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  • Clinical Research Article
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Neurodevelopmental outcomes after red cell transfusion exposure in male versus female extremely preterm infants

Pediatric Research volume 98, pages 2186–2194 (2025)Cite this article

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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Fig. 1: CONSORT diagram of infants enrolled in PENUT Trial included in this analysis.
Fig. 2: Linear associations between transfusion volume and biomarker values stratified by sex at 0–7 and 7–14 days of life.
Fig. 3: Linear association between transfusion volume and Kidokoro MRI score at 36 weeks postmenstrual age, stratified by sex.
Fig. 4: Linear association between transfusion volume and BSID-III subscales, stratified by sex.

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Acknowledgements

We would like to recognize Roberta Ballard, MD, University of California, San Francisco School of Medicine, who provided unflagging support and advice throughout the PENUT Trial, for which she was compensated. We thank the research coordinators from all 19 sites and 30 hospitals who made the PENUT study possible. Mark A. Konodi, MS, and Christopher Nefcy, BS, University of Washington, Seattle, at the data coordinating center, kept the PENUT Portal running. John A. Widness, MD, University of Iowa, Iowa City, served as PENUT Medical Monitor during the years of PENUT enrollment, for which he was compensated. The genetics core of the UW Intellectual and Developmental Disability Research Center processed the inflammatory biomarkers.

Funding

The PENUT Trial was funded by the NINDS, U01NS077955 and U01NS077953. Work for the biomarker analysis was supported in part by the NICHD, 5P50HD103524.

Author information

Author notes

  1. These authors contributed equally: Kendell German, Thomas R. Wood.

Authors and Affiliations

  1. University of Washington, Department of Pediatrics, Seattle, WA, USA

    Kendell German, Thomas R. Wood, Dennis E. Mayock, Mihai Puia-Dumitrescu, Sarah Kolnik, Ulrike Mietzsch, Janessa Law, Krystle Perez, Gregory Valentine & Sandra E. Juul

  2. University of Washington, Department of Biostatistics, Seattle, WA, USA

    Patrick J. Heagerty & Bryan A. Comstock

  3. Department of Pediatrics, Warren Alpert Medical School of Brown University, Providence, RI, USA

    Semsa Gogcu

  4. University of Washington, Department of Environmental and Occupational Health Sciences, Seattle, WA, USA

    Theo K. Bammler

  5. University of Arkansas for Medical Sciences, Little Rock, AK, USA

    Billy Thomas, Nahed Elhassan & Sarah Mulkey

  6. Methodist Children’s Hospital, San Antonio, TX, USA

    Vivek K. Vijayamadhavan

  7. University of Utah, Salt Lake City, UT, USA

    Bradley Yoder

  8. Maria Fareri Children’s Hospital at Westchester Medical Center, Valhalla, NY, USA

    Jordan S. Kase

  9. Wake Forest School of Medicine, Winston-, Salem, NC, USA

    Jennifer Check

  10. University of Minnesota Masonic Children’s Hospital, Minneapolis, MN, USA

    Erin Osterholm, Catherine Bendel, Thomas George & Michael Georgieff

  11. Beth Israel Deaconess Medical Center, Boston, MA, USA

    Camilia R. Martin & Deirdre O’Reilly

  12. Prentice Women’s Hospital, Chicago, IL, USA

    Nicolas Porta & Raye-Ann de Regnier

  13. University of Florida, Gainesville, FL, USA

    Catalina Bazacliu

  14. Johns Hopkins University, Baltimore, MD, USA

    Frances Northington & Raul Chavez Valdez

  15. Children’s Hospital of the University of Illinois, Chicago, IL, USA

    Patel Saurabhkumar

  16. South Miami Hospital, South Miami, FL, USA

    Magaly Diaz-Barbosa

Authors
  1. Kendell German
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  2. Thomas R. Wood
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  3. Semsa Gogcu
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  4. Patrick J. Heagerty
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  5. Dennis E. Mayock
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  7. Mihai Puia-Dumitrescu
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  8. Sarah Kolnik
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  10. Janessa Law
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Consortia

PENUT Trial Consortium

  • Billy Thomas
  • , Nahed Elhassan
  • , Sarah Mulkey
  • , Vivek K. Vijayamadhavan
  • , Bradley Yoder
  • , Jordan S. Kase
  • , Jennifer Check
  • , Erin Osterholm
  • , Catherine Bendel
  • , Thomas George
  • , Michael Georgieff
  • , Camilia R. Martin
  • , Deirdre O’Reilly
  • , Nicolas Porta
  • , Raye-Ann de Regnier
  • , Catalina Bazacliu
  • , Frances Northington
  • , Raul Chavez Valdez
  • , Patel Saurabhkumar
  •  & Magaly Diaz-Barbosa

Contributions

KRG, TRW, SG, PJH, DEM, BAC, MPD, SK, UM, JL, KP, GV and SEJ conceived the manuscript. TKB oversaw sample processing and generation of the biomarker immunoassay data. BAC, PJH and SEJ verified the data and TRW performed the statistical analyses. TRW made the tables and figures. KRG, TRW, SG drafted the manuscript. All authors contributed to editing the manuscript and approved the final draft. DEM, PJH and SEJ oversaw the methodology and administration of the PENUT Trial and resulting investigations. SEJ was the PI of the PENUT Trial and oversaw the Trial.

Corresponding author

Correspondence to Kendell German.

Ethics declarations

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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German, K., Wood, T.R., Gogcu, S. et al. Neurodevelopmental outcomes after red cell transfusion exposure in male versus female extremely preterm infants. Pediatr Res 98, 2186–2194 (2025). https://doi.org/10.1038/s41390-025-04149-z

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