This study examines the relationship between early-life pain exposure, neonatal brain structural connectivity, and neurodevelopmental outcomes in very preterm infants. The research involved 193 very preterm infants, with 150 having structural connectivity data and 123 having neurodevelopmental outcomes. The study found that early-life pain exposure was associated with altered maturation of neonatal structural connectivity, particularly in female infants. Female infants exposed to greater early-life pain showed slower maturation of global and local efficiency and corticostriatal connectivity. In contrast, male infants did not show significant associations. The study also found that reduced structural connectivity was associated with poorer neurodevelopmental outcomes, with specific regional effects in the striatum and limbic system. The study used magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) to assess structural connectivity and the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-3) to evaluate neurodevelopmental outcomes. The results suggest that early-life pain exposure may have sex-specific effects on brain maturation and neurodevelopment in preterm infants. The findings highlight the importance of minimizing and adequately treating pain in preterm infants, as pain exposure may lead to altered brain connectivity and poorer developmental outcomes. The study also emphasizes the need for further research into sex-specific effects of early-life pain on neonatal brain maturation and neurodevelopment.This study examines the relationship between early-life pain exposure, neonatal brain structural connectivity, and neurodevelopmental outcomes in very preterm infants. The research involved 193 very preterm infants, with 150 having structural connectivity data and 123 having neurodevelopmental outcomes. The study found that early-life pain exposure was associated with altered maturation of neonatal structural connectivity, particularly in female infants. Female infants exposed to greater early-life pain showed slower maturation of global and local efficiency and corticostriatal connectivity. In contrast, male infants did not show significant associations. The study also found that reduced structural connectivity was associated with poorer neurodevelopmental outcomes, with specific regional effects in the striatum and limbic system. The study used magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) to assess structural connectivity and the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-3) to evaluate neurodevelopmental outcomes. The results suggest that early-life pain exposure may have sex-specific effects on brain maturation and neurodevelopment in preterm infants. The findings highlight the importance of minimizing and adequately treating pain in preterm infants, as pain exposure may lead to altered brain connectivity and poorer developmental outcomes. The study also emphasizes the need for further research into sex-specific effects of early-life pain on neonatal brain maturation and neurodevelopment.