Structural and Functional Brain Development After Hydrocortisone Treatment for Neonatal Chronic Lung Disease
http://www.100md.com
《小儿科》
Departments of Pediatrics Radiology
Department of Psychiatry, University of Geneva, Geneva, Switzerland; Departments of
Neonatology Medical Child Psychology, University Medical Center, Utrecht, Netherlands
Department of Neurology, Harvard Medical School, Boston, Massachusetts
ABSTRACT
Objective. There is much concern about potential neurodevelopmental impairment after neonatal corticosteroid treatment for chronic lung disease. Dexamethasone is the corticosteroid most often used in this clinical setting, and it has been shown to impair cortical growth among preterm infants. This study evaluated long-term effects of prematurity itself and of neonatal hydrocortisone treatment on structural and functional brain development using three-dimensional MRI with advanced image-processing and neurocognitive assessments.
Methods. Sixty children born preterm, including 25 children treated with hydrocortisone and 35 children not treated with hydrocortisone, and 21 children born at term were evaluated, at a mean age of 8 years, with quantitative MRI and neurocognitive assessments (Wechsler Intelligence Scales for Children-Revised [WISC-R]). Automatic image segmentation was used to determine the tissue volumes of cerebral gray matter, white matter, and cerebrospinal fluid. In addition, the volume of the hippocampus was determined manually. WISC-R scores were recorded as mean intelligence scores at evaluation. Neonatal hydrocortisone treatment for chronic lung disease consisted of a starting dose of 5 mg/kg per day tapered over a minimum of 3 weeks.
Results. Cerebral gray matter volume was reduced among preterm children (regardless of hydrocortisone treatment), compared with children born at term (preterm: 649 ± 4.4 mL; term: 666 ± 7.3 mL). Birth weight was shown to correlate with gray matter volume at 8 years of age in the preterm group (r = 0.421). Cerebrospinal fluid volume was increased among children born preterm, compared with children born at term (preterm: 228 ± 4.9 mL; term: 206 ± 8.2 mL). Total hippocampal volume tended to be lower among children born preterm, with a more pronounced reduction of hippocampal volume among boys (preterm: 6.1 ± 0.13 mL; term: 6.56 ± 0.2 mL). The WISC-R score was lower for children born preterm, compared with children born at term (preterm: 99.4 ± 12.4; term: 109.6 ± 8.8). Children treated with neonatal hydrocortisone had very similar volumes of gray matter (preterm with hydrocortisone: 650 ± 7.0 mL; preterm without hydrocortisone: 640 ± 5.6 mL), white matter (preterm with hydrocortisone: 503 ± 6.1 mL; preterm without hydrocortisone: 510 ± 4.9 mL), and cerebrospinal fluid (preterm with hydrocortisone: 227 ± 7.4 mL; preterm without hydrocortisone: 224 ± 6.0 mL), compared with untreated infants. The hippocampal volumes were similar in the 2 groups (preterm with hydrocortisone: 5.92 ± 0.15 mL; preterm without hydrocortisone: 5.81 ± 0.12 mL). The WISC-R score assessments were within the normal range for both groups, with no difference between the groups (preterm with hydrocortisone: 100.8 ± 13; preterm without hydrocortisone: 98.6 ± 12.3).
Conclusions. Prematurity is associated with mild brain structural differences that persist at 8 years of age, with associated lower scores in neurocognitive assessments. The data suggest that perinatal hydrocortisone given at the described dosage has no long-term effects on either neurostructural brain development or neurocognitive outcomes.
Key Words: prematurity hydrocortisone brain development MRI
Abbreviations: WISC-R, Wechsler Intelligence Scales for Children-Revised IVH, intraventricular hemorrhage PVL, periventricular leukomalacia
Corticosteroids have been used widely for the prevention and treatment of chronic lung disease in the neonatal period, with proven short-term benefits, including reductions of mortality rates and rates of chronic lung disease.1 The short-term adverse effects of neonatal corticosteroids are also widely known, with increases in the incidences of hyperglycemia, arterial hypertension, gastrointestinal bleeding, and cardiac hypertrophy.2 Neonatal corticosteroid treatment has been evaluated in relation to long-term neurodevelopmental outcomes.3–5 Barrington,6 in a meta-analysis, showed an increased risk for developing cerebral palsy and neurodevelopmental disabilities after postnatal corticosteroid treatment. Most of the studies reviewed used dexamethasone as the corticosteroid treatment.3–5 Recently Short et al7 described detailed neurodevelopmental outcomes at 8 years after neonatal bronchopulmonary dysplasia and found significantly poorer performance in IQ testing among infants treated with corticosteroids, compared with the nonsteroid group. The Vermont Oxford Network Steroid Group found a marginal increase in periventricular leukomalacia (PVL) among infants treated with dexamethasone.8 These emerging long-term, neurologic, side effects prompted a statement by the American Academy of Pediatrics, which discouraged the routine use of corticosteroids, specifically dexamethasone, for the treatment of chronic lung disease among infants with very low birth weights.9 Dexamethasone, a fluorinated glucocorticoid, was shown to deplete pyramidal and dentate granular neurons and to reduce hippocampal volume in animal studies.10,11 At the cellular level, neonatal dexamethasone administration was shown to alter permanently the composition and function of the hippocampal N-methyl-D-aspartate receptor complex in rats.12 Baud et al13 described a specific neurotoxic effect of sulfites used as preservatives in intravenous dexamethasone preparations. Preliminary data on direct effects on structural brain development from three-dimensional quantitative MRI analyses showed significant reduction of cerebral cortical gray matter volume at term among preterm infants exposed to dexamethasone.14 To date, there are few data on the use of alternative corticosteroids, such as hydrocortisone, for treatment in the newborn period.15 A recent retrospective study comparing hydrocortisone and dexamethasone treatment in the newborn period showed fewer short-term and long-term adverse effects with hydrocortisone treatment.16 The focus of this study was to determine whether neonatal systemic hydrocortisone treatment for chronic lung disease among preterm infants had any effect on structural brain development, development of the hippocampus, and neurofunctional outcomes at 8 years of age, with quantitative, volumetric, three-dimensional MRI and neuropsychological assessments.
METHODS
Subjects
Three hundred seventy-five preterm infants born between March 1, 1991, and March 1, 1993, were recruited into a long-term follow-up study. They were born in or referred to the tertiary referral ICU at Wilhelmina Children's Hospital (Utrecht, Netherlands). They had a gestational age of 32 weeks and/or a birth weight of 1500 g. Sixty-four children (17%) died, and 28 (7.5%) were excluded because of congenital abnormalities and/or chromosomal disorders. Of the remaining 283 children, 22 children (7.8%) could not be traced and the parents of 25 children (8.8%) refused to participate. A total of 236 of the 283 children participated, yielding an inclusion rate of 83%. MRI was performed for all children and was successful for 226 children. During the last 6 months of the study period, quantitative, volumetric, three-dimensional MRI was added to the MRI protocol. The study presents the observations for this subgroup of 61 children who were evaluated with quantitative, three-dimensional, volumetric MRI. One child born preterm was excluded because of the presence of a large arachnoid cyst discovered on MRI scans.
At a mean age of 8 years 7 months (SD: 8.6 months), the prematurely born children were invited back to the hospital to undergo a cerebral MRI investigation and a detailed neurodevelopmental assessment. A group of 21 healthy term-born children were included in the study as a control group. At assessment, they had a mean age of 8 years 5 months (SD: 8.1 months). Of the 60 preterm children included in the MRI analysis, 25 children (mean gestational age: 28 ± 1.62 weeks; mean birth weight: 1120 ± 290 g) had been treated with hydrocortisone for chronic lung disease in the neonatal period, and 35 children (mean gestational age: 30.4 ± 1.5 weeks; mean birth weight: 1400 ± 380 g) had not received any corticosteroids during the neonatal period (Table 1). Criteria for starting hydrocortisone treatment were ventilator dependency and increasing oxygen requirements.
Neonatal hydrocortisone treatment consisted of a starting dose of 5 mg/kg per day, divided into 4 doses, for 1 week. Treatment was introduced at a median age of 18 days (minimum: 4 days; maximum: 43 days), followed by a tapering course with a median duration of treatment of 26 days (minimum: 22 days; maximum: 171 days). For 2 of the 25 infants, we were unable to obtain data on the duration of hydrocortisone treatment; therefore, the 2 infants were excluded from the analysis comparing preterm infants with hydrocortisone treatment versus no treatment. Twelve preterm children with moderate/severe perinatal brain lesions (intraventricular hemorrhage [IVH] of grade III or IV, PVL of grade II or III,17 association of PVL and IVH of grade II, or focal brain infarction) were distributed equally between the 2 groups. Neurologic examinations at the time of treatment initiation were not different between hydrocortisone-treated and untreated preterm infants.
The study was approved by the local ethics committee. Written informed parental consent was obtained for all children included in the study
MRI Acquisition
MRI scanning was performed with a 1.5-T Gyroscan ACS-NT system (Phillips Medical Systems, Best, Netherlands). For acquisition of the primary MRI data, 2 different imaging modes were applied, ie, transverse dual turbo spin echo (proton density and T2-weighted; first echo: repetition time: 4000 milliseconds; echo time: 17 milliseconds; slice thickness: 5.0 mm; gap: 1.0 mm; second echo: repetition time: 4000 milliseconds; echo time: 110 milliseconds; slice thickness: 5.0 mm; gap: 1.0 mm) and coronal inversion recovery sequences for the hippocampus (repetition time: 2933 milliseconds; echo time: 13 milliseconds; inversion time: 400 milliseconds; slice thickness: 2.0 mm, without gap).
MRI Processing
Postacquisition processing was performed on workstations (Sun Microsystems, Mountain View, CA) with specifically designed software, namely, MEDx (Sensor System, Sterling, VA) and Slicer (www.slicer.org). All brain measurements were made by a rater blinded to group affiliations. The axial slices were reformatted with MEDx to produce a three-dimensional data set, with inclusion of the gap of 1 mm. The fully automatic Brain Extraction Tool included in MEDx was used to exclude nonbrain tissue (skin, skull, and eyes) from the brain tissue assessment (Fig 1, A). The FAST algorithm (FMRIB Automated Segmentation Tool) included in MEDx was used to segment the brain into 3 separate brain tissue classes, ie, gray matter, white matter, and cerebrospinal fluid (Fig 1, B). The FAST algorithm is based on a hidden Markov random field model and an associated expectation-maximization algorithm.18 The hippocampus was segmented manually on inversion recovery coronal slices of 2-mm thickness with 3D Slicer software (www.slicer.org). The segmentation was started on coronal slices and then completed on sagittal slices. A three-dimensional reconstruction of both hippocampi was performed to check the quality of the segmentation (Fig 2).
Our measurement of the hippocampus included the hippocampus proper, the dentate gyrus, and the subiculum and excluded fimbria and alveus. Because the hippocampus, subiculum, and dentate gyrus are indistinguishable on the basis of tissue signal intensity on MRI scans, they were segmented as a single structure. The amygdala, parahippocampal gyrus, and crus of the fornix were excluded. The boundary between the amygdala and the head of the hippocampus and the boundary of the tail of the hippocampus were traced mainly on the sagittal plane. The tracing guidelines for the hippocampus used in this study were based on published guidelines by Obenaus et al,19 Pantel et al,20 and Duvernoy et al.21 The total hippocampal volume analyzed in this study was calculated with the summation of voxels of the left and right hippocampi. Hippocampal volumes were determined by 1 rater. The mean intraobserver variability for 4 right hippocampi that were segmented twice was 2.72%. The segmentation of the brain into 3 different tissue classes was achieved with a sequence of fully automated algorithms; therefore, no intraobserver variability was determined.
Segmentation of the brain into 3 tissue classes was not possible in 3 cases because of image artifacts in the double echo image series. Segmentation of the hippocampus was not performed for 2 children because the inversion recovery image series could not be completed.
Neurocognitive Assessment
Neurocognitive assessment included several subtests of cognitive functioning of the Wechsler Intelligence Scales for Children-Revised (WISC-R) (Dutch version). An estimate of the full-scale WISC-R IQ score was calculated on the basis of the subtest scores for vocabulary and block design. With the procedures and tables published by Kaufman,22 the scaled scores were converted to an estimated IQ score, which was within the 95% confidence interval of the full-scale IQ score, with a SE of the estimate of 6.3. A psychologist experienced in conducting standardized assessments with children performed all neuropsychological examinations.
Statistical Analyses
The hippocampal volume, total intracranial volume, gray matter volume, white matter volume, cerebrospinal fluid volume, and WISC-R score showed gaussian distributions. Therefore, a univariate additive model with gender as a fixed factor and intracranial volume as a covariate was chosen for analysis of cerebral gray matter, cerebral white matter, and hippocampal volumes among the 3 groups (control subjects, children born premature and treated with hydrocortisone, and children born premature and not treated with hydrocortisone). This model was established to analyze the group effect on brain tissue volume by taking into account the intrinsic variation attributable to intracranial volume and gender.
The Student's t test ( = .05) was used to analyze the differences in WISC-R scores among the groups. The Pearson correlation coefficient and linear regression analyses were also used. All statistical procedures were performed with SPSS version 11 (SPSS, Chicago, IL).
RESULTS
Results of quantitative, volumetric, MRI analyses performed at 8 years of age and neurocognitive outcomes are presented for a group of 60 prematurely born infants and 21 infants born at term. Differences in structural and functional brain development at 8 years among preterm infants, compared with term infants, were as follows.
Effects of Prematurity
Total Intracranial Volume
Children born preterm had a similar intracranial volume, compared with children born at term, after adjustment for gender differences (mean adjusted volume: preterm: 1379 ± 16 mL; term: 1398 ± 26 mL; F = 0.378, df = 1,78, R2 = 0.293, P = .541).
Gray Matter Volumes (Cerebral and Cerebellar Cortex)
Children born preterm had significantly reduced gray matter volumes, compared with control children (mean adjusted volume: preterm: 649 ± 4.4 mL; term: 666 ± 7.3 mL; F = 4.1, df = 1,74, R2 = 0.782, P = .046) (Table 2). After the exclusion of 12 children with brain lesions, the difference in gray matter volumes remained significant.
There was a modest but significant correlation between birth weight and gray matter volume at 8 years in the preterm group (r = 0.421, P = .001; regression equation: gray matter volume = 0.07 · birth weight + 558.76) (Fig 3). There was no correlation between gestational age and gray matter volume (r = 0.124, P = .358).
Cerebral White Matter Volumes
Cerebral white matter volumes were similar between children born at term and children born preterm (mean adjusted volume: preterm: 512 ± 3.8 mL; term: 513 ± 6.2 mL; F = 0.017, df = 1,74, R2 = 0.811, P = .9).
Cerebrospinal Fluid Volumes
Cerebrospinal fluid volume was significantly increased among children born preterm, compared with children born at term (mean adjusted volume: preterm: 228 ± 4.9 mL; term: 206 ± 8.2 mL; F = 5.112, df = 1,77, R2 = 0.341, P = .027).
Hippocampal Volumes
The total hippocampal volume was decreased slightly among children born preterm, compared with children born at term (mean adjusted volume: preterm: 5.86 ± 0.09 mL; term: 6.16 ± 0.15 mL; F = 2.87, df = 1,75, R2 = 0.337, P = .094), with a more pronounced reduction of hippocampal volume among boys (mean adjusted volume: preterm: 6.1 ± 0.13 mL; term: 6.56 ± 0.2 mL; F = 3.696, df = 1,40, R2 = 0.25, P = .06). A comparison of absolute hippocampal volumes for boys without adjustment for intracranial volume showed a significantly reduced hippocampal volume for prematurely born boys (mean volume: preterm: 6.07 ± 0.69 mL; term: 6.64 ± 0.91 mL; P = .03).
Neurocognitive Outcomes
WISC-R scores were found to be lower for children born preterm, compared with children born at term (WISC-R score: preterm: 99.4 ± 12.4; term: 109.6 ± 8.8; P = .001). Modest but significant correlations for the group of children born preterm were found between the gray matter volume and the WISC-R score (r = 0.361, P < .01; regression equation: WISC-R score = 0.074 · gray matter volume + 51.08) and between the hippocampal volume and the WISC-R score (r = 0.282, P < .05; regression equation: WISC-R score = 4.49 · hippocampal volume + 73.19).
Effects of Postnatal Hydrocortisone Treatment
Total Intracranial Volume
Total intracranial volumes were similar for preterm infants with and without postnatal hydrocortisone treatment (mean adjusted volume with gender as a covariate: preterm with hydrocortisone: 1373 ± 24 mL; preterm without hydrocortisone: 1378 ± 19 mL; F = 0.034, df = 1,0, R2 = 0.255, P = .854).
Gray Matter Volumes
Gray matter volumes were similar for preterm infants with and without postnatal hydrocortisone treatment (mean adjusted volume: preterm with hydrocortisone: 650 ± 7.0 mL; preterm without hydrocortisone: 640 ± 5.6 mL; F = 1.05, df = 1,0, R2 = 0.724, P = .310) (Table 3).
Cerebral White Matter Volumes
White matter volumes were not different after postnatal hydrocortisone treatment among children born preterm (mean adjusted volume: preterm with hydrocortisone: 503 ± 6.1 mL; preterm without hydrocortisone: 510 ± 4.9 mL; F = 0.649, df = 1,0, R2 = 0.790, P = .424).
Cerebrospinal Fluid Volumes
Cerebrospinal fluid volumes were not different after postnatal hydrocortisone treatment among children born preterm (mean adjusted volume: preterm with hydrocortisone: 227 ± 7.4 mL; preterm without hydrocortisone: 224 ± 6.0 mL; F = 0.084, df = 1,0, R2 = 0.397, P = .77).
Hippocampal Volumes
Hippocampal volumes were similar for preterm infants with and without postnatal hydrocortisone treatment (mean adjusted total hippocampal volume: preterm with hydrocortisone: 5.92 ± 0.15 mL; preterm without hydrocortisone: 5.81 ± 0.12 mL; F = 0.339, df = 1,0, R2 = 0.259, P = .563). When analyzed separately, boys and girls did not show any difference in any brain tissue volumes as a function of hydrocortisone treatment.
Neurocognitive Outcomes
Postnatal hydrocortisone treatment had no effect on the WISC-R scores (preterm with hydrocortisone: 100.8 ± 13; preterm without hydrocortisone: 98.6 ± 12.3; P = .53).
DISCUSSION
This study, with quantitative MRI techniques, documents mild brain structural differences among children that are attributable to premature birth and persist at 8 years of age, with associated slightly lower scores in neurocognitive assessments. The structural alterations are demonstrated specifically in a reduction of cortical gray matter volume, with a compensatory increase of cerebrospinal fluid volume. Similar results were reported by Nosarti et al23 for adolescents born very preterm. The specific reduction in brain tissue volume of cortical gray matter was also observed at term age for prematurely born infants.24,25 Our results also show a significant correlation of birth weight, rather than gestational age, and cortical gray matter volume at 8 years of age. This finding may suggest that prenatal factors affecting fetal growth, rather than gestational age itself, influence cortical gray matter development.26
The hippocampus has been shown to be a cortical gray matter structure of particular vulnerability to prematurity-associated insults, resulting in hippocampal volume reduction.23,27,28 Isaacs et al27 demonstrated a significant association of hippocampal volume reduction and deficits in everyday memory capacity for a group of adolescents born before 30 weeks of gestation. In our population, overall hippocampal volume among premature infants was reduced only marginally, compared with term infants, with a more marked, significant reduction in hippocampal volume among preterm boys, compared with term boys. A male disadvantage was reported in several outcome studies of children born preterm.29,30 Johnson and Breslau31 described specific learning difficulties present predominantly among male preterm infants. Isaacs et al32 showed the importance of the size of the hippocampus in relation to developmental amnesia, indicating that hippocampal volume had an effect on specific memory functions. Interestingly, we found significant correlations of both the cortical gray matter volume and the overall hippocampal volume with the overall IQ (measured as the WISC-R score), which emphasizes a certain structure-function relationship in brain development.
The overall IQ (measured as the WISC-R score) for our population of children born preterm was lower than the score for the children born at term. Despite this significant reduction, the absolute mean value of the IQ measured for the children born preterm remained within 2 SD of the normal range. This finding might be influenced by the age at which the children are evaluated. Ment et al33 showed possible cognitive improvement throughout childhood after premature birth. The limited number of preterm children born between 24 and 26 weeks of gestation included in this study could also explain the rather high IQ score for this group of preterm infants.
No differences in total intracranial volume, cerebral gray matter volume, white matter volume, and cerebrospinal fluid volume were observed after hydrocortisone treatment. Brain tissue volumes in the treated and untreated groups were similar despite differences in gestational age, birth weight, and the numbers of infants treated with mechanical ventilation, surfactant, and inotrope, favoring the untreated group. This is in contrast to a study of perinatal dexamethasone exposure among preterm infants at term, which found a reduction of 30% in cortical gray matter volume after dexamethasone treatment for chronic lung disease.14
The increased sensitivity of the hippocampus to corticosteroids and chronic psychosocial stress is well known.34,35 The exposure to hydrocortisone in our study did not have any lasting effect on hippocampal volume at 8 years of age. There are no other studies addressing directly the effect of postnatal corticosteroid treatment on hippocampal volume among human subjects.
In our study, the preterm infants received hydrocortisone at a starting dose of 5 mg/kg per day, equivalent to one third of the glucocorticoid activity of a dexamethasone dosage of 0.5 mg/kg per day, as used in most published studies. Moreover, the biological half-life of hydrocortisone is 5 times shorter than that of dexamethasone, which reduces the risk of cumulative dosing.36 Aside from the differences in the glucocorticoid activity and half-life of hydrocortisone, several mechanisms could explain the absence of significant effects of hydrocortisone on brain development. Both hydrocortisone and dexamethasone can cross the blood-brain barrier.37,38 Hydrocortisone, however, binds preferentially to the mineralocorticoid receptors in the brain,38,39 whereas dexamethasone binds preferentially to the glucocorticoid receptor. In neuronal cells of the dentate gyrus, this binding to the glucocorticoid receptor was shown to induce the expression of the proapoptotic molecule Bax.40 The exacerbation by dexamethasone of neuronal cell death through apoptosis in the dentate gyrus was also described by Hassan et al,41 who demonstrated a neuroprotective effect of corticosterone, the physiologic form of hydrocortisone, in rats.
Both the structural development at 8 years of age and the neurofunctional outcomes measured with a standardized neurocognitive assessment scale did not differ for the children treated with hydrocortisone. This is in agreement with the outcome data of the recently published comparison study of postnatal hydrocortisone and dexamethasone treatment, with favorable outcomes for hydrocortisone-treated infants,16 and is in contrast to several studies that examined neurocognitive outcomes after dexamethasone treatment, which showed significant associations with neurodevelopmental delays.6,42
CONCLUSIONS
We were able to show that prematurity affects long-term structural and functional brain development. Furthermore, this study showed that postnatal hydrocortisone treatment for chronic lung disease had no effect on cerebral brain tissue volumes, no effect on hippocampal development, and no negative effect on neurocognitive outcomes at 8 years of age. These findings have potentially important implications for the treatment of chronic lung disease in the neonatal period.
FOOTNOTES
Accepted Oct 29, 2004.
No conflict of interest declared.
REFERENCES
Halliday HL, Ehrenkranz RA, Doyle LW. Moderately early (7–14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2003;(1):CD001144
Stark AR, Carlo WA, Tyson JE, et al. Adverse effects of early dexamethasone in extremely-low-birth-weight infants: National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med. 2001;344 :95 –101
O'Shea TM, Kothadia JM, Klinepeter KL, et al. Randomized placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants: outcome of study participants at 1-year adjusted age. Pediatrics. 1999;104 :15 –21
Shinwell ES, Karplus M, Reich D, et al. Early postnatal dexamethasone treatment and increased incidence of cerebral palsy. Arch Dis Child Fetal Neonatal Ed. 2000;83 :F177—F181
Barrington KJ. The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. BMC Pediatr. 2001;1 :1
Vermont Oxford Network Steroid Study Group. Early postnatal dexamethasone therapy for the prevention of chronic lung disease. Pediatrics. 2001;108 :741 –748
Committee on Fetus and Newborn. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics. 2002;109 :330 –338
Uno H, Eisele S, Sakai A, et al. Neurotoxicity of glucocorticoids in the primate brain. Horm Behav. 1994;28 :336 –348
Uno H, Lohmiller L, Thieme C, et al. Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques, I: hippocampus. Brain Res Dev Brain Res. 1990;53 :157 –167
Kamphuis PJ, Gardoni F, Kamal A, et al. Long-lasting effects of neonatal dexamethasone treatment on spatial learning and hippocampal synaptic plasticity: involvement of the NMDA receptor complex. FASEB J. 2003;17 :911 –913
Baud O, Laudenbach V, Evrard P, Gressens P. Neurotoxic effects of fluorinated glucocorticoid preparations on the developing mouse brain: role of preservatives. Pediatr Res. 2001;50 :706 –711
Murphy BP, Inder TE, Huppi PS, et al. Impaired cerebral cortical gray matter growth after treatment with dexamethasone for neonatal chronic lung disease. Pediatrics. 2001;107 :217 –221
Watterberg KL, Gerdes JS, Gifford KL, Lin HM. Prophylaxis against early adrenal insufficiency to prevent chronic lung disease in premature infants. Pediatrics. 1999;104 :1258 –1263
van der Heide-Jalving M, Kamphuis PJ, van der Laan MJ, et al. Short- and long-term effects of neonatal glucocorticoid therapy: is hydrocortisone an alternative to dexamethasone Acta Paediatr. 2003;92 :827 –835
de Vries LS, Eken P, Dubowitz LM. The spectrum of leukomalacia using cranial ultrasound. Behav Brain Res. 1992;49 :1 –6
Zhang Y, Brady M, Smith S. Segmentation of brain MR images through a hidden Markov random field model and the expectation-maximization algorithm. IEEE Trans Med Imaging. 2001;20 :45 –57
Obenaus A, Yong-Hing CJ, Tong KA, Sarty GE. A reliable method for measurement and normalization of pediatric hippocampal volumes. Pediatr Res. 2001;50 :124 –132
Pantel J, O'Leary DS, Cretsinger K, et al. A new method for the in vivo volumetric measurement of the human hippocampus with high neuroanatomical accuracy. Hippocampus. 2000;10 :752 –758
Duvernoy HM, Bourgouin P. The Human Hippocampus: Functional Anatomy, Vascularization and Serial Sections With MRI. 2nd ed. New York, NY: Springer; 1998
Kaufman AS. Intelligent Testing With the WISC-R. New York, NY: Wiley; 1979
Nosarti C, Al-Asady MH, Frangou S, Stewart AL, Rifkin L, Murray RM. Adolescents who were born very preterm have decreased brain volumes. Brain. 2002;125 :1616 –1623
Peterson BS, Anderson AW, Ehrenkranz R, et al. Regional brain volumes and their later neurodevelopmental correlates in term and preterm infants. Pediatrics. 2003;111 :939 –948
Inder TE, Huppi PS, Warfield S, et al. Periventricular white matter injury in the premature infant is followed by reduced cerebral cortical gray matter volume at term. Ann Neurol. 1999;46 :755 –760
Borradori Tolsa C, Zimine S, Warfield SK, et al. Early alteration of structural and functional brain development in premature infants born with intrauterine growth restriction. Pediatr Res. 2004;56; 132 –138
Isaacs EB, Lucas A, Chong WK, et al. Hippocampal volume and everyday memory in children of very low birth weight. Pediatr Res. 2000;47 :713 –720
Abernethy LJ, Palaniappan M, Cooke RW. Quantitative magnetic resonance imaging of the brain in survivors of very low birth weight. Arch Dis Child. 2002;87 :279 –283
Verloove-Vanhorick SP, Veen S, Ens-Dokkum MH, Schreuder AM, Brand R, Ruys JH. Sex difference in disability and handicap at five years of age in children born at very short gestation. Pediatrics. 1994;93 :576 –579
Hack M, Flannery DJ, Schluchter M, Cartar L, Borawski E, Klein N. Outcomes in young adulthood for very-low-birth-weight infants. N Engl J Med. 2002;346 :149 –157
Johnson EO, Breslau N. Increased risk of learning disabilities in low birth weight boys at age 11 years. Biol Psychiatry. 2000;47 :490 –500
Isaacs EB, Vargha-Khadem F, Watkins KE, Lucas A, Mishkin M, Gadian DG. Developmental amnesia and its relationship to degree of hippocampal atrophy. Proc Natl Acad Sci USA. 2003;100 :13060 –13063
Ment LR, Vohr B, Allan W, et al. Change in cognitive function over time in very low-birth-weight infants. JAMA. 2003;289 :705 –711
Bremner JD, Randall P, Scott TM, et al. MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry. 1995;152 :973 –981
McEwen BS. Early life influences on life-long patterns of behavior and health. Ment Retard Dev Disabil Res Rev. 2003;9 :149 –154
Sperling M. Pediatric Endocrinology. 2nd ed. Philadelphia, PA: Saunders; 2002
Karssen AM, Meijer OC, van der Sandt IC, et al. Multidrug resistance P-glycoprotein hampers the access of cortisol but not of corticosterone to mouse and human brain. Endocrinology. 2001;142 :2686 –2694
De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M. Brain corticosteroid receptor balance in health and disease. Endocr Rev. 1998;19 :269 –301
Reul JM, Gesing A, Droste S, et al. The brain mineralocorticoid receptor: greedy for ligand, mysterious in function. Eur J Pharmacol. 2000;405 :235 –249
Almeida OF, Conde GL, Crochemore C, et al. Subtle shifts in the ratio between pro- and antiapoptotic molecules after activation of corticosteroid receptors decide neuronal fate. FASEB J. 2000;14 :779 –790
Hassan AH, von Rosenstiel P, Patchev VK, Holsboer F, Almeida OF. Exacerbation of apoptosis in the dentate gyrus of the aged rat by dexamethasone and the protective role of corticosterone. Exp Neurol. 1996;140 :43 –52
LeFlore JL, Salhab WA, Broyles RS, Engle WD. Association of antenatal and postnatal dexamethasone exposure with outcomes in extremely low birth weight neonates. Pediatrics. 2002;110 :275 –279(Gregory A. Lodygensky, MD)
Department of Psychiatry, University of Geneva, Geneva, Switzerland; Departments of
Neonatology Medical Child Psychology, University Medical Center, Utrecht, Netherlands
Department of Neurology, Harvard Medical School, Boston, Massachusetts
ABSTRACT
Objective. There is much concern about potential neurodevelopmental impairment after neonatal corticosteroid treatment for chronic lung disease. Dexamethasone is the corticosteroid most often used in this clinical setting, and it has been shown to impair cortical growth among preterm infants. This study evaluated long-term effects of prematurity itself and of neonatal hydrocortisone treatment on structural and functional brain development using three-dimensional MRI with advanced image-processing and neurocognitive assessments.
Methods. Sixty children born preterm, including 25 children treated with hydrocortisone and 35 children not treated with hydrocortisone, and 21 children born at term were evaluated, at a mean age of 8 years, with quantitative MRI and neurocognitive assessments (Wechsler Intelligence Scales for Children-Revised [WISC-R]). Automatic image segmentation was used to determine the tissue volumes of cerebral gray matter, white matter, and cerebrospinal fluid. In addition, the volume of the hippocampus was determined manually. WISC-R scores were recorded as mean intelligence scores at evaluation. Neonatal hydrocortisone treatment for chronic lung disease consisted of a starting dose of 5 mg/kg per day tapered over a minimum of 3 weeks.
Results. Cerebral gray matter volume was reduced among preterm children (regardless of hydrocortisone treatment), compared with children born at term (preterm: 649 ± 4.4 mL; term: 666 ± 7.3 mL). Birth weight was shown to correlate with gray matter volume at 8 years of age in the preterm group (r = 0.421). Cerebrospinal fluid volume was increased among children born preterm, compared with children born at term (preterm: 228 ± 4.9 mL; term: 206 ± 8.2 mL). Total hippocampal volume tended to be lower among children born preterm, with a more pronounced reduction of hippocampal volume among boys (preterm: 6.1 ± 0.13 mL; term: 6.56 ± 0.2 mL). The WISC-R score was lower for children born preterm, compared with children born at term (preterm: 99.4 ± 12.4; term: 109.6 ± 8.8). Children treated with neonatal hydrocortisone had very similar volumes of gray matter (preterm with hydrocortisone: 650 ± 7.0 mL; preterm without hydrocortisone: 640 ± 5.6 mL), white matter (preterm with hydrocortisone: 503 ± 6.1 mL; preterm without hydrocortisone: 510 ± 4.9 mL), and cerebrospinal fluid (preterm with hydrocortisone: 227 ± 7.4 mL; preterm without hydrocortisone: 224 ± 6.0 mL), compared with untreated infants. The hippocampal volumes were similar in the 2 groups (preterm with hydrocortisone: 5.92 ± 0.15 mL; preterm without hydrocortisone: 5.81 ± 0.12 mL). The WISC-R score assessments were within the normal range for both groups, with no difference between the groups (preterm with hydrocortisone: 100.8 ± 13; preterm without hydrocortisone: 98.6 ± 12.3).
Conclusions. Prematurity is associated with mild brain structural differences that persist at 8 years of age, with associated lower scores in neurocognitive assessments. The data suggest that perinatal hydrocortisone given at the described dosage has no long-term effects on either neurostructural brain development or neurocognitive outcomes.
Key Words: prematurity hydrocortisone brain development MRI
Abbreviations: WISC-R, Wechsler Intelligence Scales for Children-Revised IVH, intraventricular hemorrhage PVL, periventricular leukomalacia
Corticosteroids have been used widely for the prevention and treatment of chronic lung disease in the neonatal period, with proven short-term benefits, including reductions of mortality rates and rates of chronic lung disease.1 The short-term adverse effects of neonatal corticosteroids are also widely known, with increases in the incidences of hyperglycemia, arterial hypertension, gastrointestinal bleeding, and cardiac hypertrophy.2 Neonatal corticosteroid treatment has been evaluated in relation to long-term neurodevelopmental outcomes.3–5 Barrington,6 in a meta-analysis, showed an increased risk for developing cerebral palsy and neurodevelopmental disabilities after postnatal corticosteroid treatment. Most of the studies reviewed used dexamethasone as the corticosteroid treatment.3–5 Recently Short et al7 described detailed neurodevelopmental outcomes at 8 years after neonatal bronchopulmonary dysplasia and found significantly poorer performance in IQ testing among infants treated with corticosteroids, compared with the nonsteroid group. The Vermont Oxford Network Steroid Group found a marginal increase in periventricular leukomalacia (PVL) among infants treated with dexamethasone.8 These emerging long-term, neurologic, side effects prompted a statement by the American Academy of Pediatrics, which discouraged the routine use of corticosteroids, specifically dexamethasone, for the treatment of chronic lung disease among infants with very low birth weights.9 Dexamethasone, a fluorinated glucocorticoid, was shown to deplete pyramidal and dentate granular neurons and to reduce hippocampal volume in animal studies.10,11 At the cellular level, neonatal dexamethasone administration was shown to alter permanently the composition and function of the hippocampal N-methyl-D-aspartate receptor complex in rats.12 Baud et al13 described a specific neurotoxic effect of sulfites used as preservatives in intravenous dexamethasone preparations. Preliminary data on direct effects on structural brain development from three-dimensional quantitative MRI analyses showed significant reduction of cerebral cortical gray matter volume at term among preterm infants exposed to dexamethasone.14 To date, there are few data on the use of alternative corticosteroids, such as hydrocortisone, for treatment in the newborn period.15 A recent retrospective study comparing hydrocortisone and dexamethasone treatment in the newborn period showed fewer short-term and long-term adverse effects with hydrocortisone treatment.16 The focus of this study was to determine whether neonatal systemic hydrocortisone treatment for chronic lung disease among preterm infants had any effect on structural brain development, development of the hippocampus, and neurofunctional outcomes at 8 years of age, with quantitative, volumetric, three-dimensional MRI and neuropsychological assessments.
METHODS
Subjects
Three hundred seventy-five preterm infants born between March 1, 1991, and March 1, 1993, were recruited into a long-term follow-up study. They were born in or referred to the tertiary referral ICU at Wilhelmina Children's Hospital (Utrecht, Netherlands). They had a gestational age of 32 weeks and/or a birth weight of 1500 g. Sixty-four children (17%) died, and 28 (7.5%) were excluded because of congenital abnormalities and/or chromosomal disorders. Of the remaining 283 children, 22 children (7.8%) could not be traced and the parents of 25 children (8.8%) refused to participate. A total of 236 of the 283 children participated, yielding an inclusion rate of 83%. MRI was performed for all children and was successful for 226 children. During the last 6 months of the study period, quantitative, volumetric, three-dimensional MRI was added to the MRI protocol. The study presents the observations for this subgroup of 61 children who were evaluated with quantitative, three-dimensional, volumetric MRI. One child born preterm was excluded because of the presence of a large arachnoid cyst discovered on MRI scans.
At a mean age of 8 years 7 months (SD: 8.6 months), the prematurely born children were invited back to the hospital to undergo a cerebral MRI investigation and a detailed neurodevelopmental assessment. A group of 21 healthy term-born children were included in the study as a control group. At assessment, they had a mean age of 8 years 5 months (SD: 8.1 months). Of the 60 preterm children included in the MRI analysis, 25 children (mean gestational age: 28 ± 1.62 weeks; mean birth weight: 1120 ± 290 g) had been treated with hydrocortisone for chronic lung disease in the neonatal period, and 35 children (mean gestational age: 30.4 ± 1.5 weeks; mean birth weight: 1400 ± 380 g) had not received any corticosteroids during the neonatal period (Table 1). Criteria for starting hydrocortisone treatment were ventilator dependency and increasing oxygen requirements.
Neonatal hydrocortisone treatment consisted of a starting dose of 5 mg/kg per day, divided into 4 doses, for 1 week. Treatment was introduced at a median age of 18 days (minimum: 4 days; maximum: 43 days), followed by a tapering course with a median duration of treatment of 26 days (minimum: 22 days; maximum: 171 days). For 2 of the 25 infants, we were unable to obtain data on the duration of hydrocortisone treatment; therefore, the 2 infants were excluded from the analysis comparing preterm infants with hydrocortisone treatment versus no treatment. Twelve preterm children with moderate/severe perinatal brain lesions (intraventricular hemorrhage [IVH] of grade III or IV, PVL of grade II or III,17 association of PVL and IVH of grade II, or focal brain infarction) were distributed equally between the 2 groups. Neurologic examinations at the time of treatment initiation were not different between hydrocortisone-treated and untreated preterm infants.
The study was approved by the local ethics committee. Written informed parental consent was obtained for all children included in the study
MRI Acquisition
MRI scanning was performed with a 1.5-T Gyroscan ACS-NT system (Phillips Medical Systems, Best, Netherlands). For acquisition of the primary MRI data, 2 different imaging modes were applied, ie, transverse dual turbo spin echo (proton density and T2-weighted; first echo: repetition time: 4000 milliseconds; echo time: 17 milliseconds; slice thickness: 5.0 mm; gap: 1.0 mm; second echo: repetition time: 4000 milliseconds; echo time: 110 milliseconds; slice thickness: 5.0 mm; gap: 1.0 mm) and coronal inversion recovery sequences for the hippocampus (repetition time: 2933 milliseconds; echo time: 13 milliseconds; inversion time: 400 milliseconds; slice thickness: 2.0 mm, without gap).
MRI Processing
Postacquisition processing was performed on workstations (Sun Microsystems, Mountain View, CA) with specifically designed software, namely, MEDx (Sensor System, Sterling, VA) and Slicer (www.slicer.org). All brain measurements were made by a rater blinded to group affiliations. The axial slices were reformatted with MEDx to produce a three-dimensional data set, with inclusion of the gap of 1 mm. The fully automatic Brain Extraction Tool included in MEDx was used to exclude nonbrain tissue (skin, skull, and eyes) from the brain tissue assessment (Fig 1, A). The FAST algorithm (FMRIB Automated Segmentation Tool) included in MEDx was used to segment the brain into 3 separate brain tissue classes, ie, gray matter, white matter, and cerebrospinal fluid (Fig 1, B). The FAST algorithm is based on a hidden Markov random field model and an associated expectation-maximization algorithm.18 The hippocampus was segmented manually on inversion recovery coronal slices of 2-mm thickness with 3D Slicer software (www.slicer.org). The segmentation was started on coronal slices and then completed on sagittal slices. A three-dimensional reconstruction of both hippocampi was performed to check the quality of the segmentation (Fig 2).
Our measurement of the hippocampus included the hippocampus proper, the dentate gyrus, and the subiculum and excluded fimbria and alveus. Because the hippocampus, subiculum, and dentate gyrus are indistinguishable on the basis of tissue signal intensity on MRI scans, they were segmented as a single structure. The amygdala, parahippocampal gyrus, and crus of the fornix were excluded. The boundary between the amygdala and the head of the hippocampus and the boundary of the tail of the hippocampus were traced mainly on the sagittal plane. The tracing guidelines for the hippocampus used in this study were based on published guidelines by Obenaus et al,19 Pantel et al,20 and Duvernoy et al.21 The total hippocampal volume analyzed in this study was calculated with the summation of voxels of the left and right hippocampi. Hippocampal volumes were determined by 1 rater. The mean intraobserver variability for 4 right hippocampi that were segmented twice was 2.72%. The segmentation of the brain into 3 different tissue classes was achieved with a sequence of fully automated algorithms; therefore, no intraobserver variability was determined.
Segmentation of the brain into 3 tissue classes was not possible in 3 cases because of image artifacts in the double echo image series. Segmentation of the hippocampus was not performed for 2 children because the inversion recovery image series could not be completed.
Neurocognitive Assessment
Neurocognitive assessment included several subtests of cognitive functioning of the Wechsler Intelligence Scales for Children-Revised (WISC-R) (Dutch version). An estimate of the full-scale WISC-R IQ score was calculated on the basis of the subtest scores for vocabulary and block design. With the procedures and tables published by Kaufman,22 the scaled scores were converted to an estimated IQ score, which was within the 95% confidence interval of the full-scale IQ score, with a SE of the estimate of 6.3. A psychologist experienced in conducting standardized assessments with children performed all neuropsychological examinations.
Statistical Analyses
The hippocampal volume, total intracranial volume, gray matter volume, white matter volume, cerebrospinal fluid volume, and WISC-R score showed gaussian distributions. Therefore, a univariate additive model with gender as a fixed factor and intracranial volume as a covariate was chosen for analysis of cerebral gray matter, cerebral white matter, and hippocampal volumes among the 3 groups (control subjects, children born premature and treated with hydrocortisone, and children born premature and not treated with hydrocortisone). This model was established to analyze the group effect on brain tissue volume by taking into account the intrinsic variation attributable to intracranial volume and gender.
The Student's t test ( = .05) was used to analyze the differences in WISC-R scores among the groups. The Pearson correlation coefficient and linear regression analyses were also used. All statistical procedures were performed with SPSS version 11 (SPSS, Chicago, IL).
RESULTS
Results of quantitative, volumetric, MRI analyses performed at 8 years of age and neurocognitive outcomes are presented for a group of 60 prematurely born infants and 21 infants born at term. Differences in structural and functional brain development at 8 years among preterm infants, compared with term infants, were as follows.
Effects of Prematurity
Total Intracranial Volume
Children born preterm had a similar intracranial volume, compared with children born at term, after adjustment for gender differences (mean adjusted volume: preterm: 1379 ± 16 mL; term: 1398 ± 26 mL; F = 0.378, df = 1,78, R2 = 0.293, P = .541).
Gray Matter Volumes (Cerebral and Cerebellar Cortex)
Children born preterm had significantly reduced gray matter volumes, compared with control children (mean adjusted volume: preterm: 649 ± 4.4 mL; term: 666 ± 7.3 mL; F = 4.1, df = 1,74, R2 = 0.782, P = .046) (Table 2). After the exclusion of 12 children with brain lesions, the difference in gray matter volumes remained significant.
There was a modest but significant correlation between birth weight and gray matter volume at 8 years in the preterm group (r = 0.421, P = .001; regression equation: gray matter volume = 0.07 · birth weight + 558.76) (Fig 3). There was no correlation between gestational age and gray matter volume (r = 0.124, P = .358).
Cerebral White Matter Volumes
Cerebral white matter volumes were similar between children born at term and children born preterm (mean adjusted volume: preterm: 512 ± 3.8 mL; term: 513 ± 6.2 mL; F = 0.017, df = 1,74, R2 = 0.811, P = .9).
Cerebrospinal Fluid Volumes
Cerebrospinal fluid volume was significantly increased among children born preterm, compared with children born at term (mean adjusted volume: preterm: 228 ± 4.9 mL; term: 206 ± 8.2 mL; F = 5.112, df = 1,77, R2 = 0.341, P = .027).
Hippocampal Volumes
The total hippocampal volume was decreased slightly among children born preterm, compared with children born at term (mean adjusted volume: preterm: 5.86 ± 0.09 mL; term: 6.16 ± 0.15 mL; F = 2.87, df = 1,75, R2 = 0.337, P = .094), with a more pronounced reduction of hippocampal volume among boys (mean adjusted volume: preterm: 6.1 ± 0.13 mL; term: 6.56 ± 0.2 mL; F = 3.696, df = 1,40, R2 = 0.25, P = .06). A comparison of absolute hippocampal volumes for boys without adjustment for intracranial volume showed a significantly reduced hippocampal volume for prematurely born boys (mean volume: preterm: 6.07 ± 0.69 mL; term: 6.64 ± 0.91 mL; P = .03).
Neurocognitive Outcomes
WISC-R scores were found to be lower for children born preterm, compared with children born at term (WISC-R score: preterm: 99.4 ± 12.4; term: 109.6 ± 8.8; P = .001). Modest but significant correlations for the group of children born preterm were found between the gray matter volume and the WISC-R score (r = 0.361, P < .01; regression equation: WISC-R score = 0.074 · gray matter volume + 51.08) and between the hippocampal volume and the WISC-R score (r = 0.282, P < .05; regression equation: WISC-R score = 4.49 · hippocampal volume + 73.19).
Effects of Postnatal Hydrocortisone Treatment
Total Intracranial Volume
Total intracranial volumes were similar for preterm infants with and without postnatal hydrocortisone treatment (mean adjusted volume with gender as a covariate: preterm with hydrocortisone: 1373 ± 24 mL; preterm without hydrocortisone: 1378 ± 19 mL; F = 0.034, df = 1,0, R2 = 0.255, P = .854).
Gray Matter Volumes
Gray matter volumes were similar for preterm infants with and without postnatal hydrocortisone treatment (mean adjusted volume: preterm with hydrocortisone: 650 ± 7.0 mL; preterm without hydrocortisone: 640 ± 5.6 mL; F = 1.05, df = 1,0, R2 = 0.724, P = .310) (Table 3).
Cerebral White Matter Volumes
White matter volumes were not different after postnatal hydrocortisone treatment among children born preterm (mean adjusted volume: preterm with hydrocortisone: 503 ± 6.1 mL; preterm without hydrocortisone: 510 ± 4.9 mL; F = 0.649, df = 1,0, R2 = 0.790, P = .424).
Cerebrospinal Fluid Volumes
Cerebrospinal fluid volumes were not different after postnatal hydrocortisone treatment among children born preterm (mean adjusted volume: preterm with hydrocortisone: 227 ± 7.4 mL; preterm without hydrocortisone: 224 ± 6.0 mL; F = 0.084, df = 1,0, R2 = 0.397, P = .77).
Hippocampal Volumes
Hippocampal volumes were similar for preterm infants with and without postnatal hydrocortisone treatment (mean adjusted total hippocampal volume: preterm with hydrocortisone: 5.92 ± 0.15 mL; preterm without hydrocortisone: 5.81 ± 0.12 mL; F = 0.339, df = 1,0, R2 = 0.259, P = .563). When analyzed separately, boys and girls did not show any difference in any brain tissue volumes as a function of hydrocortisone treatment.
Neurocognitive Outcomes
Postnatal hydrocortisone treatment had no effect on the WISC-R scores (preterm with hydrocortisone: 100.8 ± 13; preterm without hydrocortisone: 98.6 ± 12.3; P = .53).
DISCUSSION
This study, with quantitative MRI techniques, documents mild brain structural differences among children that are attributable to premature birth and persist at 8 years of age, with associated slightly lower scores in neurocognitive assessments. The structural alterations are demonstrated specifically in a reduction of cortical gray matter volume, with a compensatory increase of cerebrospinal fluid volume. Similar results were reported by Nosarti et al23 for adolescents born very preterm. The specific reduction in brain tissue volume of cortical gray matter was also observed at term age for prematurely born infants.24,25 Our results also show a significant correlation of birth weight, rather than gestational age, and cortical gray matter volume at 8 years of age. This finding may suggest that prenatal factors affecting fetal growth, rather than gestational age itself, influence cortical gray matter development.26
The hippocampus has been shown to be a cortical gray matter structure of particular vulnerability to prematurity-associated insults, resulting in hippocampal volume reduction.23,27,28 Isaacs et al27 demonstrated a significant association of hippocampal volume reduction and deficits in everyday memory capacity for a group of adolescents born before 30 weeks of gestation. In our population, overall hippocampal volume among premature infants was reduced only marginally, compared with term infants, with a more marked, significant reduction in hippocampal volume among preterm boys, compared with term boys. A male disadvantage was reported in several outcome studies of children born preterm.29,30 Johnson and Breslau31 described specific learning difficulties present predominantly among male preterm infants. Isaacs et al32 showed the importance of the size of the hippocampus in relation to developmental amnesia, indicating that hippocampal volume had an effect on specific memory functions. Interestingly, we found significant correlations of both the cortical gray matter volume and the overall hippocampal volume with the overall IQ (measured as the WISC-R score), which emphasizes a certain structure-function relationship in brain development.
The overall IQ (measured as the WISC-R score) for our population of children born preterm was lower than the score for the children born at term. Despite this significant reduction, the absolute mean value of the IQ measured for the children born preterm remained within 2 SD of the normal range. This finding might be influenced by the age at which the children are evaluated. Ment et al33 showed possible cognitive improvement throughout childhood after premature birth. The limited number of preterm children born between 24 and 26 weeks of gestation included in this study could also explain the rather high IQ score for this group of preterm infants.
No differences in total intracranial volume, cerebral gray matter volume, white matter volume, and cerebrospinal fluid volume were observed after hydrocortisone treatment. Brain tissue volumes in the treated and untreated groups were similar despite differences in gestational age, birth weight, and the numbers of infants treated with mechanical ventilation, surfactant, and inotrope, favoring the untreated group. This is in contrast to a study of perinatal dexamethasone exposure among preterm infants at term, which found a reduction of 30% in cortical gray matter volume after dexamethasone treatment for chronic lung disease.14
The increased sensitivity of the hippocampus to corticosteroids and chronic psychosocial stress is well known.34,35 The exposure to hydrocortisone in our study did not have any lasting effect on hippocampal volume at 8 years of age. There are no other studies addressing directly the effect of postnatal corticosteroid treatment on hippocampal volume among human subjects.
In our study, the preterm infants received hydrocortisone at a starting dose of 5 mg/kg per day, equivalent to one third of the glucocorticoid activity of a dexamethasone dosage of 0.5 mg/kg per day, as used in most published studies. Moreover, the biological half-life of hydrocortisone is 5 times shorter than that of dexamethasone, which reduces the risk of cumulative dosing.36 Aside from the differences in the glucocorticoid activity and half-life of hydrocortisone, several mechanisms could explain the absence of significant effects of hydrocortisone on brain development. Both hydrocortisone and dexamethasone can cross the blood-brain barrier.37,38 Hydrocortisone, however, binds preferentially to the mineralocorticoid receptors in the brain,38,39 whereas dexamethasone binds preferentially to the glucocorticoid receptor. In neuronal cells of the dentate gyrus, this binding to the glucocorticoid receptor was shown to induce the expression of the proapoptotic molecule Bax.40 The exacerbation by dexamethasone of neuronal cell death through apoptosis in the dentate gyrus was also described by Hassan et al,41 who demonstrated a neuroprotective effect of corticosterone, the physiologic form of hydrocortisone, in rats.
Both the structural development at 8 years of age and the neurofunctional outcomes measured with a standardized neurocognitive assessment scale did not differ for the children treated with hydrocortisone. This is in agreement with the outcome data of the recently published comparison study of postnatal hydrocortisone and dexamethasone treatment, with favorable outcomes for hydrocortisone-treated infants,16 and is in contrast to several studies that examined neurocognitive outcomes after dexamethasone treatment, which showed significant associations with neurodevelopmental delays.6,42
CONCLUSIONS
We were able to show that prematurity affects long-term structural and functional brain development. Furthermore, this study showed that postnatal hydrocortisone treatment for chronic lung disease had no effect on cerebral brain tissue volumes, no effect on hippocampal development, and no negative effect on neurocognitive outcomes at 8 years of age. These findings have potentially important implications for the treatment of chronic lung disease in the neonatal period.
FOOTNOTES
Accepted Oct 29, 2004.
No conflict of interest declared.
REFERENCES
Halliday HL, Ehrenkranz RA, Doyle LW. Moderately early (7–14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2003;(1):CD001144
Stark AR, Carlo WA, Tyson JE, et al. Adverse effects of early dexamethasone in extremely-low-birth-weight infants: National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med. 2001;344 :95 –101
O'Shea TM, Kothadia JM, Klinepeter KL, et al. Randomized placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants: outcome of study participants at 1-year adjusted age. Pediatrics. 1999;104 :15 –21
Shinwell ES, Karplus M, Reich D, et al. Early postnatal dexamethasone treatment and increased incidence of cerebral palsy. Arch Dis Child Fetal Neonatal Ed. 2000;83 :F177—F181
Barrington KJ. The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. BMC Pediatr. 2001;1 :1
Vermont Oxford Network Steroid Study Group. Early postnatal dexamethasone therapy for the prevention of chronic lung disease. Pediatrics. 2001;108 :741 –748
Committee on Fetus and Newborn. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics. 2002;109 :330 –338
Uno H, Eisele S, Sakai A, et al. Neurotoxicity of glucocorticoids in the primate brain. Horm Behav. 1994;28 :336 –348
Uno H, Lohmiller L, Thieme C, et al. Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques, I: hippocampus. Brain Res Dev Brain Res. 1990;53 :157 –167
Kamphuis PJ, Gardoni F, Kamal A, et al. Long-lasting effects of neonatal dexamethasone treatment on spatial learning and hippocampal synaptic plasticity: involvement of the NMDA receptor complex. FASEB J. 2003;17 :911 –913
Baud O, Laudenbach V, Evrard P, Gressens P. Neurotoxic effects of fluorinated glucocorticoid preparations on the developing mouse brain: role of preservatives. Pediatr Res. 2001;50 :706 –711
Murphy BP, Inder TE, Huppi PS, et al. Impaired cerebral cortical gray matter growth after treatment with dexamethasone for neonatal chronic lung disease. Pediatrics. 2001;107 :217 –221
Watterberg KL, Gerdes JS, Gifford KL, Lin HM. Prophylaxis against early adrenal insufficiency to prevent chronic lung disease in premature infants. Pediatrics. 1999;104 :1258 –1263
van der Heide-Jalving M, Kamphuis PJ, van der Laan MJ, et al. Short- and long-term effects of neonatal glucocorticoid therapy: is hydrocortisone an alternative to dexamethasone Acta Paediatr. 2003;92 :827 –835
de Vries LS, Eken P, Dubowitz LM. The spectrum of leukomalacia using cranial ultrasound. Behav Brain Res. 1992;49 :1 –6
Zhang Y, Brady M, Smith S. Segmentation of brain MR images through a hidden Markov random field model and the expectation-maximization algorithm. IEEE Trans Med Imaging. 2001;20 :45 –57
Obenaus A, Yong-Hing CJ, Tong KA, Sarty GE. A reliable method for measurement and normalization of pediatric hippocampal volumes. Pediatr Res. 2001;50 :124 –132
Pantel J, O'Leary DS, Cretsinger K, et al. A new method for the in vivo volumetric measurement of the human hippocampus with high neuroanatomical accuracy. Hippocampus. 2000;10 :752 –758
Duvernoy HM, Bourgouin P. The Human Hippocampus: Functional Anatomy, Vascularization and Serial Sections With MRI. 2nd ed. New York, NY: Springer; 1998
Kaufman AS. Intelligent Testing With the WISC-R. New York, NY: Wiley; 1979
Nosarti C, Al-Asady MH, Frangou S, Stewart AL, Rifkin L, Murray RM. Adolescents who were born very preterm have decreased brain volumes. Brain. 2002;125 :1616 –1623
Peterson BS, Anderson AW, Ehrenkranz R, et al. Regional brain volumes and their later neurodevelopmental correlates in term and preterm infants. Pediatrics. 2003;111 :939 –948
Inder TE, Huppi PS, Warfield S, et al. Periventricular white matter injury in the premature infant is followed by reduced cerebral cortical gray matter volume at term. Ann Neurol. 1999;46 :755 –760
Borradori Tolsa C, Zimine S, Warfield SK, et al. Early alteration of structural and functional brain development in premature infants born with intrauterine growth restriction. Pediatr Res. 2004;56; 132 –138
Isaacs EB, Lucas A, Chong WK, et al. Hippocampal volume and everyday memory in children of very low birth weight. Pediatr Res. 2000;47 :713 –720
Abernethy LJ, Palaniappan M, Cooke RW. Quantitative magnetic resonance imaging of the brain in survivors of very low birth weight. Arch Dis Child. 2002;87 :279 –283
Verloove-Vanhorick SP, Veen S, Ens-Dokkum MH, Schreuder AM, Brand R, Ruys JH. Sex difference in disability and handicap at five years of age in children born at very short gestation. Pediatrics. 1994;93 :576 –579
Hack M, Flannery DJ, Schluchter M, Cartar L, Borawski E, Klein N. Outcomes in young adulthood for very-low-birth-weight infants. N Engl J Med. 2002;346 :149 –157
Johnson EO, Breslau N. Increased risk of learning disabilities in low birth weight boys at age 11 years. Biol Psychiatry. 2000;47 :490 –500
Isaacs EB, Vargha-Khadem F, Watkins KE, Lucas A, Mishkin M, Gadian DG. Developmental amnesia and its relationship to degree of hippocampal atrophy. Proc Natl Acad Sci USA. 2003;100 :13060 –13063
Ment LR, Vohr B, Allan W, et al. Change in cognitive function over time in very low-birth-weight infants. JAMA. 2003;289 :705 –711
Bremner JD, Randall P, Scott TM, et al. MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry. 1995;152 :973 –981
McEwen BS. Early life influences on life-long patterns of behavior and health. Ment Retard Dev Disabil Res Rev. 2003;9 :149 –154
Sperling M. Pediatric Endocrinology. 2nd ed. Philadelphia, PA: Saunders; 2002
Karssen AM, Meijer OC, van der Sandt IC, et al. Multidrug resistance P-glycoprotein hampers the access of cortisol but not of corticosterone to mouse and human brain. Endocrinology. 2001;142 :2686 –2694
De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M. Brain corticosteroid receptor balance in health and disease. Endocr Rev. 1998;19 :269 –301
Reul JM, Gesing A, Droste S, et al. The brain mineralocorticoid receptor: greedy for ligand, mysterious in function. Eur J Pharmacol. 2000;405 :235 –249
Almeida OF, Conde GL, Crochemore C, et al. Subtle shifts in the ratio between pro- and antiapoptotic molecules after activation of corticosteroid receptors decide neuronal fate. FASEB J. 2000;14 :779 –790
Hassan AH, von Rosenstiel P, Patchev VK, Holsboer F, Almeida OF. Exacerbation of apoptosis in the dentate gyrus of the aged rat by dexamethasone and the protective role of corticosterone. Exp Neurol. 1996;140 :43 –52
LeFlore JL, Salhab WA, Broyles RS, Engle WD. Association of antenatal and postnatal dexamethasone exposure with outcomes in extremely low birth weight neonates. Pediatrics. 2002;110 :275 –279(Gregory A. Lodygensky, MD)