Transfusion-transmission of human cytomegalovirus (TT-CMV) causes serious morbidity and mortality in immunocompromised recipients, including low birth weight infants (LBWI). Yeager and colleagues first demonstrated in 1981 that TT-CMV could be mitigated in high-risk LBWI through exclusive transfusion of CMV seronegative blood components. Nonetheless, since this time, in many parts of the developed world, the de facto clinical standard for transfusion support in this population has evolved to become CMV-seronegative + leukoreduced units. However, the CMV-safety of this approach has never been validated in a large prospective clinical trial. Furthermore, it is not clear whether this represents the optimal transfusion approach for recipients at high risk for CMV transmission, or whether additional safety measures (CMV NAT to identify window-phase units; 100% leukoreduction QC to prevent transfusion of units with failed leukoreduction) are needed to completely prevent TT-CMV. In this prospective multicenter cohort study, we will (Aim 1) closely follow 1300 LBWI (650 each born to CMV-seronegative and -seropositive mothers), rigorously screened to eliminate cases of maternal CMV transmission, in order to calculate accurate point estimates of the risk of TTCMV in this high risk population following uniform receipt of CMV-seronegative + leukoreduced blood. Additionally, aliquots of all transfused components will be screened by high throughput assays for CMV DNA (quantitative) and residual leukocytes (Aim 2). Episodes of documented TT-CMV will be analyzed in the context of transfusions containing CMV DNA (including viral load) and/or elevated WBC counts (> 5 x 106) to calculate the risk of TT-CMV with transfusion of units that are CMV DNA+ or failed leukoreduction. We believe this study will represent the definitive analysis of the CMV safety of CMV-seronegative + leukoreduced transfusions, and will inform future transfusion decisions for these high risk populations. This project addresses the PPG central theme since LBWI are very susceptible to opportunistic infections, like CMV: Thus, TT-CMV in this population is a serious hazard. The results of the proposed investigation will demonstrate whether CMV-seronegative + leukoreduced transfusions are optimally safe for LBWI, or whether breakthrough cases of TT-CMV occur and could be prevented by CMV NAT and 100% leukoreduction QC. This project interacts with Projects 1 and 3 and utilizes cores A and C. Both Projects 1 and 3 are focused on developing approaches (preclinical and clinical, respectively) to accelerate immune reconstitution in HPCT recipients to prevent disease from opportunistic infections, including CMV. Project 2 synergizes with this objective by validating approaches to prevent CMV transmission to this population through blood components that are optimally CMV-safe. This project will also make use of the Administrative Core (A) to oversee all IRB applications and approvals, and the Biostatistics and Data Management Core (C) for study design, ongoing statistical analysis of data, and data safety monitoring (DSM plan) functions.