This study using serial neuroimaging in preterm newborns shows strong associations between the use of postnatal glucocorticoids – either hydrocortisone or dexamethasone – and impaired cerebellar growth. Conversely, associations were not found between antenatal betamethasone use and cerebellar growth. Surprisingly, there were no associations found between the use of glucocorticoids and supratentorial brain volume. Glucocorticoid exposure is common in preterm newborns, with 85% of all patients exposed antenatally and 21% exposed postnatally in our cohort.
Hydrocortisone and dexamethasone result in decreased proliferation and increased apoptosis of the granule cells of the external granular layer of murine models during the developmental period corresponding with the preterm period in humans.(7
) All glucocorticoids tested in animal models, including hydrocortisone, dexamethasone, and corticosterone, result in similar findings of granule cell death in rats, mice, and chicken.(8
) In fact, the neonatal cerebellum has the highest levels of glucocorticoid receptors in the brain,(19
) localized in the external granular layer.(10
) These results suggest that all of these glucocorticoids impact development of the cerebellum.
Human studies, however, suggest varying effects of different glucocorticoids upon the preterm brain. In a study comparing 11 newborns exposed to postnatal dexamethasone to 30 unexposed newborns, those exposed had smaller overall brain volumes at term-equivalent age, including cerebellar volume.(11
) In a randomized controlled trial of early postnatal dexamethasone therapy, those exposed to dexamethasone were found to have decreased height and head circumference, with worse outcomes on motor and cognitive testing by 8 years of age.(12
) As a result, the American Academy of Pediatrics issued specific recommendations in 2010 against the use of high-dose dexamethasone.(13
As opposed to dexamethasone, conflicting results have been reported after hydrocortisone therapy. Benders et al.
compared 19 infants treated with hydrocortisone for chronic lung disease to 19 controls matched for gestational age at birth, showing no difference between whole brain volumes at term-equivalent age, with mean decrease in cerebellar volume of 1cm3
(95%CI −4 to 2cm3
) Follow-up of 60 preterm newborns with chronic lung disease, including 25 treated with hydrocortisone, showed no differences in brain development and neurological outcome at 8 years, but the cerebellum was not assessed in that analysis.(20
) Follow-up of 226 preterm infants to 8 years showed no difference in motor or cognitive function after adjustment for gestational age, body weight, sex, mechanical ventilation, and small for gestational age.(16
) However, when considering duration of therapy in a different cohort by 2 years, longer treatment with hydrocortisone (more than 7 days) was associated with worse developmental outcome.(21
Proposed differences for the lesser effects of hydrocortisone include its greater mineralocorticoid-mediated, as opposed to glucocorticoid-mediated, activity and shorter half-life in the brain due to specific inactivation by 11-β-hydroxysteroid dehydrogenase type 2, which has high expression in the fetal brain.(15
) However, although 11-β-hydroxysteroid dehydrogenase type 2 is capable of degrading hydrocortisone but not dexamethasone, both glucocorticoids result in injury of the external granular layer in wild-type animals. This is suggested by rodent models that show similar effects of corticosterone (a known substrate of 11-β-hydroxysteroid dehydrogenase type 2) and dexamethasone, both on granule cell apoptosis with acute glucocorticoid exposure and on inhibition of cell proliferation with chronic exposure.(22
Our study found similar results in premature newborns, showing decreased cerebellar volumes by term-equivalent age associated with either postnatal hydrocortisone or dexamethasone. In contrast to previous studies, no dose-dependent effects could be found in the clinically relevant range of exposures seen in this cohort. One reason for the lack of dose-dependent effects may be the narrow clinical range of exposures in this cohort, and lower dosage range for use of dexamethasone. Another possible reason is the small number of subjects exposed to dexamethasone, limiting the power of the study to detect a clinical effect.
Of particular interest, the mean decrease in cerebellar volume detected in this current study is comparable to that observed by Benders et al.
). In addition, with this larger sample size, statistical significance is now evident. In agreement with Benders et al.
, no changes were seen in supratentorial brain structures. Considering the high frequency of use of antenatal betamethasone in mothers in preterm labor, it is reassuring that cerebellar growth reduction is not associated with this therapy. Potential reasons for the lack of effect of antenatal betamethasone may include low dose and short exposure to the drug, earlier exposure in the antenatal period, or protective effects of placental 11-β-hydroxysteroid dehydrogenase type 2 which decreases infant exposure to the drug.(23
Many clinical factors were associated with cerebellar volume, the most important being postnatal glucocorticoid exposure, IVH, cardiorespiratory compromise as indicated by prolonged intubation, hypotension requiring medical intervention, and patent ductus arteriosus. Indeed, the continued strong association between cerebellar volume and postnatal glucocorticoid exposure after multivariate analysis supports the strength of this finding. Associations between IVH and cerebellar volume have been reported previously.(6
) The finding that several postnatal factors are associated with decreased cerebellar volume suggests a possibility that measures to correct these potentially modifiable risk factors may improve the late growth of the cerebellum. Of particular note, frank cerebellar hemorrhage was associated with increased cerebellar volumes in the perinatal period (areas of hemorrhage were not included in the cerebellar volume determinations). Since it is known that cerebellar hemorrhages result in atrophy in the long-term, these increased volumes may suggest effects of local parenchymal edema at the time of the MRIs.
The incorporation of two independent prospective cohorts and a large sample size for volumetric analysis provide strength in this study on the association between glucocorticoid exposure and cerebellar growth. However, in this observational study, no specific dosing regimen for corticosteroids was defined. Although causality cannot be concluded based on association studies, animal models are convincing for a causal pathway between glucocorticoid exposure and external granular cell apoptosis. In combination with the animal models in multiple species, this large prospective observational study suggests similar effects of glucocorticoids in human preterm newborns.
This study reports on outcomes of cerebellar volumes in the neonatal period, showing decreased growth velocity over the early postnatal period translating to a 10% decreased volume by term-equivalent age. Recent research has shown that altered brain development after preterm birth continues through childhood.(24
) As previously reported, smaller cerebellar volumes seen by 14 years of age are associated with significantly worse cognitive testing using the Wechsler Intelligence Scale for Children-Revised, the Kaufman Assessment Battery for Children, and the Schonnel reading age.(3
) Since other studies have shown no associated motor and cognitive deficits by 2 years associated with glucocorticoid exposure,(16
) follow-up to school age may be required to detect the long-term motor and cognitive consequences of impaired cerebellar development as observed by Allin et al.
at 14 years.(3
) If long-term sequelae are found by school age, decreased cerebellar volumes could be useful as an early surrogate biomarker for adverse long-term outcome after preterm birth. The use of MRI at term-equivalent age as a biomarker for long-term outcome would provide a convenient measure for rapid identification of important modifiable clinical factors such as glucocorticoid exposure, as well as a potentially rapid assessment of the efficacy of clinical management improvements on future neurological outcome.
The traditional focus of brain injury in preterm newborns has been on supratentorial injury, including IVH and WMI. This study highlights that specific modifiable clinical factors with major impacts on long-term neurological outcome, such as glucocorticoid exposure, may have specific detrimental effects on the cerebellum equivalent to, or greater than, the more traditionally studied supratentorial brain structures. Clinicians caring for preterm newborns may need to weigh the benefits of using glucocorticoids for hypotension and prolonged intubation with these findings of associated impaired cerebellar growth. With improvements in neonatal care and focus on supratentorial brain injury in the past decade, we have failed to improve neurodevelopmental outcomes.(1
) By turning our focus to modifying factors that impair cerebellar development, we may reach our critical target of improving long term outcomes after preterm birth.