Red blood cell (RBC) transfusion management includes the criteria used to determine when transfusion should occur in preterm infants. There is controversy regarding whether more restrictive or more liberal criteria would best serve the goal of optimal brain development. Although some studies have indicated that liberal transfusions may be neuroprotective, our findings from the previous 4 years of this PPG indicate that liberal transfusions result in poor long-term brain development, and this is particularly true for females. The overall aim of Project #3 is to evaluate the neurodevelopmental outcomes of differential transfusion practices from a mechanistic viewpoint. We hypothesize that liberal transfusion will result in poorer neurodevelopmental outcomes compared to restrictive transfusion practices. Potential mechanisms explored for this phenomenon include inflammation and/or erythropoietin (Epo) suppression that result from liberal RBC transfusion. Cerebral white matter and sex effects will be of particular interest.
Specific Aim 1 will be to measure the relationships between serum biomarkers (average hematocrit (HCT), iron, ferritin, c-reactive proteins, cytokines and Epo), and brain structure (using MRI) in preterm infants that are randomized to either restricted or liberal transfusion. Biomarkers and MRI scan will be obtained during the NICU stay.
Specific Aim 2 will examine the effects of differential transfusion on brain development using a longitudinal assessment of the same infants at 12 months and 24 months. Follow-up assessments will include a comprehensive battery of cognitive and developmental measures as well as a follow-up MRI scan. The current proposal is designed to 'extend'an NICHD Neonatal Research Network trial to evaluate the relationship between neonatal transfusion approach and neurodevelopmental outcome. This study is called the Impact of a Liberal Red Blood Cell Transfusion Strategy on Neurologically-lntact Survival of Extremely- Low-Birth-Weight Infants: The Transfusion and Brain Injury (TABI) Trial. The TABI protocol will be the foundation for recruitment of subjects, our current proposal would extend the TABI by: 1) assessing transfusion status and neurodevelopmental impairment (NDI) as continuous measures rather than dichotomous measures;2) use additional assessments that more sensitively and more specifically quantify brain structure and function;and 3) explore specific proposed mechanisms by which differential transfusion may impact brain development (inflammation and Epo suppression).

Public Health Relevance

Findings from the current proposal have a high likelihood of direct clinical impact: at a minimum, results that show liberal transfusion practice leads to poorer neurodevelopmental outcome will have a direct impact on clinical practice. Further, if we understand more about the roles of inflammation and/or the role of Epo, this could lead to further evaluation of potential treatments or interventions to minimize poor developmental outcomes when transfusions are required. This last point is of particular relevance in regard to the synergy of the PPG, as Project 1 is designed to evaluate the utility of Epo in the treatment of preterm anemia.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Iowa
Iowa City
United States
Zip Code
Peters, Anna L; Beuger, Boukje; Mock, Donald M et al. (2016) Clearance of stored red blood cells is not increased compared with fresh red blood cells in a human endotoxemia model. Transfusion 56:1362-9
Bastian, Thomas W; Duck, Kari A; Michalopoulos, George C et al. (2016) Eltrombopag, a thrombopoietin mimetic, crosses the blood-brain-barrier and impairs iron-dependent hippocampal neuron dendrite development. J Thromb Haemost :
Witmer, Jordan R; Wetherell, Bailey J; Wagner, Brett A et al. (2016) Direct spectrophotometric measurement of supra-physiological levels of ascorbate in plasma. Redox Biol 8:298-304
Zamora, Tara G; Guiang 3rd, Sixto F; Widness, John A et al. (2016) Iron is prioritized to red blood cells over the brain in phlebotomized anemic newborn lambs. Pediatr Res 79:922-8
Patel, Ravi M; Knezevic, Andrea; Shenvi, Neeta et al. (2016) Association of Red Blood Cell Transfusion, Anemia, and Necrotizing Enterocolitis in Very Low-Birth-Weight Infants. JAMA 315:889-97
Patel, Ravi Mangal; Meyer, Erin K; Widness, John A (2016) Research Opportunities to Improve Neonatal Red Blood Cell Transfusion. Transfus Med Rev 30:165-73
Ekhaguere, Osayame A; Morriss Jr, Frank H; Bell, Edward F et al. (2016) Predictive factors and practice trends in red blood cell transfusions for very-low-birth-weight infants. Pediatr Res 79:736-41
Weisenhorn, Erin M M; van T Erve, Thomas J; Riley, Nicholas M et al. (2016) Multi-omics Evidence for Inheritance of Energy Pathways in Red Blood Cells. Mol Cell Proteomics 15:3614-3623
Kuruvilla, Denison J; Widness, John A; Nalbant, Demet et al. (2016) A Mass Balance-Based Semiparametric Approach to Evaluate Neonatal Erythropoiesis. AAPS J 18:187-95
Al-Ghananim, Raeda T; Nalbant, Demet; Schmidt, Robert L et al. (2016) Reticulocyte Hemoglobin Content During the First Month of Life in Critically Ill Very Low Birth Weight Neonates Differs From Term Infants, Children, and Adults. J Clin Lab Anal 30:326-34

Showing the most recent 10 out of 179 publications