Association between Term Equivalent Brain Magnetic Resonance Imaging and 2-Year Outcomes in Extremely Preterm Infants: A Report from the Preterm Erythropoietin Neuroprotection Trial Cohort

Abstract

Objectives: To compare the term equivalent brain magnetic resonance imaging (MRI) findings between erythropoietin (Epo) treated and placebo control groups in infants 24^0/7-27^6/7 weeks of gestational age and to assess the associations between MRI findings and neurodevelopmental outcomes at 2 years corrected age.

Study design: The association between brain abnormality scores and Bayley Scales of Infant Development, Third Edition at 2 years corrected age was explored in a subset of infants enrolled in the Preterm Erythropoietin Neuroprotection Trial. Potential risk factors for neurodevelopmental outcomes such as treatment assignment, recruitment site, gestational age, inpatient complications, and treatments were examined using generalized estimating equation models.

Results: One hundred ten infants were assigned to Epo and 110 to placebo groups. 27% of MRI scans were rated as normal, and 60%, 10%, and 2% were rated as having mild, moderate, or severe abnormality. Brain abnormality scores did not significantly differ between the treatment groups. Factors that increased the risk of higher brain injury scores included intubation; bronchopulmonary dysplasia; retinopathy of prematurity; opioid, benzodiazepine, or antibiotic treatment >7 days; and periventricular leukomalacia or severe intraventricular hemorrhage diagnosed on cranial ultrasound. Increased global brain abnormality and white matter injury scores at term equivalent were associated with reductions in cognitive, motor, and language abilities at 2 years of corrected age.

Conclusions: Evidence of brain injury on brain MRIs obtained at term equivalent correlated with adverse neurodevelopmental outcomes as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition at 2 years corrected age. Early Epo treatment had no effect on the MRI brain injury scores compared with the placebo group.

Keywords: MRI; neurodevelopmental outcomes; preterm.

Figure 1.

CONSORT diagram of PENUT MRI cohort.

Figure 2.

MRI injury scores by treatment group and gestational age at birth. Gray bars and whisker plots – Epo-treated subjects. Black bars and whisker plots – Placebo-treated subjects. No differences in MRI brain injury scores were noted between treatment groups at any gestational age. A, Global brain abnormality scores between treatment groups. B, Global brain abnormality scores by treatment group and gestational age. C, White matter brain abnormality scores by treatment group. D, Cortical gray matter abnormality scores by treatment group. E, Deep gray matter abnormality scores bt treatment group. F, Cerebellum abnormality scores by treatment group.

Figure 3.

Brain MRI injury severity on 36-week MRI by presence of inpatient complications, use of therapeutics, and treatments. Poisson GEE models were utilized to compare MRI global abnormality scores by inpatient complication, therapeutic, or treatment status. Yes indicates that inpatient complication or treatment was present. No indicates that inpatient complication or treatment was not present. Infants with grade III/IV intracranial hemorrhage, PVL, severe ROP, and severe BPD had higher brain MRI injury scores than those infants without such complications. Interventions for greater than 7 days such as intubation, opioid, benzodiazapine, and antibiotic treatment were associated with higher brain MRI injury scores.

Figure 4.

BSID-III cognitive, motor, language scores at 22-26 months by global brain injury score, white matter score, and cerebellum score. A-C, demonstrate relationship of the BSID-III subscale scores (Motor; Cognitive; Language) to the global brain MRI injury score. D-F, demonstrate relationship of the BSID-III subscale scores (Motor; Cognitive; Language) to the white matter MRI injury score. G-I, demonstrate relationship of the BSID-III subscale scores (Motor; Cognitive; Language) to the cerebellum brain MRI injury score. All BSID-III scores were significantly related to higher brain injury scores except for cognitive and language scores for the cerebellum.

Figure 5.

Forest plot of associations between BSID-III cognitive, motor, language scores at 22-26 months of corrected age and global brain injury, white matter injury, and cerebellum injury scores. Significant associations were demonstrated between higher MRI injury scores and lower BSID-III scores except for cerebellum MRI injury and BSID-III cognitive and language scores.

Figure 6.

Inter-rater scoring between the Netherlands team and University of Washington team for 10 selected MRIs. Independent MRI injury scoring interpretations were compared between the Netherlands team and the University of Washington team. The Spearman correlation value was 0.88. The Bland-Altman plot demonstrates good agreement between the scoring team.