Long-term outcome of brain structure in female preterm infants: possible associations of liberal versus restrictive red blood cell transfusions

Abstract

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.

Anemia and Red Blood Cell Transfusions, Cerebral Oxygenation, Brain Injury and Development, and Neurodevelopmental Outcome in Preterm Infants: A Systematic Review

“…Regarding brain development, this systematic review demonstrated more available evidence for brain structure abnormalities at school age among neonates transfused under liberal transfusion thresholds (51,53,54) Children with highest average Ht-levels had lowest brain volumes at 12-years of age, supporting the notion that the abnormalities are indeed related to Ht-level (and thus to transfusion status) (51,53,54). Of note, all three follow-up studies describing brain MRI at school age included a sample of children that were initially enrolled in the same randomized controlled trial (20).…”

“…Concerning brain development, regional brain measures assessed on brain MRI were mostly smallest in female study participants, and were inversely related to average Ht-level: those children with the highest neonatal average Ht-level were the ones with the lowest volumes of white matter and thalamic volume at 12 years (51,53,54). Liberal RBC transfusion practices were associated with reduced cerebral white matter at school age, especially within the temporal lobe and subcortical nuclei (51,53,54). Brain MRI at near-term age (PMA range 34.0-36.9 weeks) showed increased fractional oxygen extraction in brain tissue in infants with lower Ht-levels, suggesting ongoing hemodynamic compensation for anemia (52).…”

Sex differences in adult social, cognitive, and affective behavioral deficits following neonatal phlebotomy‐induced anemia in mice

“…Long-term follow-up of infants from the Iowa trial demonstrated poorer longterm outcome only in males, whereas females with lower hematocrits had better outcomes than those randomized to higher hematocrits (McCoy et al, 2011;Nopoulos et al, 2011). Transfusion is a potential risk factor to the developing organs, including the brain (Benavides et al, 2019). Because of the apparent risks of transfusions, fewer infants are being transfused and more infants are allowed to maintain lower hematocrits without consideration of potential neurometabolic (Wallin et al, 2015(Wallin et al, , 2017 and behavioral consequences.…”

“…Additional research suggests that these effects differentially affect male and female preterm children (Saigal, Hoult, Streiner, Stoksopf, & Rosenbaum, 2000;Whitfielf, Grunau, & Holsti, 1997). Sex differences in outcomes of anemic preterm children have also been shown (Benavides et al, 2019;McCoy et al, 2011;Nopoulos et al, 2011). Although their significance is clear, the etiology of such long-term, sex-specific cognitive and behavioral deficits remains poorly understood because of the multiple confounding variables inherent to these clinical populations.…”

“…Although their significance is clear, the etiology of such long-term, sex-specific cognitive and behavioral deficits remains poorly understood because of the multiple confounding variables inherent to these clinical populations. Preclinical models investigating sex-specific structural and functional effects of early-life anemia can provide insights into the mechanisms of cognitive and behavioral changes in preterm infants (Benavides et al, 2019;Nopoulos et al, 2011).…”