Hypertensive Disorders of Pregnancy and Risk of Early Brain Abnormalities on MRI at Term among Infants Born at ≤32 Weeks' Gestational Age.

OBJECTIVE: To evaluate the proximal effects of hypertensive disorders of pregnancy (HDP) on a validated measure of brain abnormalities in infants born at ≤32 weeks' gestational age (GA) using magnetic resonance imaging (MRI) at term-equivalent age. STUDY DESIGN: In a multisite prospective cohort study, 395 infants born at ≤32 weeks' GA, underwent 3T MRI scan between 39 through 44 weeks' postmenstrual age. A single neuroradiologist, blinded to clinical history, evaluated the standardized Kidokoro global brain abnormality score as the primary outcome. We classified infants as HDP-exposed by maternal diagnosis of chronic hypertension, gestational hypertension, preeclampsia, or eclampsia. Linear regression analysis identified the independent effects of HDP on infant brain abnormalities, adjusting for histologic chorioamnionitis, maternal smoking, antenatal steroids, magnesium sulfate, and infant sex. Mediation analyses quantified the indirect effect of HDP mediated via impaired intrauterine growth and prematurity and remaining direct effects on brain abnormalities. RESULTS: 170/395 infants (43%) were HDP-exposed. Adjusted multivariable analyses revealed HDP-exposed infants had 27% (95% CI 5-53%) higher brain abnormality scores than those without HDP exposure (p=0.02), primarily driven by increased white matter injury/abnormality scores (p=0.01). Mediation analyses showed HDP-induced impaired intrauterine growth significantly (p=0.02) contributed to brain abnormality scores (22% of the total effect). CONCLUSIONS: Maternal hypertension independently increased the risk for early brain injury and/or maturational delays in infants born at ≤32 weeks' GA with an indirect effect of 22% resulting from impaired intrauterine growth. Enhanced prevention/treatment of maternal hypertension may mitigate the risk of infant brain abnormalities and potential neurodevelopmental impairments.

Prenatal tobacco smoke exposure and risk for cognitive delays in infants born very premature.

Prenatal tobacco smoke exposure (TSE) and prematurity are independent risk factors for abnormal neurodevelopment. The objectives were to compare differences in Bayley-III cognitive, language, and motor scores at 2 years corrected age (CA) in 395 infants born very preterm (≤ 32 weeks gestation) with and without prenatal TSE. We performed multivariable linear regression analyses to examine associations between prenatal TSE and neurodevelopmental outcomes and a mediation analysis to estimate direct effects of prenatal TSE on outcomes and indirect effects through preterm birth. In total, 50 (12.6%) infants had prenatal TSE. Infants with prenatal TSE had lower mean [95% CI] Cognitive score (82.8 [78.6, 87.1]) vs. nonexposed infants (91.7 [90.1, 93.4]). In children with and without prenatal TSE, there were significant differences in mean [95% CI] Language scores (81.7 [76.0, 87.4] vs. 92.4 [90.2, 94.6], respectively) and mean [95% CI] Motor scores (86.5 [82.2, 90.7] vs. 93.4 [91.8, 95.0], respectively); scores remained significant after controlling for confounders. Preterm birth indirectly mediated 9.0% of the total effect of prenatal TSE on Cognitive score (P = NS). However, 91% of the remaining total effect was significant and attributable to TSE's direct harmful effects on cognitive development (ß = - 5.17 [95% CI - 9.97, - 0.38]). The significant association is largely due to TSE's direct effect on cognitive development and not primarily due to TSE's indirect effect on preterm birth.

Early surgery in very preterm infants is associated with brain abnormalities on term MRI: a propensity score analysis.

OBJECTIVE: To investigate the association between exposure to surgery under general anesthesia and brain abnormalities and neurodevelopmental outcomes in very preterm infants. STUDY DESIGN: This prospective observational study includes 392 infants born at or below 32 weeks' gestational age. Participants completed brain MRI at term-equivalent age and Bayley-III assessment at 2 years corrected age. We evaluated the independent effects of surgery on brain MRI abnormalities and neurodevelopmental outcomes after propensity score matching. RESULTS: All infants completed brain MRI, and 341 (87%) completed neurodevelopmental testing. Forty-five received surgery. Surgery was associated with worse MRI abnormalities (p < 0.0001) but with none of the developmental outcomes after propensity score matching. The global brain abnormality score was associated with the Bayley Cognitive (p = 0.005) and Motor (p = 0.028) composite scores. CONCLUSIONS: Very preterm infants exposed to surgery under general anesthesia were at higher risk of brain abnormalities on MRI at term.

Prenatal tobacco smoke exposure and risk of brain abnormalities on magnetic resonance imaging at term in infants born very preterm.

BACKGROUND: Prenatal tobacco smoke exposure and preterm birth are associated with abnormal brain and neurodevelopmental outcomes in infants. Studies that can disentangle indirect mediating effects from direct effects of prenatal tobacco smoke exposure on sensitive early brain magnetic resonance imaging biomarkers in very preterm infants are needed. OBJECTIVE: This study aimed to determine whether prenatal tobacco smoke exposure in preterm infants posed any direct effects on magnetic resonance imaging-determined global brain abnormality score and secondary measures of brain abnormalities after removing any indirect mediating effects of preterm birth on neurostructural outcomes. STUDY DESIGN: We examined brain magnetic resonance imaging findings collected at 39 to 44 weeks postmenstrual age from a prospective cohort of 395 infants born very preterm (gestational age of ≤32 weeks). The primary outcome was global brain abnormality score, and the secondary outcomes were global efficiency of structural connectome, diffuse white matter abnormality volume, total brain tissue volume, total gray and white matter volumes, and cerebellar volume. Maternal reports of smoking during pregnancy were obtained. We performed multivariable linear regression analyses to examine the association between prenatal tobacco smoke exposure and our magnetic resonance imaging outcomes, controlling for prospectively collected confounders. Moreover, we performed a mediation analysis to estimate the direct effects of prenatal tobacco smoke exposure on brain abnormalities and any indirect effects through preterm birth. RESULTS: Overall, 12.6% of infants had prenatal tobacco smoke exposure. Infants with prenatal tobacco smoke exposure had a higher median global brain abnormality score than nonexposed infants (7 [interquartile range, 0-41] vs 5 [interquartile range, 0-34]; P≤.001); the findings remained significant (P<.001) after controlling for antenatal confounders. Global efficiency (P<.001), diffuse white matter volume (P=.037), and total brain tissue volume (P=.047) were significantly different between TSE groups in multivariable analyses. On mediation analysis, preterm birth mediated between 0% and 29% of the indirect effect of prenatal tobacco smoke exposure on several measures of brain abnormality outcomes. Thus, prenatal tobacco smoke exposure had a direct adverse effect between 71% and 100% on brain injury or abnormal development. CONCLUSION: Our study has identified multiple adverse effects of prenatal tobacco smoke exposure on sensitive and objective measures of neonatal brain injury and abnormal development; most cases seemed to be a direct effect of prenatal tobacco smoke exposure on fetal brain development. The results underscored the significant adverse neurostructural effects of prenatal tobacco smoke exposure to tobacco smoke pollutants.

Association between brain structural network efficiency at term-equivalent age and early development of cerebral palsy in very preterm infants.

Very preterm infants (born at less than 32 weeks gestational age) are at high risk for serious motor impairments, including cerebral palsy (CP). The brain network changes that antecede the early development of CP in infants are not well characterized, and a better understanding may suggest new strategies for risk-stratification at term, which could lead to earlier access to therapies. Graph theoretical methods applied to diffusion MRI-derived brain connectomes may help quantify the organization and information transfer capacity of the preterm brain with greater nuance than overt structural or regional microstructural changes. Our aim was to shed light on the pathophysiology of early CP development, before the occurrence of early intervention therapies and other environmental confounders, to help identify the best early biomarkers of CP risk in VPT infants. In a cohort of 395 very preterm infants, we extracted cortical morphometrics and brain volumes from structural MRI and also applied graph theoretical methods to diffusion MRI connectomes, both acquired at term-equivalent age. Metrics from graph network analysis, especially global efficiency, strength values of the major sensorimotor tracts, and local efficiency of the motor nodes and novel non-motor regions were strongly inversely related to early CP diagnosis. These measures remained significantly associated with CP after correction for common risk factors of motor development, suggesting that metrics of brain network efficiency at term may be sensitive biomarkers for early CP detection. We demonstrate for the first time that in VPT infants, early CP diagnosis is anteceded by decreased brain network segregation in numerous nodes, including motor regions commonly-associated with CP and also novel regions that may partially explain the high rate of cognitive impairments concomitant with CP diagnosis. These advanced MRI biomarkers may help identify the highest risk infants by term-equivalent age, facilitating earlier interventions that are informed by early pathophysiological changes.

Perinatal Risk and Protective Factors in the Development of Diffuse White Matter Abnormality on Term-Equivalent Age Magnetic Resonance Imaging in Infants Born Very Preterm.

OBJECTIVE: To identify perinatal clinical diseases and treatments that are associated with the development of objectively diagnosed diffuse white matter abnormality (DWMA) on structural magnetic resonance imaging (MRI) at term-equivalent age in infants born very preterm. STUDY DESIGN: A prospective cohort of 392 infants born very preterm (≤32 weeks of gestational age) was enrolled from 5 level III/IV neonatal intensive care units between September 2016 and November 2019. MRIs of the brain were collected at 39 to 45 weeks of postmenstrual age to evaluate DWMA volume. A predefined list of pertinent maternal characteristics, pregnancy/delivery data, and neonatal intensive care unit data were collected for enrolled patients to identify antecedents of objectively diagnosed DWMA. RESULTS: Of the 392 infants in the cohort, 377 (96%) had high-quality MRI data. Their mean (SD) gestational age was 29.3 (2.5) weeks. In multivariable linear regression analyses, pneumothorax (P = .027), severe bronchopulmonary dysplasia (BPD) (P = .009), severe retinopathy of prematurity (P < .001), and male sex (P = .041) were associated with increasing volume of DWMA. The following factors were associated with decreased risk of DWMA: postnatal dexamethasone therapy for severe BPD (P = .004), duration of caffeine therapy for severe BPD (P = .009), and exclusive maternal milk diet at neonatal intensive care unit discharge (P = .049). CONCLUSIONS: Severe retinopathy of prematurity and BPD exhibited the strongest adverse association with development of DWMA. We also identified treatments and nutritional factors that appear protective against the development of DWMA that also have implications for the clinical care of infants born very preterm.

Prenatal opioid exposure is associated with smaller brain volumes in multiple regions.

BACKGROUND: The impact of prenatal opioid exposure on brain development remains poorly understood. METHODS: We conducted a prospective study of term-born infants with and without prenatal opioid exposure. Structural brain MRI was performed between 40 and 48 weeks postmenstrual age. T2-weighted images were processed using the Developing Human Connectome Project structural pipeline. We compared 63 relative regional brain volumes between groups. RESULTS: Twenty-nine infants with prenatal opioid exposure and 42 unexposed controls were included. The groups had similar demographics, except exposed infants had lower birth weights, more maternal smoking and maternal Hepatitis C, fewer mothers with a college degree, and were more likely non-Hispanic White. After controlling for sex, postmenstrual age at scan, birth weight, and maternal education, exposed infants had significantly smaller relative volumes of the deep gray matter, bilateral thalamic ventrolateral nuclei, bilateral insular white matter, bilateral subthalamic nuclei, brainstem, and cerebrospinal fluid. Exposed infants had larger relative volumes of the right cingulate gyrus white matter and left occipital lobe white matter. CONCLUSIONS: Infants with prenatal opioid exposure had smaller brain volumes in multiple regions compared to controls, with two regions larger in the opioid-exposed group. Further research should focus on the relative contributions of maternal opioids and other exposures. IMPACT: Prenatal opioid exposure is associated with developmental and behavioral consequences, but the direct effects of opioids on the developing human brain are poorly understood. Prior small studies using MRI have shown smaller regional brain volumes in opioid-exposed infants and children. After controlling for covariates, infants with prenatal opioid exposure scanned at 40-48 weeks postmenstrual age had smaller brain volumes in multiple regions compared to controls, with two regions larger in the opioid-exposed group. This adds to the literature showing potential impact of prenatal opioid exposure on the developing brain.

Antecedents of Objectively Diagnosed Diffuse White Matter Abnormality in Very Preterm Infants.

BACKGROUND: Diffuse white matter abnormality (diffuse excessive high signal intensity) is the most common finding on structural brain magnetic resonance imaging (MRI) at term-equivalent age in very preterm infants. Yet, there remains a large gap in our understanding of the etiology of diffuse white matter abnormality. Our objective was to evaluate perinatal and neonatal inflammation-associated antecedents of diffuse white matter abnormality on MRI. METHODS: We prospectively enrolled 110 very preterm infants born at ≤31 weeks gestational age and collected data on multiple perinatal/neonatal exposures, especially inflammation initiating-illnesses. We performed structural MRI at term-equivalent age and quantified the volume of diffuse white matter abnormality objectively. Multivariable regression was used to identify clinical antecedents of diffuse white matter abnormality. RESULTS: The mean (S.D.) birth gestational age of the final study sample of 98 very preterm infants was 28.3 (2.5) weeks. Multiple inflammation initiating-illnesses were associated with diffuse white matter abnormality in univariate analyses. In multivariable linear regression analyses controlling for gestational age, severe retinopathy of prematurity (P < 0.001) and bronchopulmonary dysplasia (P = 0.006) were independent risk factors, whereas maternal treatment with 17-hydroxyprogesterone (P < 0.001) was protective of later development of objectively quantified diffuse white matter abnormality. CONCLUSIONS: We identified several perinatal and neonatal antecedent clinical factors associated with diffuse white matter abnormality. Although we found some support for inflammation as a common underlying mechanism, larger studies are needed to validate inflammation as a potential common pathway to the development of diffuse white matter abnormality in very preterm infants.

Neonatal Functional and Structural Connectivity Are Associated with Cerebral Palsy at Two Years of Age.

OBJECTIVE: The accuracy of structural magnetic resonance imaging (MRI) to predict later cerebral palsy (CP) in newborns with perinatal brain injury is variable. Diffusion tensor imaging (DTI) and task-based functional MRI (fMRI) show promise as predictive tools. We hypothesized that infants who later developed CP would have reduced structural and functional connectivity as compared with those without CP. STUDY DESIGN: We performed DTI and fMRI using a passive motor task at 40 to 48 weeks' postmenstrual age in 12 infants with perinatal brain injury. CP was diagnosed at age 2 using a standardized examination. RESULTS: Five infants had CP at 2 years of age, and seven did not have CP. Tract-based spatial statistics showed a widespread reduction of fractional anisotropy (FA) in almost all white matter tracts in the CP group. Using the median FA value in the corticospinal tracts as a cutoff, FA was 100% sensitive and 86% specific to predict CP compared with a sensitivity of 60 to 80% and a specificity of 71% for structural MRI. During fMRI, the CP group had reduced functional connectivity from the right supplemental motor area as compared with the non-CP group. CONCLUSION: DTI and fMRI obtained soon after birth are potential biomarkers to predict CP in newborns with perinatal brain injury.

Retinopathy of Prematurity and Bronchopulmonary Dysplasia are Independent Antecedents of Cortical Maturational Abnormalities in Very Preterm Infants.

Very preterm (VPT) infants are at high-risk for neurodevelopmental impairments, however there are few validated biomarkers at term-equivalent age that accurately measure abnormal brain development and predict future impairments. Our objectives were to quantify and contrast cortical features between full-term and VPT infants at term and to associate two key antecedent risk factors, bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP), with cortical maturational changes in VPT infants. We prospectively enrolled a population-based cohort of 110 VPT infants (gestational age ≤31 weeks) and 51 healthy full-term infants (gestational age 38-42 weeks). Structural brain MRI was performed at term. 94 VPT infants and 46 full-term infants with high-quality T2-weighted MRI were analyzed. As compared to full-term infants, VPT infants exhibited significant global cortical maturational abnormalities, including reduced surface area (-5.9%) and gyrification (-6.7%) and increased curvature (5.9%). In multivariable regression controlled for important covariates, BPD was significantly negatively correlated with lobar and global cortical surface area and ROP was significantly negatively correlated with lobar and global sulcal depth in VPT infants. Our cohort of VPT infants exhibited widespread cortical maturation abnormalities by term-equivalent age that were in part anteceded by two of the most potent neonatal diseases, BPD and ROP.

Postnatal Microstructural Developmental Trajectory of Corpus Callosum Subregions and Relationship to Clinical Factors in Very Preterm Infants.

Our objectives were to define the microstructural developmental trajectory of six corpus callosum subregions and identify perinatal clinical factors that influence early development of these subregions in very preterm infants. We performed a longitudinal cohort study of very preterm infants (32 weeks gestational age or younger) (N = 36) who underwent structural MRI and diffusion tensor imaging serially at four time points - before 32, 32, 38, and 52 weeks postmenstrual age. We divided the corpus callosum into six subregions, performed probabilistic tractography, and used linear mixed effects models to evaluate the influence of antecedent clinical factors on its microstructural growth trajectory. The genu and splenium demonstrated the most rapid developmental maturation, exhibited by a steep increase in fractional anisotropy. We identified several factors that favored greater corpus callosum microstructural development, including advancing postmenstrual age, higher birth weight, and college level or higher maternal education. Bronchopulmonary dysplasia, low 5-minute Apgar scores, caffeine therapy/apnea of prematurity and male sex were associated with reduced corpus callosum microstructural integrity/development over the first six months after very preterm birth. We identified a unique postnatal microstructural growth trajectory and associated clinical factor profile for each of the six corpus callosum subregions that is consistent with the heterogeneous functional role of these white matter subregions.

Neuropathology Associated With Diffuse Excessive High Signal Intensity Abnormalities on Magnetic Resonance Imaging in Very Preterm Infants.

BACKGROUND: Diffuse excessive high signal intensity abnormality is the most common finding on term-equivalent age magnetic resonance imaging in extremely preterm infants. Yet its clinical significance remains a matter of debate, in part because of a lack of prior imaging-pathology correlational studies. PATIENT PRESENTATIONS: We present two 24-week-gestation infants with complicated clinical courses who died at 33 and 46 weeks postmenstrual age with magnetic resonance imaging evidence of diffuse excessive high signal intensity. Two patients with periventricular leukomalacia and two without injury were examined for comparison. Immunohistochemistry characterized the presence of reactive astrocytes, microglia, myelin, and axons. Infants with periventricular leukomalacia demonstrated the typical microscopic necrosis with spheroids, gliosis/microgliosis with reduction in stainable myelin and axons. Infants with diffuse excessive high signal intensity showed vacuolated regions with increased reactive astrocytes and microglia and fewer oligodendroglial cell bodies/processes and dramatic reduction in axon number. CONCLUSION: These two individuals with diffuse excessive high signal intensity exhibited pathologic characteristics that were overlapping but distinct from those of periventricular leukomalacia.

Early Conventional MRI for Prediction of Neurodevelopmental Impairment in Extremely-Low-Birth-Weight Infants.

BACKGROUND: Extremely-low-birth-weight (ELBW; ≤1,000 g) infants are at high risk for neurodevelopmental impairments. Conventional brain MRI at term-equivalent age is increasingly used for prediction of outcomes. However, optimal prediction models remain to be determined, especially for cognitive outcomes. OBJECTIVE: The aim was to evaluate the accuracy of a data-driven MRI scoring system to predict neurodevelopmental impairments. METHODS: 122 ELBW infants had a brain MRI performed at term-equivalent age. Conventional MRI findings were scored with a standardized algorithm and tested using a multivariable regression model to predict neurodevelopmental impairment, defined as one or more of the following at 18-24 months' corrected age: cerebral palsy, bilateral blindness, bilateral deafness requiring amplification, and/or cognitive/language delay. Results were compared with a commonly cited scoring system. RESULTS: In multivariable analyses, only moderate-to-severe gyral maturational delay was a significant predictor of overall neurodevelopmental impairment (OR: 12.6, 95% CI: 2.6, 62.0; p < 0.001). Moderate-to-severe gyral maturational delay also predicted cognitive delay, cognitive delay/death, and neurodevelopmental impairment/death. Diffuse cystic abnormality was a significant predictor of cerebral palsy (OR: 33.6, 95% CI: 4.9, 229.7; p < 0.001). These predictors exhibited high specificity (range: 94-99%) but low sensitivity (30-67%) for the above outcomes. White or gray matter scores, determined using a commonly cited scoring system, did not show significant association with neurodevelopmental impairment. CONCLUSIONS: In our cohort, conventional MRI at term-equivalent age exhibited high specificity in predicting neurodevelopmental outcomes. However, sensitivity was suboptimal, suggesting additional clinical factors and biomarkers are needed to enable accurate prognostication.

Neurodevelopmental Outcomes of Extremely Preterm Infants Randomized to Stress Dose Hydrocortisone.

OBJECTIVE: To compare the effects of stress dose hydrocortisone therapy with placebo on survival without neurodevelopmental impairments in high-risk preterm infants. STUDY DESIGN: We recruited 64 extremely low birth weight (birth weight ≤1000 g) infants between the ages of 10 and 21 postnatal days who were ventilator-dependent and at high-risk for bronchopulmonary dysplasia. Infants were randomized to a tapering 7-day course of stress dose hydrocortisone or saline placebo. The primary outcome at follow-up was a composite of death, cognitive or language delay, cerebral palsy, severe hearing loss, or bilateral blindness at a corrected age of 18-22 months. Secondary outcomes included continued use of respiratory therapies and somatic growth. RESULTS: Fifty-seven infants had adequate data for the primary outcome. Of the 28 infants randomized to hydrocortisone, 19 (68%) died or survived with impairment compared with 22 of the 29 infants (76%) assigned to placebo (relative risk: 0.83; 95% CI, 0.61 to 1.14). The rates of death for those in the hydrocortisone and placebo groups were 31% and 41%, respectively (P = 0.42). Randomization to hydrocortisone also did not significantly affect the frequency of supplemental oxygen use, positive airway pressure support, or need for respiratory medications. CONCLUSIONS: In high-risk extremely low birth weight infants, stress dose hydrocortisone therapy after 10 days of age had no statistically significant effect on the incidence of death or neurodevelopmental impairment at 18-22 months. These results may inform the design and conduct of future clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT00167544.

Perinatal factors and regional brain volume abnormalities at term in a cohort of extremely low birth weight infants.

Our objective was to investigate diverse clinical antecedents of total and regional brain volume abnormalities and white matter hyperintensity volume on term MRI in extremely low birth weight (birth weight ≤1000 g) survivors. A consecutive cohort of extremely low birth weight infants who survived to 38 weeks postmenstrual age (n = 122) and a control group of 16 healthy term newborns underwent brain MRI at term-equivalent age. Brain volumes were measured using semi-automated and manual segmentation methods. Using multivariable linear regression, clinical antecedents were correlated with volumes of total brain tissue, white matter hyperintensities, and regional tissues/structures, adjusted for age at MRI, total cranial volume, and total tissue volume. Regional brain volumes were markedly reduced in extremely low birth weight infants as compared to term newborns (relative difference range: -11.0%, -35.9%). Significant adverse clinical associations for total brain tissue volume included: small for gestational age, seizures, caffeine therapy/apnea of prematurity, duration of parenteral nutrition, pulmonary hemorrhage, and white matter injury (p<0.01 for each; relative difference range: -1.4% to -15.0%). Surgery for retinopathy of prematurity and surgery for necrotizing enterocolitis or spontaneous intestinal perforation were significantly associated with increasing volume of white matter hyperintensities. Regional brain volumes are sensitive to multiple perinatal factors and neonatal morbidities or interventions. Brain growth measurements in extremely low birth weight infants can advance our understanding of perinatal brain injury and development.

Pilot randomized trial of hydrocortisone in ventilator-dependent extremely preterm infants: effects on regional brain volumes.

OBJECTIVE: To test the hypothesis that high-risk ventilator-dependent extremely low birth weight (birth weight ≤1000 g) infants treated with 7 days of hydrocortisone will have larger total brain tissue volumes than placebo treated infants. STUDY DESIGN: A predetermined sample size of 64 extremely low birth weight infants, between 10-21 days old and ventilator-dependent with a respiratory index score ≥2, were randomized to systemic hydrocortisone (17 mg/kg cumulative dose) or saline placebo. Primary outcome was total brain tissue volume. Volumetric magnetic resonance imaging was performed at 38 weeks postmenstrual age; brain tissue regions were segmented and quantified automatically with a high degree of accuracy and 9 structures were segmented manually. All analyses of regional brain volumes were adjusted by postmenstrual age at magnetic resonance imaging scan. RESULTS: The study groups were similar at baseline and 8 infants died in each arm. Unadjusted total brain tissue volume (mean ± SD) in the hydrocortisone (N = 23) and placebo treated infants (N = 21) was 272 ± 40.3 cm(3) and 277.8 ± 59.1 cm(3), respectively (adjusted mean difference: 6.35 cm(3) (95% CI: (-20.8, 32.5); P = .64). Three of the 31 hydrocortisone treated infants and 5 of the 33 placebo treated infants survived without severe bronchopulmonary dysplasia (relative risk 0.62, 95% CI: 0.13, 2.66; P = .49). No significant differences were noted in prespecified secondary outcomes of regional structural volumes or days on respiratory support. No adverse effects of hydrocortisone were observed. CONCLUSIONS: Low dose hydrocortisone in high-risk ventilator-dependent infants after a week of age had no discernible effect on regional brain volumes or pulmonary outcomes prior to neonatal intensive care unit discharge.