Christchurch Hospital, Christchurch, New Zealand
b Department of Pediatrics, Hôpital Bon-Secours, Metz, France
c Canterbury Child Development Research Group, University of Canterbury, Christchurch, New Zealand
d Departments of Pediatrics, Neurology, and Radiology, St Louis Children's Hospital, Washington University, St Louis, Missouri


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. There is an urgent need for a bedside method to assess the effectiveness of neonatal therapies designed to improve cerebral development in very low birth-weight infants. The aim of this study was to assess the impact of preterm birth on the serial growth of the corpus callosum and how soon it could be detected after birth with cranial ultrasound.

METHODS. We recruited 61 very low birth-weight infants admitted to a single regional level III NICU from 1998 to 2000. Study infants had 2 cranial sonograms ≥7 days apart in the first 2 weeks of life and further sonograms at 6 weeks and at term equivalent. At each time point, the length of the corpus callosum and cerebellar vermis was measured on midline sagittal images, with growth rates calculated in millimeters per day. We compared growth of corpus callosum and cerebellar vermis in individuals, between birth age groups, and with corrected gestational age. We used antenatal growth rate of the corpus callosum of 0.2 to 0.27 mm/day as a reference. Relationships between corpus callosum growth rates and neurodevelopmental outcome at 2 years of age (corrected) were also examined.

RESULTS. Growth of the corpus callosum was normal in most infants during the first 2 weeks of life but slowed after this (0.21 mm/day from 0–2 weeks vs 0.11 mm/day for weeks 2–6). Slowing of corpus callosum growth below expected reference range was consistently detectable by age 6 weeks for 96% of infants born between 23 and 33 weeks' gestation. Although some improvement in growth rate was observed for 15% of infants after 6 weeks, this was confined to infants born after 28 weeks. Vermis length correlated strongly with corpus callosum length. By 2 years of age, serious motor delay and cerebral palsy were associated with poorer growth of the length of the corpus callosum between 2 and 6 weeks after birth.

CONCLUSIONS. The effect of preterm birth on growth of the corpus callosum is detectable by 6 weeks after delivery in preterm infants born at gestations of 23 to 33 weeks. Reduced growth of the corpus callosum in weeks 2 to 6, places these infants at elevated risks of later psychomotor delay and cerebral palsy.

Key Words: corpus callosum • cerebellum • ultrasonography • brain • growth and development • leucomalacia • periventricular • infant • very low birth weight • developmental disabilities • cerebral palsy

Abbreviations: VLBW—very low birth weight • TE—echo time • FOV—field of view • NEX—number of excitations • MDI—mental development index • PDI—psychomotor development index • IVH—intraventricular hemorrhage • IUGR—intrauterine growth restriction • PVL—periventricular leucomalacia

The neurodevelopmental outcome of the preterm infant is of major concern with ≤50% of very low birth-weight (VLBW) infants having serious cognitive or behavioral deficits during childhood.1 A variety of neuroprotective strategies are being assessed to improve cerebral development in these VLBW infants, including mild hypothermia, inhibitors of free radical production, and free radical scavengers.2,3 Preterm infants have been shown to have reduced volumes of white and gray matter on MRI at term equivalent compared with term infants,4,5 thinning of the corpus callosum,6–10 and reduced cerebellar volume.11,12 However, there is conflicting evidence as to whether smaller size (area) of the corpus callosum measured on MRI during later childhood correlates with severity of spastic diplegia and poor motor skills13–16 or not.8,17 Cranial ultrasound is a potentially important tool for assessing the growth of the corpus callosum (particularly serial growth). Unlike MRI, cranial ultrasound is a bedside examination that is portable and able to be used repeatedly for very sick infants. It is, therefore, desirable to develop an ultrasound method for assessing brain development to assist in the evaluation of the effectiveness of neuroprotective therapies.

At 23 to 33 weeks' gestation, the brain is developing rapidly. Neuronal migration is completed during this time, with cortical and subcortical connectivity, followed by myelination.10,17 Promoters and inhibitors, some of which are released by oligodendrocytes and their precursors,18 modify growth and movement of axons and dendrites. It seems likely that the efficient organization of a limited number of structural connections within the brain permits later development of functional connectivity.19 These varied developmental changes are complex and difficult to image directly in the premature infant.20 We considered that growth of the corpus callosum (supratentorial) and the cerebellar vermis (infratentorial) might represent a synthesis of these complex structural developments.

Sonographic two-dimensional measurements of brain structures, including the corpus callosum and cerebellar vermis, have limited correlation with three-dimensional volumetric measures.21 We wished to find a measurable brain structure that reflected global brain growth and connectivity. We have found that the growth rate of the corpus callosum in VLBW infants from birth to term equivalent is ~0.1 mm/day,22 half of that expected from antenatal growth rates of 0.2 to 0.27 mm/day.23,24 We have found that shorter corpus callosum at term equivalent is associated with poorer neurodevelopmental outcome in VLBW infants but that the growth rate of the corpus callosum between birth and term equivalent has a weaker association. We wished to determine when the poorer growth of the corpus callosum begins and whether there was a vulnerable time period. We chose to assess growth of the corpus callosum, because it is the major white matter connection between cerebral hemispheres. In addition, we chose the cerebellar vermis, because it is a major connection between the cerebellar hemispheres, which has important connections with supratentorial structures and the spinal cord. The cerebellar vermis is readily identifiable and measurable using cranial ultrasound.25,26

Our first aim was to determine how soon after birth a reduction in growth of the corpus callosum could be detected. The second aim was to assess whether cerebellar vermis growth was altered. The third aim was to determine the extent to which corpus callosum growth predicted cognitive and motor development of very premature children by 2 years of age (corrected). This study builds on our earlier publication about corpus callosum growth22 and uses the same cohort of infants.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Selection Criteria
We recruited 100 VLBW infants (born with gestational age <33 weeks and birth weight <1500 g) admitted to a single regional level III NICU from November 1998 to November 2000. This was composed of 91% of infants eligible for recruitment. For the purposes of this study, we included only those infants who had 2 scans >7 days apart in the first 2 weeks of life, a scan at 6 weeks, and a scan at term equivalent. Of the 100 infants, we excluded 39, because the corpus callosum and cerebellar vermis were inadequately imaged for measurement purposes (3), the films were missing (13), or scans had not been performed at the appropriate time (23). An examination of the effects of this sample loss on the representativeness of the current sample found no significant differences between those included and those excluded from the study on measures of birth weight and gestational age. There was a nonsignificant trend for those excluded to have a poorer outcome than those included: 3 of the excluded infants had severe motor delay, and 4 had severe cognitive delay at 2 years of age.

Study Group Characteristics
The study group was composed of 61 infants (31 boys) with a mean gestational age of 28 weeks (range: 23–33 weeks) and a mean birth weight of 1086 g (range: 630–1475 g). These infants were stratified into 3 groups according to their gestational age at birth. Ten infants were born at 23 to 25 weeks' gestation, 33 at 26 to 29 weeks' gestation, and 18 at 30 to 33 weeks' gestation. Fifty-five of these 61 had neurodevelopmental assessment at 2 years of age (corrected for gestation at birth). Of these 55, 24 were boys, 47 had steroids given antenatally, 19 had birth weight ≤10th centile for gestation, 17 had premature rupture of membranes, 18 were from multiple births, and 19 were delivered by caesarean section. Postnatally, 33 needed intermittent positive pressure ventilation for ≤62 days, 17 were still oxygen dependent at 36 weeks' corrected gestational age, 8 had intraventricular hemorrhage (IVH), 19 required inotropic support, and 19 were treated for patent ductus arteriosus. The mean length of hospital stay was 85 days (range: 45–184 days).

Cranial Sonography and Measurement of Length and Growth Rate of Corpus Callosum (and Cerebellar Vermis)
Cranial sonography was performed using Sequoia (8 MHz) or Aspen (7 MHz) ultrasound machines (Acuson-Siemens, Mountain View, CA). Study infants had 2 cranial sonograms ≥7 days apart in the first 2 weeks of life and an additional sonogram at 6 weeks of age. Another cranial sonogram was performed at 40 weeks' corrected gestational age, at the same time as a volumetric MRI scan. Sonograms at other times were performed for clinically indicated reasons, such as prolonged episodes of desaturation, sudden drop in hemoglobin level, or follow-up of IVH. In total, >276 sonograms were completed for the 61 study infants, with the mean number of sonograms per infant being 5 (range: 4–9).

All of the images were digitized using a Vidar Diagnostic Pro Plus digitizer (VIDAR Systems Corporation, Herndon, VA), at a resolution of 150 dots per inch in 12-bit grayscale format. Measurements were performed on the digitized images using Efilm software (Merge Technology, Milwaukee, WI). For each sonogram, we obtained two-dimensional measurements of the length of the corpus callosum, because these do not require complex image processing and can be easily measured using standard image viewing software. The corpus callosum was measured from genu to splenium on a midline sagittal image obtained through the anterior fontanelle (Fig 1). The methodology has been published previously; reproducibility was high for the same observer (intraclass correlation: 0.993) and for different observers (mean agreement: –0.35 mm; SD: 0.96 mm).22 The length of the cerebellar vermis was measured from the base of the fourth ventricle to the junction of folium and tuber vermis25 on an image through either the anterior or posterior fontanelle.


Figure 1
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  		FIGURE 1 Midline sagittal cranial sonogram of 23 weeks' gestation infant, showing method for measuring length of corpus callosum (thin arrows) and cerebellar vermis (thick arrows).

 
The growth rate of the corpus callosum and cerebellar vermis were calculated in millimeters per day by dividing the difference in length by the number of days between scans. We chose the age band of 0 to 2 weeks after birth after visually inspecting the individual growth curves of the corpus callosum, because there seemed to be a hip in the graph of many infants at ~2 to 3 weeks (Fig 2). We chose 6 weeks and term as analysis points, because all of the infants were scanned at these clinical time points. Not all of the infants had either appropriately timed images or images suitable for measurement purposes (failure to obtain a midline image with both the genu and splenium of the corpus callosum clearly delineated). Therefore, the growth rate of the corpus callosum was measured between age 0 and 2 weeks in 49 infants, 2 and 6 weeks in 50 infants, and 6 weeks and term in 49 infants.


Figure 2
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  		FIGURE 2 Plot comparing size of corpus callosum (—) and cerebellar vermis (–) from birth to term equivalent in 2 infants born at 23 weeks' gestation. The slope of the lines indicates the growth rate. The slope of the corpus callosum graphs is greater in the first 2 to 3 weeks after birth. The shape of the graph for corpus callosum and cerebellar vermis is similar. {blacktriangleup}, 1 infant born at 23 weeks' gestation who developed severe cerebral palsy and was severely impaired on MDI and PDI scoring at Bayley 2 examination. {blacksquare}, another infant born at 23 weeks' gestation who developed mild cerebral palsy and had moderately impaired MDI score at Bayley 2 examination. {blacksquare}, expected growth rate of corpus callosum of 0.2 to 0.27 mm/day from antenatal data.23,24

 
MRI Brain at Term Equivalence
MRI was performed in 55 infants using the 1.5-T magnet (General Electric Medical Systems, Waukesh, WI). After feeding, the infants were placed on a vacuum beanbag (S&S Radiograph Products, Brooklyn, NY). MRI sequences included sagittal T1 two-dimensional spin echo, echo time (TE) of 15 ms, repetition time of 500 ms, 4-mm slice, 1-mm gap, field of view (FOV) of 20 cm x 20 cm, 256 x 192 matrix, and 2 number of excitations (NEX); axial dual echo, two-dimensional fast spin echo, echo train length of 16, first TE of 30 ms, second TE of 100 ms, repetition time of 3000 ms, FOV of 18 cm x 18 cm, 256 x 256 matrix, interleaved 3.0-mm slice thickness, and 1 NEX; inversion recovery prepped fast spoiled-gradient recalled echo coronal three-dimensional, flip angle 20°, TE minimum, T1 of 500 ms, FOV of 18 cm x 13 cm, 256 x 256 matrix, slice thickness of 1.5 mm, 124 locations, and 1 NEX. All of the sequences used variable bandwidth and autoshim. Corpus callosum thinning and morphology were assessed subjectively from the sagittal images. White matter abnormalities were assessed according to a previously published scoring system27 based on 5 variables: white matter signal abnormality (shortening T1-weighted imaging), reduction in white matter volume, cystic abnormality, lateral ventricular size, and corpus callosum and myelination. White matter abnormality was then further classified into 4 categories: no white matter abnormality, mild white matter abnormality, moderate-to-severe noncystic white matter abnormality, or moderate-to-severe cystic white matter abnormality.27 Of the 55 infants, 41 had cranial ultrasound examinations at appropriate times to calculate corpus callosal growth rates.

Bayley Scales of Infant Development
At 2 years of age (corrected for prematurity), a comprehensive neurodevelopmental assessment was completed for 55 of these study infants (1 later died, and 8 were lost to clinical follow-up). This assessment included the Bayley Scales of Infant Development-II,28 which provides a measure of children's cognitive (mental development index [MDI]) and psychomotor (psychomotor development index [PDI]) development. The MDI assesses early information processing, visual spatial ability, and language development. The PDI assesses both fine and gross motor development. Both scales have a normative mean of 100 and SD of 15. On the basis of their standard scores, study children were classified into 4 groups: (1) accelerated (score >100), (2) average (score 85–100), (3) mild delay (score 70–84), and (4) serious delay (score <70). In addition, all of the children were assessed for cerebral palsy using standard classification criteria and severity assessment as described by Palisano et al.29

Statistical Analysis
We compared the growth of corpus callosum and cerebellar vermis in individuals, between birth age groups, and with corrected gestational age using analysis of variance. We assessed the approximate correlation of corpus callosum length and cerebellar vermis size with gestational age and each other. We calculated the regression coefficient (and mean error) from a mixed-effects model accounting for multiple examinations. Separately, we calculated a simple correlation coefficient (without accounting for repeated examinations). Then we used the relationship between the linear regression coefficient and correlation coefficient to recalculate an approximate correlation coefficient (Table 1).


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  		TABLE 1 Relationship of Size of Cerebellar Vermis and Corpus Callosum to Corrected Gestational Age for 276 Sonograms in 61 Very Premature Infants

 
We compared the rates of growth of the corpus callosum across the 3 time zones with antenatal factors, postnatal factors, Bayley scores, and cerebral palsy using Student's t test or analysis of variance. We grouped the rates of growth of the corpus callosum into <0.1 mm/day, 0.1 to 0.2 mm/day, and >0.2, mm/day. Then we used analysis of variance to determine whether there was a correlation between clinical parameters and growth rate of the corpus callosum in each of the postnatal time periods (Table 2). We compared corpus callosal growth rates and length of corpus callosum at term equivalent with the MDI and PDI using analysis of variance.


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  		TABLE 2 Correlation Using Analysis of Variance of Rates of Growth of Corpus Callosum (Millimeters per Day) With Clinical Features in 55 VLBW Infants

 
Ethical Approval
The Regional Ethics Committee approved all aspects of this study, and informed consent was obtained from all of the parents.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Corpus Callosum: Growth Rate and Length at Term Equivalent
Figure 3 describes the growth of the corpus callosum over time for infants in the 3 gestational age groups and shows 3 major findings. First, there was evidence of a slowing in the growth rate of the corpus callosum after 2 weeks of age across all 3 of the gestational groups; only 5 (8%) of the 61 infants had an increase in growth rate of the corpus callosum. Second, a reduction in the growth rate of the corpus callosum was detectable by 6 weeks of age for 59 (96%) of the 61 infants born between 23 and 33 weeks' gestation. Third, the growth rate remained reduced from 2 weeks to term equivalent in all of the infants except 9 born after 28 weeks' gestation.


Figure 3
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  		FIGURE 3 Plots of growth rate of corpus callosum at 0 to 2 weeks, 2 to 6 weeks, and 6 weeks to term equivalent for 10 infants born at 23 to 25 weeks' gestation, 33 infants born at 26 to 29 weeks' gestation, and 18 infants born at 30 to 33 weeks' gestation. Figure 3, normal growth rate of 0.2 to 0.27 mm/day, based on prenatal data.23,24 These plots show that growth rate slows after 2 weeks of age in all 3 age groups and remains reduced in all infants except some born after 29 weeks' gestation. The drop in growth rate is detectable by 6 weeks of age.

 
The growth rate of the corpus callosum in the first 2 weeks after birth was measured in 49 infants. It was normal in all but 1 of the infants born at 23 to 25 weeks' gestation, an infant with severe intrauterine growth restriction (IUGR). In contrast, the growth rates of corpus callosum during the first 2 weeks for those born at 26 to 33 weeks' gestation were evenly distributed above and below the expected norm. Growth rate of corpus callosum was ≤0.1 mm/day (half the expected) in the first 2 weeks of life in 1 of 10 infants born at 23 to 25 weeks' gestation, 9 of 31 born at 26 to 29 weeks' gestation, and 1 of 8 born at 30 to 33 weeks' gestation. Of these 11, 6 had birth weights below the 10th centile, including the only 2 infants with severe intrauterine growth restriction.

The reduction in growth rate was related to age after birth rather than the corrected gestational age. Across all of the age groups, the mean growth rate was 0.21 mm/day from 0 to 2 weeks compared with 0.11 mm/day for weeks 2 to 6 (P < .0001) and showed much greater variance (P < .0001). Improvement in growth rate was seen only in some infants after 6 weeks of age and only in those born after 29 weeks' gestation. The mean growth rate at 6 weeks to term was 0.16 mm/day in those born at 30 to 33 weeks' gestation, significantly greater than the mean of 0.09 mm/day for those born at 23 to 29 weeks' gestation (P = .004) and with much greater variance (P < .0001).

Relationship of Size of Cerebellar Vermis and Corpus Callosum
A strong correlation was found between corpus callosum and vermis length (R2 = 0.68; Table 1 and Fig 4) from birth to term equivalent. As shown in Table 1 and Fig 5, both corpus callosum (R2 = 0.61) and the cerebellar vermis size (R2 = 0.57) correlated moderately strongly with corrected gestational age. There was no significant difference in growth rates of the cerebellar vermis between age groups or at the different ages after birth. Adjusting for gestation at birth did not affect the magnitude of any of the above associations, and there was no evidence that these associations varied with gestation at birth. The lengths of the corpus callosum and cerebellar vermis are correlated even after correcting for gestational age at the time of the sonogram (Table 1).


Figure 4
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  		FIGURE 4 Plot comparing length of corpus callosum with length of cerebellar vermis at 276 cranial ultrasound examinations obtained in 61 infants born at 23 to 33 weeks' gestation. This graph plots the same measurements obtained in FIGURE 5. There is a strong correlation (R2 = 0.68) regardless of gestational age at birth and allowing for multiple examinations in the same individual. The apparent increase in variation among infants born at 30 to 33 weeks' gestation is not statistically significant.

 

Figure 5
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  		FIGURE 5 Plot of length of corpus callosum and cerebellar vermis against corrected gestational age obtained at cranial ultrasound examinations performed between birth and term equivalent in 61 infants born at 23 to 33 weeks' gestation. A total of 276 cranial ultrasound examinations were performed. This graph plots the same measurements obtained in FIGURE 4. The correlation between length and age is strong for both the corpus callosum (R2 = 0.61), and cerebellar vermis (R2 = 0.57) allowing for repeated examinations in the same infant (see Table 1).

 
Rate of Growth of Corpus Callosum Related to Clinical Factors
Table 2 shows the relationship between growth rate of the corpus callosum during the 3 time periods after birth and a range of clinical factors reflecting infant health during the postnatal period. Growth of the corpus callosum in the first 2 weeks of life tended to be poorer among boys (boys: mean 0.19 mm/day; girls: 0.25 mm/day; P = .05), as well as infants characterized by severe IUGR (R = –0. 27; P = .05; Fig 6). Infants who developed a patent ductus arteriosus requiring treatment had a greater growth rate of the corpus callosum in the first 2 weeks (mean: 0.27 mm/day vs 0.19 mm/day; P = .002). The growth rate of the corpus callosum at 2 to 6 weeks or 6 weeks to term showed no significant association with any of the antenatal or postnatal clinical factors.


Figure 6
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  		FIGURE 6 Plot comparing growth rate of corpus callosum in first 2 weeks after birth in 49 VLBW infants showing that the 2 with severe IUGR had lower corpus callosum growth rates. Mean growth rate was 0.045 mm/day for those with IUGR vs 0.23 mm/day for the remainder (Pearson correlation coefficient R = –0.27; P = .02). Figure 6, expected lower limit of growth of corpus callosum from antenatal data.23,24 –, mean value of growth rate of corpus callosum for the group without severe IUGR.

 
Corpus Callosum and Outcome
As shown in Table 3, those with serious motor delay or cerebral palsy had significantly poorer growth of the length of the corpus callosum from 2 to 6 weeks after birth. This association was not found at other time periods or with serious cognitive delay.


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  		TABLE 3 Correlation of Rate of Growth of length of Corpus Callosum With Outcome in 46 VLBW Infants at 2 Years of Age (Corrected)

 
Corpus Callosum Growth Rate and MR
Three of the infants developed grade III/IV IVH. Two developed cystic periventricular leucomalacia (PVL). There was no correlation of corpus callosum growth rate with IVH (Table 2) or cystic PVL, although numbers were very small. There was a trend for those with marked changes in the white matter at the MRI brain scan to have poorer rates of growth of the corpus callosum at 2 to 6 weeks and at 6 weeks to term, (Table 4). Thinning of the corpus callosum seen on MRI was associated with poorer growth of the corpus callosum in the preceding 6 weeks but not with growth at 0 to 6 weeks after birth.


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  		TABLE 4 Correlation of Rate of Growth of Length of Corpus Callosum With MRI Performed at Term Equivalent in 41 VLBW Infants

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Our prospective observational study has revealed 5 key findings about the growth of the corpus callosum and cerebellar vermis in premature infants that have important implications for the timing and monitoring of interventions aimed at improving cerebral development. The first key finding is that reduced growth in length of the corpus callosum is detectable by 6 weeks of age in all infants born at 23 to 33 weeks' gestation. Instead of growing 8 mm on average, findings from the present sample suggest that, in VLBW infants, the corpus callosum only grew 4 mm on average during the first 6 weeks of life. This reduction in growth was related to age after birth, not age at birth. The clinical importance of this finding is that the effectiveness of strategies to improve cerebral development in the very premature infant can be assessed as early as 6 weeks of age by a simple bedside ultrasound examination. We recommend adding measurement of corpus callosum length to any clinical or research protocol aimed at neuroprotection in the very premature infant.

The second key finding is that most infants had relatively normal corpus callosum growth in the first 2 weeks of life, with only 11 of the 61 infants characterized by growth that was less than or equal to half of the expected rate during this period. Because cystic change associated with PVL is manifest on ultrasound at 14 to 22 days after the insult,30,31 it seems likely that alteration in the length of the corpus callosum may take a similar length of time. Severe IUGR correlated with reduced callosum growth rate in the first 2 weeks of life, suggesting that low growth rate of the corpus callosum in the first 2 weeks after birth may reflect impaired white matter growth during the prenatal period. It is of interest that this was seen in only 1 of the infants born at 23 to 25 weeks' gestation but in 9 of the 35 infants born at 26 to 29 weeks' gestation. This finding is consistent with white matter injury occurring predominantly after 23 weeks' gestation and predominantly after birth, as suggested previously by MRI and postmortem findings.31 Perhaps the antenatal risk factors of infection and placental abnormality32 prime the white matter for damage in the postnatal environment.

The third key finding is that serious motor delay and cerebral palsy are associated with even poorer growth of the corpus callosum at weeks 2 to 6 after birth, rather than at other time periods. This suggests that the first few weeks after birth seem to be a particularly vulnerable time period. Nearly all of the VLBW infants had poor growth of the corpus callosum during this time period, but the rate of growth was even poorer in those with serious motor delay. However, it is important to note that the number of infants with serious motor delay was small, so further replication is needed. We did not find a significant association between serious cognitive delay and earlier corpus callosum growth. However, further follow-up of these infants will be important to see if those infants characterized by poorer corpus callosum growth are at elevated risk of more subtle cognitive deficits observed frequently among very premature infants during their school-age years.1 Our results should be regarded as preliminary because of the small numbers of very poor outcomes among our study group.

The fourth key finding is that the growth and development of the corpus callosum and cerebellar vermis seem to be linked in very premature infants, with both structures showing similar growth patterns over time. The size of the vermis and corpus callosum correlated strongly with corrected gestational age and with each other (Table 1 and Fig 2). That is, changes in growth of the corpus callosum and cerebellar vermis occur at the same time and in the same direction. We are observing the macroscopic effect of their connectivity. This finding adds to previous reports linking growth of the cerebrum and cerebellum.33–35 Severe cerebellar injury is associated with less severe cerebral injury in some very premature infants with cerebral palsy.33 Cerebral injury is associated with injury to the contralateral cerebellar hemisphere in VLBW infants.34 Our finding that cerebellar vermis growth is reduced in VLBW infants supports the findings of Messerschmidt et al,35 who concluded that cerebellar growth was vulnerable in infants born before 30 weeks' gestation. Injury to periventricular white matter36,37 and corpus callosum38 in the immature brain seems to be linked to injury to oligodendrocyte precursors. The importance of trying to limit injury to white matter is not only to improve myelination13,36,38 but also to improve connectivity. One of the characteristic features of PVL is the loss of corticospinal tract neurons, yet the remaining corticospinal axons retain the ability to remake connections.39 In our study, corpus callosal growth was reduced in all of the infants regardless of whether they developed cystic PVL or high-grade IVH.

The corpus callosum contains myelinated and unmyelinated axon fibers arranged from front to back in a consistent and orderly arrangement.13 The size and length of the corpus callosum is proportional to axon numbers and the extent of myelination. Myelination proceeds in an orderly fashion from lower centers to higher; it can be seen in the cerebellar vermis at MRI by 25 weeks' gestation; and myelin is detectable histologically ≤4 weeks before it can be seen at MRI.40 In our study group, the postnatal growth profile of the corpus callosum and cerebellar vermis mirror one another for much of the time until near term equivalent when the vermis has a less marked fluctuation in growth than the corpus callosum in individuals (Figs 2 and 5). Thus, the growth pattern of the major supratentorial and infratentorial connections seems to be largely similar in very premature infants for several weeks after premature birth. The purpose of any neuroprotective therapy is to not only improve myelination but to improve structural connectivity within the brain, that is, to improve the quantity as well as the quality of those connections. Increasing myelin around existing axons may not fully compensate for missing connections.

The fifth key finding is that there can be an improvement in growth of the corpus callosum in some infants born at 30 to 33 weeks' gestation after 6 weeks of age. None of the infants born before 30 weeks' gestation showed any significant improvement in corpus callosum growth. It seems likely, therefore, that the eventual size of the corpus callosum in these infants depends on how well it had grown before birth, and by implication, the quantity and quality of periventricular white matter is likely to depend on how much was present at birth. This might explain why infants born at 23 to 25 weeks' gestation have a poorer developmental outcome than older ones: poor growth of white matter matters most to those who have the least white matter at birth. The rate of growth of the corpus callosum has no relationship to any of the usual prenatal and postnatal assessment criteria, except that growth restriction was associated with poor growth in the first 2 weeks after birth. This suggests that the reduction in growth rate of the corpus callosum after birth is a phenomenon common to most VLBW infants regardless of their early postnatal course. The growth rate of the corpus callosum influences its absolute size at term equivalent.

Although there was an almost uniform reduction in the growth of the corpus callosum across study children, we could not demonstrate an association with postnatal clinical parameters. Our hypothesis to explain this is that there are greater environmental differences between intrauterine and extrauterine life (which we have not measured) than the usually measured parameters of IVH, inotrope and oxygen requirements, and so forth. However, the power of our study was not high enough to exclude any relationship.

A previous study of this cohort demonstrated a significant association between the length of the corpus callosum at term equivalent and later MDI and PDI scores.22 However, this examination of the neurodevelopmental correlates of early corpus callosum growth suggests that poor growth between 2 and 6 weeks after birth might place very premature infants at elevated risk of later motor deficits or cerebral palsy. This association may reflect injury of anatomically adjacent brain areas impacting on the corpus callosum. Our results regarding cerebral palsy and severe cognitive or motor impairment should be regarded as preliminary because of the small numbers. Further research is needed to substantiate this finding and to clarify the nature and neurologic mechanisms underlying it. Nonetheless, this preliminary finding does further highlight the potential vulnerability of white matter development during the first few weeks of postnatal life among premature infants, as well as suggesting that white matter injury most likely commences soon after birth.

Corpus callosal thinning has a variable correlation with outcome.6–9,13,14,16 This might be related to our finding that thinning of the corpus callosum tends to correlate with poorer growth of the corpus callosum at 6 weeks to term equivalent but that psychomotor outcome correlates better with growth of the corpus callosum at 2 to 6 weeks after birth. We have demonstrated some objective evidence linking the reduced growth rate of the corpus callosum with global white matter abnormality at MRI (Table 4).

Disadvantages of our study include the small number of infants with IVH or cystic PVL and the exclusion of a number of patients who did not have an ultrasound at term (including some with very poor outcomes). We could have reduced the number excluded if we had ensured that the midline sagittal image of the cranial sonogram always included the genu and splenium of the corpus callosum. We were unable to correlate corpus callosum growth with head circumference because of an inconsistent measurement protocol at the time. That policy has since been corrected.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Our findings support the following conclusions. White matter injury is very common in infants born from 23 to 33 weeks' gestation. This injury commences from around the time of birth in most, but before birth in some. The effect of the injury on growth of the corpus callosum is detectable by 6 weeks of age or earlier if the injury occurred prenatally. Because the damage seems to occur from ≥23 weeks' gestation, it seems likely that neuroprotective strategies should be implemented as soon after birth as possible. Attempting to implement neuroprotective strategies before birth, although ideal, may be less effective than implementing them in the NICU.


   ACKNOWLEDGMENTS
 
This research was supported in part by a grant from the Neurologic Foundation of New Zealand

We thank Patrick Graham, biostatistician, for statistical help with the correlations between size of cerebellar vermis and corpus callosum. We are also grateful to Nicola Austin, neonatologist, who performed the assessment for cerebral palsy on all infants; Michelle VanDyk for developmental follow-up; Carole Spencer, research nurse for study coordination; and Lisa Borkus for data management.


   FOOTNOTES
 
Accepted Apr 13, 2006.

Address correspondence to Nigel G. Anderson, MBChB, FRANZCR, Department of Radiology, Christchurch Hospital, Riccarton Avenue, Christchurch 8001, New Zealand. E-mail: nigel.anderson{at}cdhb.govt.nz

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
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