Sex-specific cytokine responses and neurocognitive outcome after blood transfusions in preterm infants

Abstract

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.

Early Biomarkers of Hypoxia and Inflammation and Two-Year Neurodevelopmental Outcomes in the Preterm Erythropoietin Neuroprotection (PENUT) Trial

“…In line with the study goals, we only examined associations between biomarkers and outcomes and did not examine infant or other factors associated with elevations of individual biomarkers, largely due to the complex time-varying nature of many of these potential factors such as occurrence of sepsis. For instance, a recent study has described sex-dependent alterations in pro-inflammatory cytokines in response to transfusions in preterm infants [63]. While the Epo group did require fewer transfusions, [64] the effect of transfusions or other variables on biomarker levels is beyond the scope of this study examining their potential for outcome prediction.…”

Immunologic effects of red blood cell and platelet transfusions in neonates

“…Repeat RBC transfusions, to which most preterm infants are exposed, have also been associated with incremental increases in plasma pro-inflammatory cytokines [13]. Most recently, Benavides et al [14 ▪▪ ] serially measured a panel of plasma cytokines in a subset of extremely preterm infants randomized to liberal or restrictive transfusion thresholds as part of the TOP study, and found nine pro-inflammatory cytokines that increased significantly in proportion to the number of transfusions received. Taken together, the available studies suggest that RBC transfusions have systemic pro-inflammatory effects in neonates, although the mechanisms mediating these effects are unclear.…”

“…In the study by Benavides et al [14 ▪▪ ], one of the measured cytokines (monocyte chemoattractant protein-1 [MCP-1, CCL2]), changed in a sex-specific manner, rising in females with each additional transfusion, but not in males. Furthermore, higher concentrations of MCP-1 were associated with worse cognitive and motor outcomes at 12 months of age.…”

Red Blood Cell Donor Sex Associated Effects on Morbidity and Mortality in the Extremely Preterm Newborn

“…Intriguingly, there is emerging evidence that preterm newborns may themselves exhibit sex-specific inflammatory responses to RBC transfusion [ 67 ]. In an analysis of 19 cytokines and inflammatory biomarkers measured pre- and post-transfusion in preterm newborns enrolled in the Transfusion of Prematures (TOP) trial [ 68 ], Benavides and colleagues reported significantly greater increases with each additional transfusion in monocyte chemoattractant protein (MCP-1) in females but not in males [ 67 ]. In addition, higher concentrations of MCP-1 were associated with worse neurodevelopmental outcomes determined by Bayley-III assessment.…”