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Head Growth in Preterm Infants: Correlation With Magnetic Resonance Imaging and Neurodevelopmental Outcome

^a Victorian Infant Brain Studies, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
^b Department of Neonatal Services, Royal Women's Hospital, Melbourne, Australia
^c Department of Neonatal Medicine, Royal Children's Hospital, Melbourne, Australia
^d Department of Obstetrics & Gynaecology, University of Melbourne, Melbourne, Australia
^e Neuroimaging & Neuroinformatics, Howard Florey Institute, Melbourne, Australia
^f Department of Pediatrics, St Louis Children's Hospital, Washington University, St Louis, Missouri

	ABSTRACT

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OBJECTIVE. Extremely preterm birth is associated with adverse neurodevelopmental sequelae. Head circumference has been used as a measure of brain growth. There are limited data relating head circumference to MRI. The purpose of this work was to establish the relationship between head circumference with brain MRI at term-equivalent age and to relate head circumference with neurodevelopmental outcome at 2 years.

PATIENTS AND METHODS. Two hundred and twenty-seven preterm infants (birth weight of <1250 g or <30 weeks’ gestation) were recruited. Head circumference was measured at birth, term, and 2 years’ corrected age, and z scores were computed. Microcephaly was defined as a head circumference z score of less than –2 SDs for age and gender. MRI scans at term (n = 214) were graded for white and gray matter abnormalities, and segmented volumes were calculated for different tissue types. Outcome at 2 years’ corrected age (n = 202) included scores on the Bayley Scales of Infant Development II.

RESULTS. Microcephaly increased from 7.5% at term to 29.7% at 2 years. There was no significant relationship between head circumference and white or gray matter abnormalities on MRI. There was a strong correlation between head circumference and brain volume at term. At term, microcephalic infants had significantly decreased volumes for total brain tissue and most segmented volumes compared with infants with normal head circumference, but only deep nuclear gray matter volume remained significantly lower when adjusted for total intracranial volume. At 2 years, microcephaly was associated with poorer cognitive and motor development and an increased rate of cerebral palsy.

CONCLUSIONS. Brain volume is a determinant of head size at term. Microcephaly is associated with a reduction of brain tissue volumes, especially deep nuclear gray matter, which suggests a selective vulnerability. Poor postnatal head growth in preterm infants becomes more evident by 2 years and is strongly associated with poor neurodevelopmental outcome and cerebral palsy.

Key Words: head circumference • MRI • neurodevelopmental outcome • preterm infant

Abbreviations: HC—head circumference • MR—magnetic resonance • CSF—cerebrospinal fluid • CGM—cortical gray matter • DNGM—deep nuclear gray matter • MWM—myelinated white matter • unMWM—unmyelinated white matter • MDI—Mental Developmental Index • PDI—Psychomotor Developmental Index • CI—confidence interval

With advances in neonatal intensive care, the survival of preterm infants has improved dramatically. However, these infants are still at considerable risk of adverse neurodevelopmental outcomes; 5% to 15% have cerebral palsy, and an additional 40% have minor motor, cognitive, learning, and behavioral disorders that persist into young adulthood and affect their adaptive functioning.^1–4

Occipitofrontal head circumference (HC) has traditionally been used as a measure of brain size and is associated with general IQ. However, the association between HC measurements and cognitive outcome varies according to the developmental stage at which the HC measurement occurs. For example, the association between HC and later cognitive outcome is weak at birth but becomes stronger later in infancy and childhood.^5–10 Failure of catch-up head growth in infancy is also an important predictor of IQ.⁸ These findings have led to the speculation that postnatal head growth may have a more important role in determining cognitive outcome than intrauterine head growth. Other studies have found that there may be different critical periods of brain growth that influence motor and cognitive outcome. Head growth in the early postnatal period correlates with motor outcome, whereas HC at 4 and 15 years of age correlates significantly with IQ.¹⁰

HC has been shown to correlate well with brain volume in postmortem cases.¹¹ However, to date, there are limited data correlating HC measurements with qualitative and quantitative MRI changes of the brain, and, therefore, little is known about the brain pathology and underlying cerebral structures that contribute to poor head growth.

The aims of this study were to establish the relationship between HC and head growth in very preterm infants with MRI-documented brain pathology and quantitative brain volumes at term-equivalent age, and to relate HC and head growth to neurodevelopmental outcome at 2 years. We hypothesized that, in comparison with very preterm infants with normal head size, very preterm infants with poor head growth would have significant brain pathology, decreased brain volumes, and poorer neurodevelopmental outcome at 2 years.

	METHODS

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Patients
Between 2001 and 2004, 230 preterm infants (birth weight of <1250 g or gestational age of <30 weeks) who were inpatients at the Royal Women's Hospital were recruited for the study. Ethical permission was granted by the Royal Women's Hospital's Research and Ethics Committees, and written informed parental consent was necessary for participation.

MRI
Magnetic resonance (MR) examination was performed between 38 and 42 weeks’ corrected gestational age using a 1.5-T General Electric Signa System (GE Medical Systems, Buckinghamshire, United Kingdom) with the following sequences: a 3-dimensional Fourier transform spoiled gradient recalled sequence (1.5-mm coronal sections, 45° flip angle, repetition time of 35 milliseconds, echo time of 5 milliseconds, field of view of 18 cm, and matrix 256 x 256) and a double-echo (proton density and T2-weighted) spin-echo sequence (dual-echo; 3-mm axial sections, repetition time of 3000 milliseconds, echo time of 36 and 162 milliseconds, field of view of 18 cm, matrix 256 x 256, and interleaved acquisition). Before the MR examination, infants were fed, swaddled, and placed in a Vac Fix (Radiation Products Design Inc, Albertville, MN) beanbag designed to keep the infant still and supported in the MR scanner. MR scans were scored using a standardized scoring system¹² by 2 independent raters who were blinded to the clinical history and the cranial ultrasound findings.

Qualitative MRIs were classified according to the degree of white matter and gray matter abnormality. White matter abnormality was graded according to 5 scales, which assessed the (1) nature and extent of white matter signal abnormality, (2) loss of periventricular white matter, (3) presence of cysts, (4) degree of ventricular dilatation, and (5) thinning of the corpus callosum. The scores from individual scales were then combined to give an overall white matter abnormality score, which was further categorized as normal-mild or moderate-severe white matter abnormality. Gray matter abnormality was graded according to 3 scales, which assessed the (1) presence of cortical gray matter signal abnormality, (2) quality of gyral maturation, and (3) size of the subarachnoid space. The individual scores were combined and categorized as normal and abnormal gray matter. Interrater agreement on assignment of categories was 96%.

Quantitative volumetric MR analysis was performed on the brain MRI scans. Analysis was undertaken on Sun Microsystems workstations (Palo Alto, CA). Linear transformation algorithms were applied to align the T2 images to the spoiled gradient recalled images for tissue classification. A nonparametric supervised estimator of tissue class conditional probability density functions was performed. This method uses the k-nearest neighbor density estimation, which is an optimal estimator that asymptotically approaches the minimum possible classification error rate R* as R*(1 + 1/K). The optimal density function estimates were created by interactively selecting representative voxels as training points of cerebrospinal fluid (CSF), cortical gray matter (CGM), deep nuclear gray matter (DNGM), myelinated white matter (MWM), and unmyelinated white matter (unMWM), each of which differ in intensity. After iterative supervised training, a spatially varying model was identified through alignment with an anatomic atlas of a 40-week-old infant.¹³ Maximum likelihood estimation was used to select the most likely tissue class label for each voxel.^13,14 Tissue segmentation was conducted by a single operator (Ms Thompson). Tissue segmentation was completed on 5 infants blinded for 10 segmentations with intraobserver reliability on tissue segmentation of CSF 0.99, CGM 0.85, MWM 0.73, unMWM 0.83, and DNGM 0.61. In addition, the intracranial cavity volume was measured by creating a brain versus nonbrain tissue mask on the T1-weighted image. The intracranial volume included all of the gray matter, white matter, and CSF within the skull.

Head Circumference
The maximum occipital-frontal HC was measured at birth, at the time of the MRI examination (ie, at term corrected age), and at the 2-year follow-up assessments. The HC z scores were then computed relative to the British Growth Reference data.¹⁵ Microcephaly was defined as having an HC z score of less than –2 SDs for age and gender. Head growth was defined as the difference in z scores for HCs within 2 specified periods, that is, birth to term and term to 2 years.

Neurodevelopmental Assessments
Neurodevelopmental assessments were performed between 22 and 26 months (corrected for prematurity) by examiners who were blinded to the perinatal course and MRI findings. Every child had a cognitive and psychomotor developmental assessment using the Bayley Scales of Infant Development II.¹⁶ The Mental Developmental Index (MDI) assesses the environmental responsiveness and sensory and perceptual abilities, memory, learning, and early language and communication abilities. The Psychomotor Developmental Index (PDI) assesses both gross and fine motor skills. Severe motor or cognitive delay was defined by a PDI of <70 or MDI of <70, respectively, which are >2 SDs, or 30 points, below the normative mean of 100.

Children had a standardized pediatric neurologic evaluation to assess the quality of their motor skills, coordination, gait, and behavior. Cerebral palsy was diagnosed with the use of standard criteria: location or body part impaired (eg, diplegia or hemiplegia), degree of impairment of muscle tone and reflexes, and the effects of coordination on ambulation.¹⁷ In addition, vision and hearing were assessed.

Social Risk Assessment
Social risk was assessed based on a composite index modeled following previously published social risk scales.¹⁸ Scores (0, 1, or 2) were given for 6 categories, that is, family structure, education and employment status of primary caregiver, occupation of primary income earner, language spoken at home, and maternal age at birth. The individual scores were summed up to give an overall score that was then categorized into 2 groups, that is, low and high social risk.

Statistical Analysis
Data between groups were compared using ² for categorical variables and t tests for continuous data as appropriate. A P value of .05 was considered significant. The relationship between HC and brain volume at term was analyzed by using a linear regression model. The association between HC and outcome was adjusted for social risk using multiple regression models.

	RESULTS

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Of the 230 preterm infants who were recruited, 3 infants were excluded because of congenital abnormalities or major syndromes (Klinefelter syndrome, craniosynostosis, and septo-optic dysplasia with hydrocephalus). A total of 214 infants (94%) had MRI scans between 38 and 42 weeks’ corrected gestational age, with the remaining infants scanned outside this window. At 2 years of age, 202 of these children (94%) completed the neurodevelopmental assessments: 1 infant died before follow-up and 11 had moved overseas, refused, or was untraceable. Although qualitative MR analysis was conducted for all of the infants, quantitative volumetric MR analysis was possible on 186 (87%) because of movement or imaging artifact. The clinical characteristics of the infants are summarized in Table 1. Fifteen infants (11.5%) were microcephalic at birth, 17 (7.5%) infants were microcephalic at term-equivalent age, and 65 (29.7%) infants were microcephalic at 2 years.

HC and Qualitative MRI
There were no significant differences in HC at birth, term, and 2 years of age between infants with different grades of white matter and gray matter abnormalities on MRI. In addition, there were also no significant differences noted in the head growth between birth to term and term to 2 years of age between infants with different grades of white matter and gray matter abnormalities on MRI (Table 2).

View larger version (9K): [in this window] [in a new window]   FIGURE 1 The relationship between HC SD and brain volume (total intracranial volume minus CSF volume) at term (r = 0.68; R2 = 0.46; P < .001).

Compared with children who had normal head growth between term and 2 years, children with deterioration of their HC z scores had significantly lower MDI (mean [SD]: 80.5 [22.3] vs 89.4 [19.1]; mean difference: –8.9 [95% CI: –14.8 to –3.0]; P = .003) but not PDI (mean [SD]: 87.9 [18.1] vs 90.6 [16.9]; mean difference: –2.7 [95% CI: –7.7 to 2.4]; P = .31) or cerebral palsy (P = .9).

HC and Relation to Other Growth Parameters
There was a significant correlation among HC, weight, and length z scores at 2 years’ corrected age. The correlation between the HC and weight was stronger (r = 0.54; R² = 0.29; P < .001) than the correlation of HC with length (r = 0.3; R² = 0.09; P < .001).

	DISCUSSION

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This study of very preterm infants has demonstrated important associations between head size at different ages, cerebral MRI, and neurodevelopmental outcome at 2 years. At birth and term, the incidence of microcephaly was 7% to 10%, and there was no significant association with qualitative MRI changes and 2-year neurodevelopmental outcome. HC measurements at term correlated with brain tissue volume, and microcephaly at this age was associated with decreased total brain tissue, especially DNGM. By 2 years of age, the incidence of microcephaly in very preterm infants increased threefold, and microcephaly at this age was strongly associated with poorer cognitive and motor development and a higher rate of cerebral palsy. A decrease in HC z scores between term and 2 years was associated with lower MDI scores.

In keeping with previous studies, we found that the incidence of microcephaly increased between term and early childhood.^19,20 Head growth is particularly rapid in the first year after birth, and failure of optimal head growth during this period may have important implications for later neurodevelopmental outcomes.²¹ In a study of nonpreterm children, poor head growth in infancy had effects on later cognitive outcomes that could not be compensated for by more rapid head growth after infancy.^6,21 The factors important in postnatal brain growth are, therefore, worthy of additional investigation in the preterm infant, including nutrition, environmental exposures, or hypoxic injury.

We were unable to demonstrate any significant association between head size and head growth with qualitative white matter and gray matter abnormalities on MRI. This surprised us given the association between our grading system and 2-year neurodevelopmental outcomes,²² but may reflect a more global disturbance in brain growth not reflected in these tissue-specific grading scales.

Head size at term-equivalent age was associated with brain tissue volumes on MRI, suggesting that brain volume is a determinant of head size. Microcephalic infants had significantly decreased volumes in total brain tissue, CSF, and all of the brain tissue types, with the exception of MWM. Even after adjusting for total intracranial volume, microcephalic infants have reduced DNGM volume. This may suggest a more selective vulnerability of DNGM in very preterm infants who then display subsequent poor head growth. Reductions in DNGM have been demonstrated in very preterm infants at term, more so in infants with white matter abnormalities, and this reduction in DNGM volume can persist up to 8 years of age.^23–25 In addition to DNGM, other brain regions have been reported to be reduced in preterm infants, including the cerebellum, hippocampus, amygdala, and corpus callosum, which correlate with specific cognitive deficits in adolescence.^25–28 The identification of vulnerable structures may be beneficial for the development of targeted interventions in the preterm newborn.

The finding that MWM volumes were similar in those with microcephaly and normal HC may be explained by several factors. At term-equivalent age, myelination is limited to deep subcortical regions, particularly the brain stem, and the volume of MWM is very small. The segmentation technique used in this study may have lacked the sensitivity required to detect differences in the tissue volumes between the groups.

Head size has been found by other groups to correlate with neurocognitive outcome.^{5,7,8,10,29,30} In keeping with previous studies, we found that HC at 2 years, but not at an earlier age, correlated with cognitive and motor outcome. This gives more credence to the speculation that postnatal head growth is more important than antenatal growth in determining neurodevelopmental outcome in very preterm infants. It is known that children with cerebral palsy generally have poor appetite and growth. When children with cerebral palsy were excluded from the analysis, only cognitive outcome remained significantly worse in children with microcephaly, which suggests that poorer motor outcome in children with microcephaly may partly be explained by poor growth in cerebral palsy children. In contrast to a previous study that found that motor outcome correlated with HC at discharge,¹⁰ we did not find this association in our cohort. However, the follow-up assessment in that study was at 8 years of age compared with 2 years in our study, and subtle motor difficulties are likely to be more evident at later ages. In our study, we controlled for the potential effects of social risk and gender and found that HC was still an important independent predictor of neurodevelopmental outcome. This may suggest that altered brain growth is a factor that is not entirely modulated by social risk or gender in determining outcome. We did not adjust for factors like intraventricular hemorrhage and illness severity, because these factors could potentially be part of the causal pathway to poorer neurodevelopmental outcome.

There have been conflicting data on the effect of postnatal corticosteroids on head growth. Some studies have shown a deleterious effect on somatic growth, including HC,^31–33 but others have not shown any effects.³⁴ The studies that have shown effects on head growth have been associated with the earlier administration of corticosteroids and higher doses than those used in our institution. Of the 21 infants in this study who received postnatal corticosteroids, 3 (14%) were microcephalic at term, and 8 (38%) were microcephalic at 2 years.

This study has several strengths. It is a large prospective cohort study where subjects underwent MRI examination and detailed neurodevelopmental assessments. However, there are also several limitations. The HC data at birth were available on just >50% of the infants. The missing birth HC data could be explained by the fact that some of the infants were outborn and would not have had HC measured routinely at birth. With the increasing practice of early continuous positive pressure ventilation, respiratory support equipment is connected to the infant as soon as possible, complicating access for the routine measurement of HC at birth. We performed a comparison of the clinical characteristics of infants with and without HC measurements and found that there were no significant differences between the groups in a broad range of perinatal variables. There were also no data on HC between term and 2 years to enable the assessment of catch-up growth in early infancy, which has been shown to be an important predictor of cognitive outcome.³⁵ Finally, there were no data available on parental HC to account for the genetic influence on head size.

	CONCLUSIONS

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Our data support that postnatal head growth is an important clinical indicator of brain growth. Poor head growth reflects poor growth in most tissues within the brain, but there may be specific tissue types or regions, such as the DNGM, that are more vulnerable and, thus, may be a target for neuroprotective interventions. The association between head size in early childhood and neurodevelopmental outcome highlights its importance as a useful clinical indicator in the follow-up of high-risk preterm infants.

	ACKNOWLEDGMENTS

 
This work was supported by grants from the National Health and Medical Research Council of Australia (project grant 237117), Murdoch Childrens Research Institute, the Royal Women's Hospital Research Foundation, and the Jack Brockhoff Foundation.

We thank all of the families for their willingness to participate in this study.

	FOOTNOTES

 
Accepted Dec 13, 2007.

Address correspondence to Jeanie L. Y. Cheong, FRACP, Royal Women's Hospital, Department of Neonatal Services, 132 Grattan St, Carlton 3053, Melbourne, Australia. E-mail: jeanie.cheong{at}rwh.org.au

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

What's Known on This Subject Head growth in preterm infants is related to neurodevelopmental outcome.

 

What This Study Adds We examined the relationship between head growth and MRI and provide information about brain pathology and cerebral structures that might contribute to poor head growth.

 

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 

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This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via CrossRef Google Scholar Articles by Cheong, J. L. Y. Articles by Doyle, L. W. PubMed Articles by Cheong, J. L. Y. Articles by Doyle, L. W. Related Collections Premature & Newborn

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