Impact of clinical risk factors on white matter microstructure in preterm-born infants: Investigation with diffusion MRI and tractography at term-equivalent age

Premature birth occurs during a phase of intense brain maturation, making white matter (WM) particularly vulnerable to injury. Beyond major lesions, subtle and widespread microstructural alterations also contribute to later neurodevelopmental impairments. We aimed to characterize the impact of key clinical risk factors on global and tract-specific WM microstructure at term-equivalent age (TEA), using 3T-diffusion-MRI data of 111 infants born before 33 weeks of gestation. We developed a lesion-robust tractography pipeline suitable for heterogeneous neonatal anatomy and extracted diffusion tensor imaging (DTI) metrics in sensorimotor tracts: corticospinal tract (CST), superior thalamic radiation (STR), frontal aslant tract (FAT), forceps minor (FMI) and middle cerebellar peduncle (MCP). Associations with risk factors were assessed accounting for age at MRI or global WM microstructure. Tractography succeeded in most infants despite marked anatomical variability and/or overt lesions. Being a male, small for gestational age (SGA) at birth, encountering sepsis and having severe Kidokoro radiological score for WM were associated with altered global WM metrics. At the tract level, CST and STR showed the strongest susceptibility to SGA, prolonged parenteral nutrition, and Kidokoro score. In contrast, for FAT, associations with extreme prematurity, SGA and invasive ventilation were contrary to the expected direction, after adjustment for global WM microstructure. Findings were partially replicated in infants without macroscopic abnormalities, supporting the presence of WM dysmaturation even in the absence of visible injury. DTI metrics thus provide tract-specific biomarkers of early WM microstructure in preterm infants, which are sensitive to risk factors and could inform targeted prevention and intervention.