Neurocognitive profiles of preterm infants randomly assigned to lower or higher hematocrit thresholds for transfusion

Abstract

Objective-Preterm infants are frequently transfused with red blood cells based on standardized guidelines or clinical concern that anemia taxes infants' physiological compensatory mechanisms and thereby threatens their health and well-being. The impact of various transfusion guidelines on long-term neurocognitive outcome is not known. The purpose of this study is to evaluate longterm neurocognitive outcome on children born prematurely and treated at birth with different transfusion guidelines.Methods-Neurocognitive outcomes were examined at school age for 56 preterm infants randomly assigned to a liberal (n = 33) or restrictive (n = 23) transfusion strategy. Tests of intelligence, achievement, language, visual-spatial/motor, and memory skills were administered. Between-group differences were assessed.Results-Those in the liberal transfusion group performed more poorly than those in the restrictive group on measures of associative verbal fluency, visual memory, and reading.Conclusions-Findings highlight possible long-term neurodevelopmental consequences of maintaining higher hematocrit levels. KeywordsPreterm; Neuropsychology; Red Blood Cell Transfusion; Hematocrit; LongitudinalThe high incidence of anemia in preterm, very low birth weight (VLBW; <1500 grams) infants mandates frequent red blood cell (RBC) transfusions during the first few weeks after birth. Though all infants experience decreased hemoglobin (i.e., physiologic anemia) during the first months after birth, anemia of prematurity is common in infants weighing less than 1 kg (< 32 weeks gestation), and is essentially low endogenous erythropoietin (EPO; a hormone that stimulates RBC production in response to low oxygen saturation) production and exaggeration of physiologic anemia in which hemoglobin levels fall 7-10 g/dl more than in term infants and remain lower for longer periods of time (Bain & Blackburn, 2004). Concern regarding the preterm infant's capacity to tolerate anemia as well as the potential consequences (e.g., increased risk of death), have resulted in routine RBC transfusions among preterm infants (Hebert et al., 1999; Straus, 1995). Views on the risks of anemia and the effectiveness of RBC transfusion in addressing these risks, however, are varied, while the clinical signs of anemia are nonspecific and require significant physician interpretation (Maier et al., 2000;Strauss, 1995). Information has begun to emerge about the impact of transfusion strategy on the outcome of anemic preterm infants, but the outcomes analyzed to date have been limited to the neonatal period and later infancy (i.e., up to 18 to 21 months of (Whyte et al., 2009). Evaluating long-term neurodevelopmental outcomes associated with different transfusion thresholds is critical for assessing the safety of current transfusion practice especially in terms of potential cognitive and behavioral morbidity. The Impact of Preterm Birth on Neurocognitive OutcomesThe survival rate of preterm infants has improved in recent decades as a result of advances in neonatal in...

Cognitive Outcomes of Preterm Infants Randomized to Darbepoetin, Erythropoietin, or Placebo

“…Kirpalani and colleagues 28 randomized 451 infants to a low or high threshold hemoglobin strategy and reported no difference in neurologic morbidities between groups; however, analyses at 2 years of age revealed an increased number of infants who had BSID II mental developmental index ,80 in the low hemoglobin threshold group. 29 Conversely, improved cognitive and MRI outcomes were reported in the restrictively transfused group of the Iowa study by Bell et al, 18,19,30 underscoring the need for long-term evaluation and more comprehensive study. Of note, none of the infants in either the Iowa or Preterm Infants in Need of Transfusion (PINT) studies received ESAs.…”

“…Also, ESA recipients in the current study were exposed to fewer transfusions, which possibly impacted their neurodevelopmental outcomes. 18,19 In animal models, ESAs are protective in the developing brain, suggesting the possibility that they might be of benefit to very premature infants who are at risk for intraventricular hemorrhage, hypoxicischemic injury, and developmental delay. The neuroprotective mechanisms of ESAs include decreased neuronal apoptosis, decreased inflammation, promotion of oligodendrocyte differentiation and maturation, and improved white matter survival.…”

The ‘Effects of Transfusion Thresholds on Neurocognitive Outcome of Extremely Low Birth-Weight Infants (ETTNO)’ Study: Background, Aims, and Study Protocol

“…This study was criticized because (a) the primary endpoint for sample size determination was the number of transfusions and not a clinically relevant outcome parameter, (b) the combined outcome of intraventricular hemorrhage grade 4 or periventricular leukomalacia had not been a predefined outcome measure, (c) intraventricular hemorrhage usually occurs at a time when infants had not yet been enrolled into that study, (d) there was an excess of male patients in the restrictive-transfusion group and male infants tend to have poorer outcomes, (e) only 52% of the patients had a late cranial ultrasound, despite the latter being required to assess the true incidence of periventricular leukomalacia [29][30][31] . In contrast to the initial findings, long-term follow-up showed poorer results in measures of associative verbal fluency, visual memory, and reading in the liberally transfused group [32] and liberally transfused girls had the most prominent abnormalities on magnetic resonance imaging [33] . Again, these latter results have to be interpreted with caution because only about half of the patients initially enrolled in the trial completed these follow-up examinations.…”

A Randomized, Masked, Placebo-Controlled Study of Darbepoetin Alfa in Preterm Infants

“…Kirpalani and colleagues 7 randomized 451 infants to low-or high-threshold hemoglobin strategies and reported no difference in neurologic morbidities in the low-hemoglobin threshold group; however, analyses at 2 years of age revealed increased mild cognitive impairment in the low-hemoglobin threshold group. 8 Conversely, improved cognitive and MRI outcomes were reported in the restrictively transfused group of the Iowa study, 9,10 underscoring the need for long-term evaluation and more comprehensive study.…”

“…However, long-term neurodevelopmental outcomes among those randomized to be liberally transfused were considerably worse. 9,10 Recent studies suggest an association between preterm infant morbidities, such as necrotizing enterocolitis (NEC) and significant intracranial hemorrhage (ICH), with transfusions [11][12][13] ; therefore, using ESAs to avoid these possible risks might prove clinically important.…”