Brainstem size in extremely preterm infants: reference values and association with neurodevelopmental outcomes

Abstract Background and objectives Extremely preterm infants are at high risk for neurodevelopmental impairment. The brainstem plays a critical role in early development. This study aimed to establish reference values for two-dimensional brainstem measurements on cerebral magnetic resonance imaging (cMRI) at term-equivalent age (TEA), assess the impact of severe neonatal brain injury, and examine associations with neurodevelopment. Methods In this retrospective cohort study, preterm infants underwent routine cMRI at TEA. Standardized midsagittal brainstem measurements were obtained. Reference values and z -scores were derived from infants without severe brain injury (high-grade IVH, CBH, or cystic WMI). In the reference cohort, associations with Bayley-III outcomes at 2 years’ corrected age were evaluated using multivariable regression. Brainstem z -scores were compared between infants with and without severe brain injury. Results Reference values were established for 242 infants born between 22 + 1 and 27 + 6 weeks’ gestation. Brainstem size increased with gestational age and was significantly smaller in infants with severe brain injury. Higher brainstem z -scores were independently associated with better cognitive (adjusted β = 3.56, 95% CI: 0.44–6.69) and motor (adjusted β = 2.80, 95% CI: 0.39–5.22) outcomes. Conclusions Brainstem size was associated with neonatal brain injury and later neurodevelopment, supporting its potential as a clinically applicable cMRI biomarker in extremely preterm infants. Impact Reference values and z -scores for two-dimensional brainstem measurements at term-equivalent age in extremely preterm infants without severe brain injury. Reduced brainstem size in infants with severe brain injury, and association with cognitive and motor outcomes at 2 years’ corrected age. Brainstem size is a simple and reproducible MRI biomarker.