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. 2025 Jun 2.
doi: 10.1038/s41390-025-04149-z. Online ahead of print.

Neurodevelopmental outcomes after red cell transfusion exposure in male versus female extremely preterm infants

Kendell German #  1 , Thomas R Wood #  2 , Semsa Gogcu  3 , Patrick J Heagerty  4 , Dennis E Mayock  2 , Bryan A Comstock  4 , Mihai Puia-Dumitrescu  2 , Sarah Kolnik  2 , Ulrike Mietzsch  2 , Janessa Law  2 , Krystle Perez  2 , Gregory Valentine  2 , Theo K Bammler  5 , Sandra E Juul  2 ; PENUT Trial Consortium
Collaborators, Affiliations

Neurodevelopmental outcomes after red cell transfusion exposure in male versus female extremely preterm infants

Kendell German et al. Pediatr Res. .

Abstract

Background: Packed red blood cell (pRBC) transfusions are often required in extremely premature infants but are associated with increased pro-inflammatory cytokines and adverse neurodevelopment, which may differ by sex.

Methods: In this post-hoc analysis of the Preterm Erythropoietin Neuroprotection (PENUT) Trial, associations between pRBC transfusion volume and cytokines at 0-7 and 7-14 days, MRI injury, and Bayley Scales of Infant Development (BSID-III) scores at 24 months corrected age were evaluated. Graphical network and generalized estimating equation models were used to examine interactions by sex as well as the influence of hematocrit level.

Results: 182 and 164 infants were assessed with biomarkers at 0-7 and 7-14 days, 220 infants had MRIs, and 692 infants had at least one BSID-III assessment. Infant sex modified the association between pRBC transfusion volume and IL-6 at 7-14 days but did not impact the association between transfusion volume or hematocrit and BSID-III scores. Total pRBC transfusion volume was significantly negatively associated with all BSID-III subscales after accounting for anemia and severity of illness.

Conclusion: Infant sex may impact short-term cytokine responses to transfusions but not the association between transfusion volume and long-term outcomes.

Impact: In a post hoc analysis of extremely preterm infants from the PENUT Trial, the relationship between transfusion exposure and pro-inflammatory cytokines, MRI scores and neurodevelopment were evaluated by sex. The impact of transfusions on inflammatory cytokines may vary by sex. However, this does not appear to lead to differences in neurodevelopmental outcomes. Based on current evidence, providers should not alter their transfusion practices based on sex of the infant.

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Conflict of interest statement

Competing interests: Dr Juul reported receiving grants from the National Institutes of Health (NIH), CP Alliance, and Gates Foundation Grant during the conduct of the study. Mr. Comstock reported receiving grants from the NIH during the conduct of the study. Dr Heagerty reported receiving grants from the NIH to the University of Washington during the conduct of the study. No other disclosures were reported. Ethical approval and consent for approval: The families of all participants in the primary PENUT Trial provided informed, written consent for their participation in the randomized trial. This consent included the use of data in secondary analyses, such as this one.

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