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

Amanda Benavides, Edward F. Bell, Michael K. Georgieff, Cassandra D. Josephson, Sean R. Stowell, Henry A. Feldman, Demet Nalbant, Alexander Tereshchenko, Martha Sola-Visner, Peggy Nopoulos

Research output: Contribution to journalArticlepeer-review


Background: The objective of this study was to determine sex-specific differences in inflammatory cytokine responses to red blood cell (RBC) transfusion in preterm infants in the neonatal period and their relationship to later neurocognitive status. Methods: Infants with a birth weight <1000 g 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. Nineteen cytokines and biomarkers were analyzed from 71 infants longitudinally during the neonatal period. Twenty-six 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-1, MCP-1, rose substantially in females (8.9% change per additional transfusion), but not in 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). Conclusions: 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. Impact: It is important to understand the risk factors for abnormal neurodevelopment in preterm infants, including anemia and RBC transfusion, in order to improve outcomes and provide potential targets for therapy.Our study investigates and provides the first evidence of sex-specific differences in inflammatory cytokine responses to RBC transfusions in preterm infants in the neonatal period, and their relationship to later cognitive outcomes.This study critically suggests that different transfusion thresholds may have a sex-specific effect on neurodevelopment: females have worse cognitive outcomes with increased number of transfusions, while males have worse outcomes with lower number of transfusions.

Original languageEnglish (US)
JournalPediatric Research
StateAccepted/In press - 2021

Bibliographical note

Funding Information:
The design and conduct of this research study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript were made possible by National Institute for Heart, Lung, and Blood (NHLBI) Parent Project Grant #5P01HL046925-22, Sub-Project ID 5779, “Immunologic and Neurode-velopmental Consequences of Neonatal Anemia and Thrombocytopenia and Their Treatments—Project 4,” and National Institute for Mental Health (NIMH) Program Grant #5T32MH019113-26 “Iowa Neuroscience Specialty Program in Research Education (INSPIRE) Program Grant.” We confirm that this manuscript has not been previously published and has not been submitted simultaneously for publication elsewhere. I, A.B., had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Funding Information:
A.B. was involved in conceptualization/design, methodology, data curation and formal analysis, and writing initial draft of this manuscript, and confirms that all authors participated in the conceptualization/design, review, and editing of this manuscript. Additionally, D.N. provided significant expertise in the methodology of transfusion, blood banking, and cytokine sampling used in this study. H.A.F. contributed significantly to the supervision/oversight, statistical methodology, and formal analysis of all data presented in this manuscript. As part of multi-institutional program project grant, H.A.F., M.K.G., C.D.J., P.N., S.R.S., and M.S.-V. provided acquisition of funding for this manuscript, as well as critical supervision/oversight and feedback for revision throughout the manuscript writing and submission process. All authors have reviewed and approved the final version of the manuscript as submitted and agree with its submission to Pediatric Research.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.

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