PRBC Transfusion -- a Risk Factor for NEC in Premature Infants
PRBC Transfusion -- a Risk Factor for NEC in Premature Infants
Objective: To determine whether a temporal association exists between antecedent packed red blood cell (PRBC) transfusions and necrotizing enterocolitis (NEC) in premature infants.
Study Design: This case–control study included inborn infants from a single center who developed NEC during a 2-year period. For every NEC infant, two matched controls from the same period were chosen based on gestational age and birth weight. Transfusion-related NEC was defined as antecedent PRBC transfusion within 48 h prior to the onset of any symptoms attributable to NEC. Bivariate analyses were used to compare baseline characteristics of all infants. To determine the raw odds ratio for the presence of exposure (transfusion) versus outcome (NEC), the hospital course (ages 6 to 63 days) of all study infants was divided into 48-h epochs; occurrence of transfusion and NEC was noted within each epoch. Generalized estimating equations were used to estimate the adjusted odds for developing NEC within an epoch with and without antecedent transfusion, controlling chronological age within infant as well as for gestational age, gender, feeding status in prior 48-h epoch and indicators of disease severity.
Result: There were 3652 48-h epochs and 557 transfusions among 49 NEC infants and 97 controls; 17 infants had transfusion-related NEC, yielding a raw odds ratio of 3.01 (P<0.001). The adjusted odds ratios were 2.97 (P=0.003) for transfusion and 2.76 (P=0.05) for feeding status in the prior 48-h epoch. Infants who were being fed in the 48-h period prior to transfusion were more than eight times more likely to develop NEC than infants who were neither fed nor transfused.
Conclusion: Antecedent PRBC transfusion appears to be an independent risk factor for developing NEC during the subsequent 48-h period.
The relationship between packed red blood cell (PRBC) transfusion and the development of necrotizing enterocolitis (NEC) has been a controversial topic for nearly 3 decades. In the 1980 to 1990s, several observational studies noted an association between blood transfusion and NEC that appeared to be related to erythrocyte T antigen activation. As a result, clinicians were advised to use blood products free of plasma, and to reduce infants' exposure to immunoglobulin and white cells in blood given to preterm infants. Currently, most preterm infants are transfused PRBCs, which are leukoreduced, irradiated and cytomegalovirus antibody negative. Despite these precautions, reports of the occurrence of a temporal association between NEC and PRBC transfusion persist, raising the question of whether PRBC transfusion poses a risk factor for the development of NEC.
In the neonatal intensive care unit (NICU), small premature infants may be transfused for a variety of reasons. Transfusions may be given for anemia accompanying exacerbations of severe illnesses such as sepsis, NEC or respiratory distress syndrome, or for subtle increases in symptoms of cardiorespiratory instability in a stable, growing infant. However, premature infants may have delayed or inadequate erythropoiesis, and transfusions may also be given pre-emptively in response to severe physiologic anemia or to replace the accumulated volume blood drawn for laboratory testing. Thus, several challenges confront the investigator who seeks to use epidemiologic data to establish the association between antecedent transfusion and NEC. Susceptibility to NEC may change over the course of an infant's hospitalization and may be influenced by antecedent history of illness and feeding status. Premature infants have a limited symptom repertoire to manifest disparate illnesses with complex pathophysiologies; the symptoms of anemia that may justify a transfusion often resemble early indicators of NEC. It may be difficult to determine retrospectively, or even prospectively, whether a transfusion preceded the onset of NEC, and thus might have caused it, or was given as a result of symptoms related to the disease.
This study explores several strategies to deal with these challenges. In order to provide a basis for comparing rates of occurrence of transfusion and non-transfusion-related NEC, while controlling for the effects of chronologic age, gestational age and markers of illness severity, we divided each infant's hospitalization into 48-h epochs. We used these epochs as the unit of analysis in bivariate and multivariate mixed effects analyses that controlled for chronological age of the patient. We restricted the definition of transfusion-associated NEC to include only those cases of NEC in which a temporarily related transfusion clearly preceded any symptoms that might have been attributable to NEC. When any symptom possibly related to NEC preceded the transfusion, the transfusion was considered non-transfusion-associated. With this definition we created an a priori bias toward the null hypothesis of no association between NEC and transfusion, in the hope of providing more convincing evidence of a true association (if one were found) than has previously been presented.
Abstract and Introduction
Abstract
Objective: To determine whether a temporal association exists between antecedent packed red blood cell (PRBC) transfusions and necrotizing enterocolitis (NEC) in premature infants.
Study Design: This case–control study included inborn infants from a single center who developed NEC during a 2-year period. For every NEC infant, two matched controls from the same period were chosen based on gestational age and birth weight. Transfusion-related NEC was defined as antecedent PRBC transfusion within 48 h prior to the onset of any symptoms attributable to NEC. Bivariate analyses were used to compare baseline characteristics of all infants. To determine the raw odds ratio for the presence of exposure (transfusion) versus outcome (NEC), the hospital course (ages 6 to 63 days) of all study infants was divided into 48-h epochs; occurrence of transfusion and NEC was noted within each epoch. Generalized estimating equations were used to estimate the adjusted odds for developing NEC within an epoch with and without antecedent transfusion, controlling chronological age within infant as well as for gestational age, gender, feeding status in prior 48-h epoch and indicators of disease severity.
Result: There were 3652 48-h epochs and 557 transfusions among 49 NEC infants and 97 controls; 17 infants had transfusion-related NEC, yielding a raw odds ratio of 3.01 (P<0.001). The adjusted odds ratios were 2.97 (P=0.003) for transfusion and 2.76 (P=0.05) for feeding status in the prior 48-h epoch. Infants who were being fed in the 48-h period prior to transfusion were more than eight times more likely to develop NEC than infants who were neither fed nor transfused.
Conclusion: Antecedent PRBC transfusion appears to be an independent risk factor for developing NEC during the subsequent 48-h period.
Introduction
The relationship between packed red blood cell (PRBC) transfusion and the development of necrotizing enterocolitis (NEC) has been a controversial topic for nearly 3 decades. In the 1980 to 1990s, several observational studies noted an association between blood transfusion and NEC that appeared to be related to erythrocyte T antigen activation. As a result, clinicians were advised to use blood products free of plasma, and to reduce infants' exposure to immunoglobulin and white cells in blood given to preterm infants. Currently, most preterm infants are transfused PRBCs, which are leukoreduced, irradiated and cytomegalovirus antibody negative. Despite these precautions, reports of the occurrence of a temporal association between NEC and PRBC transfusion persist, raising the question of whether PRBC transfusion poses a risk factor for the development of NEC.
In the neonatal intensive care unit (NICU), small premature infants may be transfused for a variety of reasons. Transfusions may be given for anemia accompanying exacerbations of severe illnesses such as sepsis, NEC or respiratory distress syndrome, or for subtle increases in symptoms of cardiorespiratory instability in a stable, growing infant. However, premature infants may have delayed or inadequate erythropoiesis, and transfusions may also be given pre-emptively in response to severe physiologic anemia or to replace the accumulated volume blood drawn for laboratory testing. Thus, several challenges confront the investigator who seeks to use epidemiologic data to establish the association between antecedent transfusion and NEC. Susceptibility to NEC may change over the course of an infant's hospitalization and may be influenced by antecedent history of illness and feeding status. Premature infants have a limited symptom repertoire to manifest disparate illnesses with complex pathophysiologies; the symptoms of anemia that may justify a transfusion often resemble early indicators of NEC. It may be difficult to determine retrospectively, or even prospectively, whether a transfusion preceded the onset of NEC, and thus might have caused it, or was given as a result of symptoms related to the disease.
This study explores several strategies to deal with these challenges. In order to provide a basis for comparing rates of occurrence of transfusion and non-transfusion-related NEC, while controlling for the effects of chronologic age, gestational age and markers of illness severity, we divided each infant's hospitalization into 48-h epochs. We used these epochs as the unit of analysis in bivariate and multivariate mixed effects analyses that controlled for chronological age of the patient. We restricted the definition of transfusion-associated NEC to include only those cases of NEC in which a temporarily related transfusion clearly preceded any symptoms that might have been attributable to NEC. When any symptom possibly related to NEC preceded the transfusion, the transfusion was considered non-transfusion-associated. With this definition we created an a priori bias toward the null hypothesis of no association between NEC and transfusion, in the hope of providing more convincing evidence of a true association (if one were found) than has previously been presented.
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