Background: The literature on brain imaging in premature infants, is mostly made up of studies that evaluate neonates, yet the most dynamic time of brain development happens from birth to one year of age. This study was designed to obtain quantitative brain measures from Magnetic Resonance Imaging (MRI) scans of infants born prematurely at 12 months of age. Methods: The subject group was designed to capture a wide range of gestational age (GA) from premature to full term infants. An age-specific atlas generated quantitative brain measures. A regression model was used to predict effects of gestational age, sex, on brain measures. Results: There was a primary effect of sex on: 1) intracranial volume (ICV), males > females; 2) proportional cerebral cortical gray matter (females > males) and 3) cerebral white matter (males> females). GA predicted cerebral volume and cerebral spinal fluid (CSF). GA also predicted cortical gray matter in a sex specific manner with GA having a significant effect on cortical volume in the males, but not in females. Conclusions and Relevance: Sex differences in brain structure are large early in life. GA had sex specific effects highlighting the importance evaluating sex effects in neurodevelopmental outcomes of premature infants.

Background: Preterm infants who receive differential red blood cell (RBC) transfusions at birth may show brain structure differences across development, including abnormalities in white matter (WM) structure and organization. This study investigated long-term outcomes of brain structure in female infants born preterm, at an average age of 13 years old, who received red blood cell (RBC) transfusions in the neonatal period according to a liberal or restrictive approach. Results from this study will increase understanding of the effects of transfusion on the developing brain. Study design and methods:This follow-up study included female preterm infants who participated in a clinical trial and had been randomized at birth to either a liberal or restrictive hematocrit threshold. Brain structures were measured in childhood using structural magnetic resonance imaging (MRI) scans. Due to the low number of females in the restrictive transfusion group at follow-up, additional females were recruited for inclusion. Main outcome measures included cerebral and subcortical brain region volumes.Results: Total intracranial volume was significantly decreased in females who were randomized to higher average hematocrit levels at birth. Infants in the liberal transfusion group had proportionately smaller volumes in all measures of regional cerebral WM and subcortical brain volumes, reaching significance for temporal lobe WM and caudate volumes. Conclusion:Female premature infants who received a liberal transfusion threshold at birth had decreased WM volumes, which suggests the potential long-term neurodevelopmental risks associated with liberal transfusion practices.

BACKGROUND: The objective of this study was to determine sex-specific differences in inflammatory cytokine responses to RBC transfusion in preterm infants in the neonatal period and their relationship to later neurocognitive status. METHODS: Infants with a birth weight <1000 grams and gestational age 22–29 weeks were enrolled in the Transfusion of Prematures (TOP) trial. The total number of transfusions was used as a marker of transfusion status. 19 cytokines and biomarkers were analyzed from 71 infants longitudinally during neonatal period. 26 infants completed the Bayley Scales of Infant & Toddler Development, 3rd Edition (Bayley-III) at 12 months’ corrected age. RESULTS: Nine cytokine levels were significantly elevated in proportion to the number of transfusions received. Of those, one cytokine showed a sex-specific finding (p=0.004): monocyte chemoattractant protein, MCP-1, rose substantially in females (8.9% change per additional transfusion), but not males (−0.8% change). Higher concentrations of MCP-1 exclusively were associated with worse Bayley-III scores: decreased cognitive raw scores (p=0.0005) and motor scaled scores (p<0.0001). CONCLUSION: This study provides evidence of a sex-specific difference in the inflammatory response to RBC transfusions during neonatal life, with MCP-1 levels rising only in females and inversely correlating with neurocognitive status at 12 months old.

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