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Original Contribution |

Clinical Outcomes Following Institution of Universal Leukoreduction of Blood Transfusions for Premature Infants FREE

Dean Fergusson, MHA; Paul C. Hébert, MD, MHSc; Shoo K. Lee, MBBS, PhD; C. Robin Walker, MBChB; Keith J. Barrington, MBChB; Lawrence Joseph, PhD; Morris A. Blajchman, MD; Stan Shapiro, PhD
[+] Author Affiliations

Author Affiliations: Departments of Epidemiology and Biostatistics (Mr Fergusson and Drs Joseph and Shapiro) and Pediatrics (Dr Barrington), McGill University, Montreal, Quebec; University of Ottawa Centre for Transfusion Research, Ottawa Hospital (Mr Fergusson and Dr Hèbert), Clinical Epidemiology Unit, Ottawa Health Research Institute (Mr Fergusson and Dr Hébert), and Department of Pediatrics, University of Ottawa (Dr Walker), Ottawa, Ontario; Department of Pediatrics, University of British Columbia, Vancouver (Dr Lee); and Department of Pathology, McMaster University Medical Center, and Canadian Blood Services, Hamilton, Ontario (Dr Blajchman).


JAMA. 2003;289(15):1950-1956. doi:10.1001/jama.289.15.1950.
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Published online

Context Leukocytes present in stored blood products can have a variety of biological effects, including depression of immune function, thereby increasing nosocomial infections and possibly resulting in organ failure and death. Premature infants, given their immature immune state, may be uniquely predisposed to the effects of transfused leukocytes.

Objective To evaluate the clinical outcomes following implementation of a universal prestorage red blood cell (RBC) leukoreduction program in premature infants admitted to neonatal intensive care units (NICUs).

Design and Setting Retrospective before-and-after study conducted in 3 Canadian tertiary care NICUs from January 1998 to December 2000.

Patients A total of 515 premature infants weighing less than 1250 g who were admitted to the NICU, received at least 1 RBC transfusion, and survived at least 48 hours were enrolled. The intervention group consisted of infants admitted in the 18-month period following the introduction of universal leukoreduction (n = 247) and the control group consisted of infants admitted during the 18 months prior to the introduction of universal leukoreduction (n = 268).

Main Outcome Measures Primary outcomes were nosocomial bacteremia and NICU mortality, compared before and after implementation of universal leukoreduction using multivariate regression. Secondary outcomes included bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and intraventricular hemorrhage.

Results The proportion of infants who acquired bacteremia after an RBC transfusion was 79/267 (29.6%) in the nonleukoreduction period and 63/246 (25.6%) in the leukoreduction period. For NICU mortality, there were 45 deaths (16.8%) in the nonleukoreduction period and 44 deaths (17.8%) in the leukoreduction period. The adjusted odds ratio (OR) for bacteremia was 0.59 (95% confidence interval [CI], 0.34-1.01) and for mortality was 1.22 (95% CI, 0.59-2.50). The adjusted ORs for bronchopulmonary dysplasia and retinopathy of prematurity were 0.42 (95% CI, 0.25-0.70) and 0.56 (95% CI, 0.33-0.93), respectively. The adjusted ORs for necrotizing enterocolitis and grade 3 or 4 intraventricular hemorrhage were 0.39 (95% CI, 0.17-0.90) and 0.65 (95% CI, 0.35-1.19), respectively. The adjusted OR for a composite measure of any major neonatal morbidity was 0.31 (95% CI, 0.17-0.56). Crude and adjusted rates for all secondary outcomes suggest that leukoreduction was associated with improved outcomes.

Conclusion Implementation of universal prestorage leukoreduction was not associated with significant reductions in NICU mortality or bacteremia but was associated with improvement in several clinical outcomes in premature infants requiring RBC transfusions.

More than 50% of infants weighing less than 1250 g at birth and who are admitted to neonatal intensive care units (NICUs) require red blood cell (RBC) transfusions.1 Despite recent trends in decreasing transfusion thresholds and the development of technologies designed to avoid exposure to blood, such as erythropoietin, transfusions remain an important lifesaving measure in the care of premature infants.

Leukocytes present in RBC transfusions may depress immune function, thereby increasing the presence of nosocomial infections and possibly resulting in organ failure and death.2,3 However, randomized trials, conducted exclusively in adults in a variety of surgical settings, have not all observed increased rates of postoperative nosocomial infections.4,5 In addition, there is a paucity of studies examining the possible risks and benefits of leukoreduction of RBC products in premature infants.6 Given their immature immune systems, neonates may be uniquely predisposed to the effects of transfused leukocytes. Leukocytes from transfusions may depress the immune response, generate alloantibodies, and, perhaps, produce widespread microvascular injury through the enhanced generation of free radicals in susceptible tissue beds such as the lungs and retina.2 Furthermore, it is conceivable that the leukoreduction process increases RBC hemolysis or results in unexpected clinical consequences.7 Based on the available research, the benefits of leukoreduction remain unclear in this vulnerable population.

We therefore evaluated clinical outcomes following the institution of a national universal prestorage leukoreduction program among premature infants weighing less than 1250 g who were admitted to a NICU.

Study Design and Participants

The implementation of a nationwide Canadian universal prestorage leukoreduction program for RBC products in 1999 enabled us to conduct a before-and-after study using 3 study sites from the Canadian Neonatal Network. The study was conducted at 3 tertiary care NICUs: Children and Women's Health Centre in Vancouver, British Columbia; Royal University Hospital in Saskatoon, Saskatchewan; and Mt Sinai Hospital in Toronto, Ontario.

The intervention group consisted of patients admitted to the NICU in the 18-month period following the introduction of leukoreduction. The control group, the nonleukoreduction cohort, consisted of all eligible infants admitted to the NICU in the 18-month period preceding the introduction of universal leukoreduction.

All premature infants from the 3 NICUs who weighed less than 1250 g, received at least 1 allogeneic RBC transfusion, and survived at least 48 hours were included. Infants surviving less than 48 hours were excluded to remove those with an extremely poor prognosis, such as overwhelming infections acquired from their mothers. Infants were also excluded if they were previously admitted to the NICU or received both leukoreduced and nonleukoreduced RBC transfusions. The research ethics committees of all participating institutions approved the study protocol.

Data Collection

Information gathered on each admission from the Canadian Neonatal Network database included the patient's gestational age and sex, illness severity scores including the SNAP II (Score for Neonatal Acute Physiology) on days 1 and 3, and Apgar scores at 1 and 5 minutes. Important interventions were recorded, including use of supplemental oxygen, continuous positive airway pressure (CPAP) and mechanical ventilation, central and peripheral venous access, RBC and platelet transfusions, use of intravenous immunoglobulin, cardiopulmonary resuscitation, and number of blood draws. The use of medications such as vasoactive drugs, antibiotics, surfactants, and corticosteroids was also recorded. Recorded maternal risk factors included type of delivery (cesarean vs vaginal) and use of any antenatal steroids. Information on the number, date, and volume of RBCs transfused was collected from the Canadian Neonatal Network database for 1 site (Royal University Hospital) and from the respective blood banks for the 2 other sites.

Data abstractors for the Canadian Neonatal Network database were responsible for collecting standardized information from every eligible admission to the NICU. Infants who were moribund at admission were not included. Data were gathered from medical records during admission to the NICU and transcribed directly into computerized case report forms. Standardized definitions were instituted to ensure consistency among sites. Any data items not available were scored as missing.

Description of Intervention and Transfusion Parameters

Canadian Blood Services introduced universal prestorage leukoreduction throughout Canada during 1999. Once collected, RBCs are passed through a Leukotrap-RC leukocyte reduction filtration system (Pall Corp, Port Washington, NY). Leukoreduction with this technology reduces white blood cell content of a unit of RBCs from an average 3.0 × 109 per unit to 2.5 × 105 per unit, a decrease of 4 logarithms. An anticoagulant solution of citrate, phosphate, and double dextrose (CPD-2) is then added to each unit with 100 mL of additive solution 3 (AS-3). All blood products were produced by 1 agency that conducts national quality control measures of the leukofiltration program.8 Prior to transfusion, each unit is divided into aliquots suitable for the neonatal population.

Transfused RBCs were not leukofiltrated in the control period at any site. One site (Children and Women's Health Centre) washed RBC transfusions designated for premature infants during the entire nonleukoreduction period and during the first 4 months of the leukoreduction period. Washing of RBCs reduces the proportion of leukocytes by 85% compared with a reduction of greater than 99.9% for prestorage leukoreduction. This site was included because it (1) had not used prestorage leukoreduction in the nonleukoreduction period; (2) provided a large sample of patients; (3) made our results more generalizable to include centers that currently wash RBCs; and (4) would not unfavorably bias the results of our study. In fact, including this site would only bias our results toward the null if washing RBCs is beneficially associated with our outcomes of interest.

Study Outcome Measures

The primary outcome measures in this study were nosocomial bacteremia and NICU mortality. Nosocomial bacteremia was defined as a positive blood culture for bacteria whether or not it was subsequently considered to be a contaminant. For a new infection, there had to be a new organism or a second positive blood culture drawn at least 7 days after the initial positive test. Survival status during the index hospitalization was ascertained from medical records.

Major secondary outcomes included bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and intraventricular hemorrhage. Bronchopulmonary dysplasia was defined as the ongoing need for assisted ventilation or supplemental oxygen on day 28 of life. The presence of any grade of retinopathy was recorded as an outcome in this study. Without documentation of an eye examination, retinopathy was defined as being absent. A diagnosis of necrotizing enterocolitis was based on a grade of stage 2 or higher using the criteria of Bell et al.9 A diagnosis of intraventricular hemorrhage required the presence of intraventricular blood on a routine image such as an ultrasound, computed tomography, or magnetic resonance image of the brain. Intraventricular hemorrhage was graded based on standard criteria developed by Papile.10 For the purposes of this study, a composite of grades 3 and 4 intraventricular hemorrhage was included as an outcome. As a means of evaluating the overall effect of leukoreduction on multiple organs simultaneously, all secondary outcomes were compared both separately and as a composite measure.

Length of stay in the NICU and both minor and major interventions received while in the NICU were recorded as tertiary outcomes. Major interventions included all major surgical procedures, such as laparotomies and thoracotomies. Minor interventions included cryogenic or laser therapy for retinopathy of prematurity, tracheostomy, endoscopic procedures such as bronchoscopy, and all transcutaneous procedures, such as nephrostomy and cardiac catheterizations. Use of umbilical vein and artery lines, peripheral arterial lines, venous cutdowns, and needle aspiration of body fluids were excluded from this category.

Information was also recorded that reflected the intensity of care on day 1 provided to each premature infant. On day 1, use of supplemental oxygen, conventional and high-frequency mechanical ventilation, and arterial and central venous access, as well as the use of medications such as vasopressors, glucocorticoids, antibiotics, and muscle relaxants, were recorded. Supplemental oxygen was defined as administration of continuous enriched oxygen in concentrations exceeding 21% via oxygen hood, nasal cannula, nasal catheter, or face mask or other forms of respiratory support. The use of "blow-by" oxygen alone was not sufficient to meet the definition, nor was oxygen administered for a hyperoxia test. Mechanical ventilation was defined as use of conventional mechanical ventilation regardless of the respiratory rate. We also recorded use of high-frequency ventilation using a jet ventilator or oscillator.

Peripheral intravenous access was defined as the presence of 1 or more intravenous catheters, including heparin locks used for drug administration. An arterial line was defined as the presence of a central line, including an umbilical venous line, a Broviac line, or a percutaneous catheter placed centrally. Unsuccessful attempts at line placement were not reported.

The use of vasopressors was defined as the administration of vasoactive medications administered through intravenous, intramuscular, or aerosol routes. Glucocorticoid and antibiotic use on day 1 was documented if an intravenous, oral, or nebulized preparation was used. Use of muscle relaxants was recorded daily if at least 1 dose of the medication was administered during the interval in question.

Statistical Analysis

Baseline characteristics before and after the introduction of leukoreduction were evaluated using measures of central tendency and dispersion. Absolute differences between periods were calculated for each characteristic with appropriate 95% confidence intervals (CIs). All a priori primary outcomes were compared using crude and adjusted odds ratios (ORs) with 95% CIs. Crude and adjusted ORs were also calculated independently for secondary outcomes, including bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and intraventricular hemorrhage.

As a second step, we incorporated all secondary outcomes associated with prematurity into a composite measure. Lengths of NICU stay were compared using multivariate regression analysis. Based on a priori input of experts in neonatology and transfusion medicine, all multivariate models incorporated clinically important variables, including gestational age, sex, center, type of delivery, antenatal use of glucocorticoids, Apgar score at 5 minutes, SNAP II as a measure of illness severity, number of days receiving CPAP, interventions on day 1 including use of supplemental oxygen and mechanical ventilation, and medications used on day 1 including glucocorticoids or surfactants, vasopressors, muscle relaxants, and antibiotics.

Adjusted ORs were also calculated for infants who received surfactants on day 1 vs those who did not as well as for infants who were administered CPAP and mechanical ventilation on day 1. To better understand the relationship between mortality and secondary complications of prematurity, we compared baseline characteristics stratified by survival status and leukoreduction. As a second step, we compared all outcomes by study period in patients who died. Causes of death also were compared between infants receiving leukoreduced and nonleukoreduced RBC transfusions.

In reporting our results, an OR less than 1 suggests that fewer infants in the leukoreduction group were affected by that outcome, while an OR greater than 1 suggests that fewer infants in the nonleukoreduction group were affected by that outcome. Measures of effect for multivariate linear regression were expressed as number of days of NICU stay saved with 95% CIs. Missing data for 3 variables (birth weight [3 imputations], Apgar score at 5 minutes [14 imputations], and SNAP II on day 1 [48 imputations]) were estimated using the multivariate normal procedure.11 The outcome estimates for the models with and without imputed data were comparable, so we report the results from the imputation model only. Analyses were carried out using NCSS statistical software, 2000 (Kaysville, Utah).

Baseline Characteristics

A total of 516 premature infants weighing less than 1250 g were identified from the 3 sites: 237 (107 before and 130 after universal leukoreduction) from Children and Women's Health Centre, 54 (38 before and 16 after universal leukoreduction) from Royal University Hospital, and 225 (124 before and 101 after universal leukoreduction) from Mt Sinai Hospital. One infant from Mt Sinai was removed because the patient received both nonleukoreduced and leukoreduced RBCs. Thus, a total of 515 neonates who underwent transfusion were included in the analysis; 268 infants received nonleukoreduced RBC transfusions and 247 received leukoreduced RBC transfusions.

All baseline characteristics except for some respiratory interventions were comparable in infants in the nonleukoreduction and leukoreduction periods (Table 1). More infants in the nonleukoreduction group required mechanical ventilation (89.7% vs 81.3%), while fewer patients in this group received supplemental oxygen (77.4% vs 84.6%), CPAP (16.7% vs 51.3%), high-frequency ventilation (4.8% vs 9.2%), and use of surfactants (53.6% vs 67.5%) compared with premature infants receiving leukoreduced RBC transfusions.

Table Graphic Jump LocationTable 1. Baseline Characteristics of 515 Premature Infants Who Underwent Transfusion Before and After Universal Leukoreduction Implementation*
Main Outcome Measures

Crude and adjusted rates of nosocomial bacteremia and all separately assessed secondary outcomes except grade 3 or 4 intraventricular hemorrhages were lower in infants who received leukoreduced RBCs (Table 2). The results were not significantly different for NICU mortality (adjusted OR, 1.22; 95% CI, 0.59-2.50). When bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and intraventricular hemorrhage were considered together as a composite outcome, the adjusted OR was 0.31 (95% CI, 0.17-0.56). The adjusted length of NICU stay was decreased by 11.62 days (95% CI, 3.61-19.64) in infants who received leukoreduced RBCs.

Table Graphic Jump LocationTable 2. Outcomes and Odds Ratios Among 515 Premature Infants Who Underwent Transfusion

Results of the unadjusted subgroup analyses for all major outcomes also suggest a consistent beneficial effect of leukoreduction in infants who did not receive surfactants, mechanical ventilation, or CPAP on day 1, except for those who did not receive mechanical ventilation and experienced bronchopulmonary dysplasia, and those who received surfactants and experienced bacteremia or grade 3 or 4 intraventricular hemorrhage (Table 3). The CIs for the former 3 associations all included 1.

Table Graphic Jump LocationTable 3. Unadjusted Subgroup Analyses of Impact of Respiratory Interventions on Day 1*

A post hoc analysis was conducted to examine the influence of leukoreduction on major neonatal morbidities in infants who had died. The mean (SD) NICU length of stay was 18.5 (5.3) days for nonsurvivors vs 85.9 (3.6) days for those who survived. Leukoreduction had an apparent protective but non–statistically significant effect on bacteremia in nonsurvivors (35.6% among nonleukoreduction vs 20.5% in the leukoreduction group [OR, 0.47; 95% CI, 0.17-1.22]. There was no apparent association between leukoreduction and bronchopulmonary dysplasia or grade 3 or 4 intraventricular hemorrhage in infants who died (OR, 1.03; 95% CI, 0.38-2.78 and OR, 1.06; 95% CI, 0.45-2.50, respectively). There were too few cases of necrotizing enterocolitis (n = 11) and retinopathy of prematurity (n = 4) to comment on associations.

Since Children and Women's Health Centre washed RBCs prior to the implementation of universal prestorage leukoreduction, we conducted a post hoc analysis to examine the influence of that site on our results. When data from this site were removed from the analyses, the unadjusted OR for bacteremia was 0.47 (95% CI, 0.23-0.99) and for mortality was 1.43 (95% CI, 0.76-2.68), whereas the ORs for all of the secondary outcomes except necrotizing enterocolitis (OR, 0.64; 95% CI, 0.29-1.42) shifted farther away from the null.

This study demonstrates that the implementation of universal prestorage leukoreduction of allogeneic RBC transfusions was not associated with reduced NICU mortality in premature infants weighing less than 1250 g but was associated with improvements in all major secondary outcomes. Indeed, if these secondary outcomes are considered as a composite outcome, for each 10 premature infants undergoing transfusion with leukoreduced RBCs, leukoreduction was associated with the prevention of 1 major secondary complication of premature birth. This clinical benefit was accompanied by an average decrease of 11 days of NICU stay.

To examine secular trends, we analyzed data for infants who did not receive any RBC transfusions. In infants weighing less than 1250 g who did not undergo transfusion, unadjusted rates of bacteremia, mortality, bronchopulmonary dysplasia, retinopathy of prematurity, and intraventricular hemorrhage were all increased in the leukoreduction period compared with the nonleukoreduction period (Table 4). However, the rate of necrotizing enterocolitis and the length of stay in the NICU decreased in the leukoreduction period compared with the nonleukoreduction period. Given the increase in rates for 5 of the 7 outcomes, it does not appear that our observed results are confounded by changes in care.

Table Graphic Jump LocationTable 4. Outcomes in 399 Infants Who Did Not Undergo Transfusion

Our study demonstrates little about the relationship between leukoreduction and mortality except that it essentially rules out differences greater than 50% in either direction. Post hoc examination revealed that 50 (56%) of the 89 deaths occurred within the first 14 days and 73 (82%) occurred within the first 29 days. Thus, as with many interventions, the benefit of leukoreduction in this population is doubtful. For infants who survive longer than 1 month, we would have required a much greater sample size to detect differences in mortality because the probability of death is very low.

To date, we are unaware of any other published study that has examined the association between leukoreduction of allogeneic RBC products and major clinical outcomes in premature neonates, including bacteremia, mortality, or other major complications of prematurity, such as bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and intraventricular hemorrhage.6 A few studies have shown that RBC transfusions correlate with an increased risk of bronchopulmonary dysplasia and retinopathy of prematurity.1216 However, the specific role of leukocytes and leukoreduction in the pathogenesis of these conditions had not been assessed. If transfused leukocytes result in or increase the severity of such complications, then this may be mediated by the enhanced generation of free radicals or caused by some other poorly defined effect either on the immune system or the microvasculature.1719 The beneficial effect of leukoreduction of RBC products on several organ systems simultaneously suggests that the putative role of leukoreduction is having a widespread effect throughout the body in many organ systems.

There are potential sources of bias in this study, particularly in the sampling of patients. The greatest threat to the observed effects is the possibility of secular trends. There was evidence of important changes in respiratory management in the 36-month period of study. Use of surfactants increased during this time, as did use of CPAP as a mode of ventilatory support compared with other modes of mechanical ventilation. These secular trends were likely to be most evident in the development of bronchopulmonary dysplasia. However, multivariate and stratified analyses consistently demonstrated a beneficial decrease in the odds of bronchopulmonary dysplasia with or without the use of surfactants (Table 3). Similarly, the effects of different ventilatory strategies appeared unrelated to any of the outcomes except for the unadjusted association between mechanical ventilation and bronchopulmonary dysplasia. The magnitude and consistency of the findings among all patient groups in all major outcomes strengthen our conclusions.

One of the major advantages of this study is that our cohort of premature infants included all consecutive admissions, both with and without transfusion, during both periods. This patient sampling strategy enabled us to add an extra level of control in comparing the risks and benefits of leukoreduction in this population. Additionally, both periods were 18 months in duration and, thus, reasonably short and symmetrical. This duration minimizes seasonal variation in the patterns of admission or patient care. Also, the use of multivariate analyses enabled us to control for the confounding influence of a number of factors simultaneously.

Other design choices may have limited the inferences drawn from the data. The relatively small sample size did not allow us to detect meaningful clinically important differences in the rates of mortality and bacteremia, if truly present. Indeed, the 95% CIs are quite wide, given the sample size of 515 infants who underwent transfusion. Also, in limiting our choice of index nosocomial infections solely to the presence of bacteremia, we may have missed other important immunomodulating effects of leukoreduction. Because of resource constraints, one of the additional limitations of our study was our inability to document the dates of diagnoses of major complications such as retinopathy of prematurity and intraventricular hemorrhage. Therefore, we remain uncertain about the time and total exposure to RBC transfusions in these infants prior to their diagnosis. However, we believe that this information would not significantly change our results because each of the complications occurs after prolonged stays in a NICU. More than 50% of infants received an RBC transfusion within the first 5 days of NICU admission and greater than 75% did within the first 15 days. The issue of timing was not a concern for other major outcomes, including mortality, bacteremia, and bronchopulmonary dysplasia, for which accurate estimates of dates were available.

Despite these limitations, the present study has a number of strengths. First is the methodological quality of data abstraction and entry by the Canadian Neonatal Network investigators, who used trained data abstractors, a set of clear definitions, and rigorous data checks and follow-up.2022 Second, the study included a consecutive census of premature infants weighing less than 1250 g admitted to 3 NICUs representing 3 different geographic regions of Canada.

In conclusion, implementation of universal prestorage leukoreduction is associated with improved clinical outcomes in premature infants requiring allogeneic RBC transfusions as part of their care in the NICU, even though there were no significant reductions in NICU mortality or bacteremia. Until there is evidence of harm, we would recommend the adoption of universal leukoreduction in the care of all infants requiring RBC transfusions. While we believe these data are persuasive, we would appeal for and endorse the conduct of a large randomized controlled trial to definitively determine the effectiveness of prestorage leukoreduction in the neonatal population as well as laboratory and clinical studies to elucidate the mechanisms of action of such effects.

Strauss RG. Practical issues in neonatal transfusion practice.  Am J Clin Pathol.1997;107(4 suppl 1):S57-S63.
Vamvakas EC, Blajchman MA. Immunomodulatory Effects of Blood TransfusionBethesda, Md: AABB Press; 1999.
Blajchman MA. Allogeneic blood transfusions, immunomodulation, and postoperative bacterial infection: do we have the answers yet?  Transfusion.1997;37:121-125.
McAlister FA, Clark HD, Wells PS, Laupacis A. Perioperative allogeneic blood transfusion does not cause adverse sequelae in patients with cancer: a meta-analysis of unconfounded studies.  Br J Surg.1998;85:171-178.
Vamvakas EC, Blajchman MA. Deleterious clinical effects of transfusion-associated immunomodulation: fact or fiction?  Blood.2001;97:1180-1195.
Fergusson D, Hèbert PC, Barrington KJ, Shapiro SH. Effectiveness of WBC reduction in neonates: what is the evidence of benefit?  Transfusion.2002;42:159-165.
Muller-Steinhardt M, Janetzko K, Kandler R, Flament J, Kirchner H, Kluter H. Impact of various red cell concentrate preparation methods on the efficiency of prestorage white cell filtration and on red cells during storage for 42 days.  Transfusion.1997;37:1137-1142.
 A Report to Canadians 2000/2001.  Ottawa, Ontario: Canadian Blood Services; 2001.
Bell MJ, Ternberg JL, Feigin RD. Neonatal necrotizing enterocolitis: therapeutic decisions based upon clinical staging.  Ann Surg.1978;187:1-7.
Papile LA. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1500 gm.  J Pediatr.1978;92:529-534.
Little R, Rubin D. Statistical Analysis With Missing DataNew York, NY: John Wiley & Sons; 1987.
Silvers KM, Gibson AT, Russell JM, Powers HJ. Antioxidant activity, packed cell transfusions, and outcome in premature infants.  Arch Dis Child Fetal Neonatal Ed.1998;78:F214-F219.
Korhonen P, Tammela O, Koivisto AM, Laippala P, Ikonen S. Frequency and risk factors in bronchopulmonary dysplasia in a cohort of very low birth weight infants.  Early Hum Dev.1999;54:245-258.
Seiberth V, Linderkamp O. Risk factors in retinopathy of prematurity: a multivariate statistical analysis.  Ophthalmologica.2000;214:131-135.
Englert JA, Saunders RA, Purohit D, Hulsey TC, Ebeling M. The effect of anemia on retinopathy of prematurity in extremely low birth weight infants.  J Perinatol.2001;21:21-26.
Dani C, Reali MF, Bertini G, Martelli E, Pezzati M, Rubaltelli FF. The role of blood transfusions and iron intake on retinopathy of prematurity.  Early Hum Dev.2001;62:57-63.
Hirano K, Morinobu T, Kim H.  et al.  Blood transfusion increases radical promoting non-transferrin bound iron in preterm infants.  Arch Dis Child Fetal Neonatal Ed.2001;84:F188-F193.
Lackmann GM, Hesse L, Tollner U. Reduced iron-associated antioxidants in premature newborns suffering intracerebral hemorrhage.  Free Radic Biol Med.1996;20:407-409.
Buonocore G, Zani S, Sargentini I, Gioia D, Signorini C, Bracci R. Hypoxia-induced free iron release in the red cells of newborn infants.  Acta Paediatr.1998;87:77-81.
Lee SK, McMillan DD, Ohlsson A.  et al. and the Canadian NICU Network.  Variations in practice and outcomes in the Canadian NICU Network: 1996-1997.  Pediatrics.2000;106:1070-1079.
Sankaran K, Chien LY, Walker R, Seshia M, Ohlsson A. Variations in mortality rates among Canadian neonatal intensive care units.  CMAJ.2002;166:173-178.
Chien LY, Ohlsson A, Seshia MM, Boulton J, Sankaran K, Lee SK. Variations in antenatal corticosteroid therapy: a persistent problem despite 30 years of evidence.  Obstet Gynecol.2002;99:401-408.

Figures

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics of 515 Premature Infants Who Underwent Transfusion Before and After Universal Leukoreduction Implementation*
Table Graphic Jump LocationTable 2. Outcomes and Odds Ratios Among 515 Premature Infants Who Underwent Transfusion
Table Graphic Jump LocationTable 3. Unadjusted Subgroup Analyses of Impact of Respiratory Interventions on Day 1*
Table Graphic Jump LocationTable 4. Outcomes in 399 Infants Who Did Not Undergo Transfusion

References

Strauss RG. Practical issues in neonatal transfusion practice.  Am J Clin Pathol.1997;107(4 suppl 1):S57-S63.
Vamvakas EC, Blajchman MA. Immunomodulatory Effects of Blood TransfusionBethesda, Md: AABB Press; 1999.
Blajchman MA. Allogeneic blood transfusions, immunomodulation, and postoperative bacterial infection: do we have the answers yet?  Transfusion.1997;37:121-125.
McAlister FA, Clark HD, Wells PS, Laupacis A. Perioperative allogeneic blood transfusion does not cause adverse sequelae in patients with cancer: a meta-analysis of unconfounded studies.  Br J Surg.1998;85:171-178.
Vamvakas EC, Blajchman MA. Deleterious clinical effects of transfusion-associated immunomodulation: fact or fiction?  Blood.2001;97:1180-1195.
Fergusson D, Hèbert PC, Barrington KJ, Shapiro SH. Effectiveness of WBC reduction in neonates: what is the evidence of benefit?  Transfusion.2002;42:159-165.
Muller-Steinhardt M, Janetzko K, Kandler R, Flament J, Kirchner H, Kluter H. Impact of various red cell concentrate preparation methods on the efficiency of prestorage white cell filtration and on red cells during storage for 42 days.  Transfusion.1997;37:1137-1142.
 A Report to Canadians 2000/2001.  Ottawa, Ontario: Canadian Blood Services; 2001.
Bell MJ, Ternberg JL, Feigin RD. Neonatal necrotizing enterocolitis: therapeutic decisions based upon clinical staging.  Ann Surg.1978;187:1-7.
Papile LA. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1500 gm.  J Pediatr.1978;92:529-534.
Little R, Rubin D. Statistical Analysis With Missing DataNew York, NY: John Wiley & Sons; 1987.
Silvers KM, Gibson AT, Russell JM, Powers HJ. Antioxidant activity, packed cell transfusions, and outcome in premature infants.  Arch Dis Child Fetal Neonatal Ed.1998;78:F214-F219.
Korhonen P, Tammela O, Koivisto AM, Laippala P, Ikonen S. Frequency and risk factors in bronchopulmonary dysplasia in a cohort of very low birth weight infants.  Early Hum Dev.1999;54:245-258.
Seiberth V, Linderkamp O. Risk factors in retinopathy of prematurity: a multivariate statistical analysis.  Ophthalmologica.2000;214:131-135.
Englert JA, Saunders RA, Purohit D, Hulsey TC, Ebeling M. The effect of anemia on retinopathy of prematurity in extremely low birth weight infants.  J Perinatol.2001;21:21-26.
Dani C, Reali MF, Bertini G, Martelli E, Pezzati M, Rubaltelli FF. The role of blood transfusions and iron intake on retinopathy of prematurity.  Early Hum Dev.2001;62:57-63.
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